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1
Bayly, R. C., A. Duncan, J. W. May, M. Schembri, A. Semertjis, G. Vasiliadis, and W. G. C. Raper. "Microbiological and Genetic Aspects of the Synthesis of Polyphosphate by Species of Acinetobacter." Water Science and Technology 23, no. 4-6 (February 1, 1991): 747–54. http://dx.doi.org/10.2166/wst.1991.0525.
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Strains of Acinetobacter which showed marked variation in their ability to accumulate intracellular polyphosphate (Pn) were isolated from a pilot-plant which was removing phosphate biologically. Variants which could not accumulate Pn under the same growth conditions were derived from two of the isolates which accumulated high levels of Pn. The activities of five enzymes reported to have a role in Pn synthesis showed no significant differences between the two variants, their parent strains and two other natural isolates. In the presence of 20 µm N,N'-dicyclohexylcarbodiimide (DCCD), growth of the variant strains was suppressed, whereas the parent strains were still able to grow and form polyphosphate. A mechanism which depends upon the trans-membrane proton gradient of the cell is proposed to account for the high levels of polyphosphate formed by some strains of Acinetobacter. Each of the Acinetobacter strains isolated from the pilot-plant carried several plasmids. Comparison of one strain, which accumulated a high level of Pn, and its variant, showed that a deletion of approximately 20 kb of plasmid DNA from the parent strain had occurred.
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Ellingwood, Sara S., and Alan Cheng. "Biochemical and clinical aspects of glycogen storage diseases." Journal of Endocrinology 238, no. 3 (September 2018): R131—R141. http://dx.doi.org/10.1530/joe-18-0120.
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The synthesis of glycogen represents a key pathway for the disposal of excess glucose while its degradation is crucial for providing energy during exercise and times of need. The importance of glycogen metabolism is also highlighted by human genetic disorders that are caused by mutations in the enzymes involved. In this review, we provide a basic summary on glycogen metabolism and some of the clinical aspects of the classical glycogen storage diseases. Disruptions in glycogen metabolism usually result in some level of dysfunction in the liver, muscle, heart, kidney and/or brain. Furthermore, the spectrum of symptoms observed is very broad, depending on the affected enzyme. Finally, we briefly discuss an aspect of glycogen metabolism related to the maintenance of its structure that seems to be gaining more recent attention. For example, in Lafora progressive myoclonus epilepsy, patients exhibit an accumulation of inclusion bodies in several tissues, containing glycogen with increased phosphorylation, longer chain lengths and irregular branch points. This abnormal structure is thought to make glycogen insoluble and resistant to degradation. Consequently, its accumulation becomes toxic to neurons, leading to cell death. Although the genes responsible have been identified, studies in the past two decades are only beginning to shed light into their molecular functions.
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Andriotis, Vasilios M. E., Martin Rejzek, Michael D. Rugen, Birte Svensson, Alison M. Smith, and Robert A. Field. "Iminosugar inhibitors of carbohydrate-active enzymes that underpin cereal grain germination and endosperm metabolism." Biochemical Society Transactions 44, no. 1 (February 9, 2016): 159–65. http://dx.doi.org/10.1042/bst20150222.
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Starch is a major energy store in plants. It provides most of the calories in the human diet and, as a bulk commodity, it is used across broad industry sectors. Starch synthesis and degradation are not fully understood, owing to challenging biochemistry at the liquid/solid interface and relatively limited knowledge about the nature and control of starch degradation in plants. Increased societal and commercial demand for enhanced yield and quality in starch crops requires a better understanding of starch metabolism as a whole. Here we review recent advances in understanding the roles of carbohydrate-active enzymes in starch degradation in cereal grains through complementary chemical and molecular genetics. These approaches have allowed us to start dissecting aspects of starch degradation and the interplay with cell-wall polysaccharide hydrolysis during germination. With a view to improving and diversifying the properties and uses of cereal grains, it is possible that starch degradation may be amenable to manipulation through genetic or chemical intervention at the level of cell wall metabolism, rather than simply in the starch degradation pathway per se.
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Alkhzouz, Camelia, Simona Bucerzan, Maria Miclaus, Andreea-Manuela Mirea, and Diana Miclea. "46,XX DSD: Developmental, Clinical and Genetic Aspects." Diagnostics 11, no. 8 (July 30, 2021): 1379. http://dx.doi.org/10.3390/diagnostics11081379.
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Differences in sex development (DSD) in patients with 46,XX karyotype occur by foetal or postnatal exposure to an increased amount of androgens. These disorders are usually diagnosed at birth, in newborns with abnormal genitalia, or later, due to postnatal virilization, usually at puberty. Proper diagnosis and therapy are mostly based on the knowledge of normal development and molecular etiopathogenesis of the gonadal and adrenal structures. This review aims to describe the most relevant data that are correlated with the normal and abnormal development of adrenal and gonadal structures in direct correlation with their utility in clinical practice, mainly in patients with 46,XX karyotype. We described the prenatal development of structures together with the main molecules and pathways that are involved in sex development. The second part of the review described the physical, imaging, hormonal and genetic evaluation in a patient with a disorder of sex development, insisting more on patients with 46,XX karyotype. Further, 95% of the etiology in 46,XX patients with disorders of sex development is due to congenital adrenal hyperplasia, by enzyme deficiencies that are involved in the hormonal synthesis pathway. The other cases are explained by genetic abnormalities that are involved in the development of the genital system. The phenotypic variability is very important in 46,XX disorders of sex development and the knowledge of each sign, even the most discreet, which could reveal such disorders, mainly in the neonatal period, could influence the evolution, prognosis and life quality long term.
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Frank, S., A. A. Brindley, E. Deery, P. Heathcote, A. D. Lawrence, H. K. Leech, R. W. Pickersgill, and M. J. Warren. "Anaerobic synthesis of vitamin B12: characterization of the early steps in the pathway." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 811–14. http://dx.doi.org/10.1042/bst0330811.
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The anaerobic biosynthesis of vitamin B12 is slowly being unravelled. Recent work has shown that the first committed step along the anaerobic route involves the sirohydrochlorin (chelation of cobalt into factor II). The following enzyme in the pathway, CbiL, methylates cobalt-factor II to give cobalt-factor III. Recent progress on the molecular characterization of this enzyme has given a greater insight into its mode of action and specificity. Structural studies are being used to provide insights into how aspects of this highly complex biosynthetic pathway may have evolved. Between cobalt-factor III and cobyrinic acid, only one further intermediate has been identified. A combination of molecular genetics, recombinant DNA technology and bioorganic chemistry has led to some recent advances in assigning functions to the enzymes of the anaerobic pathway.
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Hellemond, Jaap J. van, Anita van der Klei, SusanneW H. van Weelden, and Aloysius G. M. Tielens. "Biochemical and evolutionary aspects of anaerobically functioning mitochondria." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 358, no. 1429 (January 29, 2003): 205–15. http://dx.doi.org/10.1098/rstb.2002.1182.
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Mitochondria are usually considered to be the powerhouses of the cell and to be responsible for the aerobic production of ATP. However, many eukaryotic organisms are known to possess anaerobically functioning mitochondria, which differ significantly from classical aerobically functioning mitochondria. Recently, functional and phylogenetic studies on some enzymes involved clearly indicated an unexpected evolutionary relationship between these anaerobically functioning mitochondria and the classical aerobic type. Mitochondria evolved by an endosymbiotic event between an anaerobically functioning archaebacterial host and an aerobic α–proteobacterium. However, true anaerobically functioning mitochondria, such as found in parasitic helminths and some lower marine organisms, most likely did not originate directly from the pluripotent ancestral mitochondrion, but arose later in evolution from the aerobic type of mitochondria after these were already adapted to an aerobic way of life by losing their anaerobic capacities. This review will focus on some biochemical and evolutionary aspects of these fermentative mitochondria, with special attention to fumarate reductase, the synthesis of the rhodoquinone involved, and the enzymes involved in acetate production (acetate : succinate CoA–transferase and succinyl CoA–synthetase).
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Sebezhko, O. I., K. N. Narozhnykh, O. S. Korotkevich, D. A. Alexandrova, and I. N. Morozov. "Contemporary aspects of cholesterol metabolism in cattle." Bulletin of NSAU (Novosibirsk State Agrarian University), no. 2 (July 13, 2021): 91–105. http://dx.doi.org/10.31677/2072-6724-2021-59-2-91-105.
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The literature review presents the current understanding of cholesterol metabolism occurring under physiological conditions. The homeostasis of cholesterol in the body is determined by its endogenous synthesis, the transition to the cell from plasma as part of low-densitylipoproteins( LDL), the release of their cells as part of high-density lipoproteins (HDL). The molecular-genetic mechanisms of regulation of cholesterol homeostasis are described in detail. The genes for cholesterol biosynthesis in major multicellular animals were inherited from their last common eukaryotic ancestor and are evolutionarily conserved for cholesterol biosynthesis. Non-coding variants of singlenucleotide polymorphisms can significantly contribute to the phenotypic variability of cholesterol, and missense variants that lead to the replacement of amino acids in proteins can have a significant effect on the phenotypic variability. The modern aspects of cholesterol homeostasis in cattle are formed and sufficiently fully presented. During absence of exogenous intake, the balance of cholesterol in cattle is maintained by endogenous synthesis, occurring mainly in the liver, the intake of lipoproteins, as well as reverse transport mechanisms. This review gives an idea that the stability of homeostasis can be achieved only with the complex interaction of all systems (transport, enzyme, receptor) involved in this process. The analysis of the latest scientific works concerning the problem of the content and regulation of cholesterol in cow’s milk is presented. Significant single-nucleotide polymorphisms localized in the ACAT2, LDLR, DGAT, and AGPAT1 genes involved in the exchange of cholesterol in the liver or its transport and associated with the level of cholesterol in milk are described. Part of the review is devoted to cholesterol deficiency syndrome in Holstein cattle (HCD). Modern data on the prevalence, molecular and genetic basis, clinical and laboratory manifestations of the syndrome are presented.
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Ershov, Pavel, Leonid Kaluzhskiy, Yuri Mezentsev, Evgeniy Yablokov, Oksana Gnedenko, and Alexis Ivanov. "Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context." Biomedicines 9, no. 8 (July 26, 2021): 895. http://dx.doi.org/10.3390/biomedicines9080895.
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A global protein interactome ensures the maintenance of regulatory, signaling and structural processes in cells, but at the same time, aberrations in the repertoire of protein–protein interactions usually cause a disease onset. Many metabolic enzymes catalyze multistage transformation of cholesterol precursors in the cholesterol biosynthesis pathway. Cancer-associated deregulation of these enzymes through various molecular mechanisms results in pathological cholesterol accumulation (its precursors) which can be disease risk factors. This work is aimed at systematization and bioinformatic analysis of the available interactomics data on seventeen enzymes in the cholesterol pathway, encoded by HMGCR, MVK, PMVK, MVD, FDPS, FDFT1, SQLE, LSS, DHCR24, CYP51A1, TM7SF2, MSMO1, NSDHL, HSD17B7, EBP, SC5D, DHCR7 genes. The spectrum of 165 unique and 21 common protein partners that physically interact with target enzymes was selected from several interatomic resources. Among them there were 47 modifying proteins from different protein kinases/phosphatases and ubiquitin-protein ligases/deubiquitinases families. A literature search, enrichment and gene co-expression analysis showed that about a quarter of the identified protein partners was associated with cancer hallmarks and over-represented in cancer pathways. Our results allow to update the current fundamental view on protein–protein interactions and regulatory aspects of the cholesterol synthesis enzymes and annotate of their sub-interactomes in term of possible involvement in cancers that will contribute to prioritization of protein targets for future drug development.
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Kulkarni, R. N., K. Baskaran, and Tripta Jhang. "Breeding medicinal plant, periwinkle [Catharanthus roseus(L) G. Don]: a review." Plant Genetic Resources 14, no. 4 (May 2, 2016): 283–302. http://dx.doi.org/10.1017/s1479262116000150.
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AbstractPeriwinkle [Catharanthus roseus(L) G. Don] has become one of the very extensively investigated medicinal plants after the discovery of two powerful anti-cancer alkaloids, vinblastine and vincristine, in its leaves more than 50 years ago. These alkaloidal drugs are still in clinical use. Also, periwinkle is still the only source of these alkaloids and their precursors, catharanthine and vindoline. Low concentrations of these alkaloids in the plant and, therefore, high costs of their extraction have led to tremendous efforts towards understanding their biosynthesis and exploration of alternate ways of their production such as, chemical synthesis, cell, tissue and hairy root cultures, and metabolic engineering of heterologous organisms. Literature on this plant is quite voluminous, with an average of about 80 publications per year during last three decades (1985–2015). Nearly 60% of these publications are on physiology, biochemistry, cell and tissue culture, phytochemistry, metabolic and genetic engineering aspects. In spite of these efforts, an economically viable alternative to field-grown periwinkle plants as a source of these alkaloids has not yet been found. Biosynthesis ofC. roseusalkaloids is a complex process involving many genes, enzymes, regulators, inter- and intra-cellular transporters, cell types, organelles and tissues and its current understanding is still considered to be incomplete to produceC. roseusalkaloids through metabolic engineering/synthetic biology. Till such time, breeding periwinkle varieties with higher concentrations of anti-cancer alkaloids for cultivation can be an alternate approach to meet the demand for these alkaloids and reduce their costs. While literature on cell and tissue culture, phytochemistry, metabolic and genetic engineering aspects of periwinkle has been reviewed periodically, crop production and plant breeding aspects have received little attention. In this paper, an attempt has been made to bring together published information on genetics and breeding of periwinkle as a medicinal plant. Some probable constraints which may have hindered taking up periwinkle breeding are identified. Initially, quite a few attempts have been made at genetic improvement of periwinkle through induced polyploidy, and subsequently through induced mutagenesis. Mutations, both natural and induced, provide a valuable resource for use in breeding and in functional and reverse genomics research. It is only during last 6–7 years, genetic diversity has been assessed using molecular markers and very recently molecular markers have been identified for marker-assisted selection for alkaloid yield.
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Müllner, Heidemarie, and Günther Daum. "Dynamics of neutral lipid storage in yeast." Acta Biochimica Polonica 51, no. 2 (June 30, 2004): 323–47. http://dx.doi.org/10.18388/abp.2004_3574.
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Since energy storage is a basic metabolic process, the synthesis of neutral lipids occurs in all kingdoms of life. The yeast, Saccharomyces cerevisiae, widely accepted as a model eukaryotic cell, contains two classes of neutral lipids, namely steryl esters and triacylglycerols. Triacylglycerols are synthesized through two pathways governed by the acyl-CoA diacylglycerol acyltransferase Dga1p and the phospholipid diacylglycerol acyltransferase Lro1p, respectively. Steryl esters are formed by the two steryl ester synthases Are1p and Are2p, two enzymes with overlapping function which also catalyze triacylglycerol formation, although to a minor extent. Storage of neutral lipids is tightly linked to the biogenesis of so called lipid particles. The role of this compartment in lipid homeostasis and its interplay with other organelles involved in neutral lipid dynamics, especially the endoplasmic reticulum and the plasma membrane, are subject of current investigations. In contrast to neutral lipid formation, mobilization of triacylglycerols and steryl esters in yeast are less characterized at the molecular level. Only recently, the triacylglycerol lipase Tgl3p was identified as the first yeast enzyme of this kind by function. Genes and gene products governing steryl ester mobilization still await identification. Besides biochemical properties of enzymes involved in yeast neutral lipid synthesis and degradation, regulatory aspects of these pathways and cell biological consequences of neutral lipid depletion will be discussed in this minireview.
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Suzuki, Tateki, Akiyoshi Nakamura, Koji Kato, Dieter Söll, Isao Tanaka, Kelly Sheppard, and Min Yao. "Structure of the Pseudomonas aeruginosa transamidosome reveals unique aspects of bacterial tRNA-dependent asparagine biosynthesis." Proceedings of the National Academy of Sciences 112, no. 2 (December 29, 2014): 382–87. http://dx.doi.org/10.1073/pnas.1423314112.
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Many prokaryotes lack a tRNA synthetase to attach asparagine to its cognate tRNAAsn, and instead synthesize asparagine from tRNAAsn-bound aspartate. This conversion involves two enzymes: a nondiscriminating aspartyl-tRNA synthetase (ND-AspRS) that forms Asp-tRNAAsn, and a heterotrimeric amidotransferase GatCAB that amidates Asp-tRNAAsn to form Asn-tRNAAsn for use in protein synthesis. ND-AspRS, GatCAB, and tRNAAsn may assemble in an ∼400-kDa complex, known as the Asn-transamidosome, which couples the two steps of asparagine biosynthesis in space and time to yield Asn-tRNAAsn. We report the 3.7-Å resolution crystal structure of the Pseudomonas aeruginosa Asn-transamidosome, which represents the most common machinery for asparagine biosynthesis in bacteria. We show that, in contrast to a previously described archaeal-type transamidosome, a bacteria-specific GAD domain of ND-AspRS provokes a principally new architecture of the complex. Both tRNAAsn molecules in the transamidosome simultaneously serve as substrates and scaffolds for the complex assembly. This architecture rationalizes an elevated dynamic and a greater turnover of ND-AspRS within bacterial-type transamidosomes, and possibly may explain a different evolutionary pathway of GatCAB in organisms with bacterial-type vs. archaeal-type Asn-transamidosomes. Importantly, because the two-step pathway for Asn-tRNAAsn formation evolutionarily preceded the direct attachment of Asn to tRNAAsn, our structure also may reflect the mechanism by which asparagine was initially added to the genetic code.
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Lovio-Fragoso, José Pablo, Damaristelma de Jesús-Campos, José Antonio López-Elías, Luis Ángel Medina-Juárez, Diana Fimbres-Olivarría, and Corina Hayano-Kanashiro. "Biochemical and Molecular Aspects of Phosphorus Limitation in Diatoms and Their Relationship with Biomolecule Accumulation." Biology 10, no. 7 (June 22, 2021): 565. http://dx.doi.org/10.3390/biology10070565.
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Diatoms are the most abundant group of phytoplankton, and their success lies in their significant adaptation ability to stress conditions, such as nutrient limitation. Phosphorus (P) is a key nutrient involved in the transfer of energy and the synthesis of several cellular components. Molecular and biochemical mechanisms related to how diatoms cope with P deficiency are not clear, and research into this has been limited to a few species. Among the molecular responses that have been reported in diatoms cultured under P deficient conditions is the upregulation of genes encoding enzymes related to the transport, assimilation, remobilization and recycling of this nutrient. Regarding biochemical responses, due to the reduction of the requirements for carbon structures for the synthesis of proteins and phospholipids, more CO2 is fixed than is consumed by the Calvin cycle. To deal with this excess, diatoms redirect the carbon flow toward the synthesis of storage compounds such as triacylglycerides and carbohydrates, which are excreted as extracellular polymeric substances. This review aimed to gather all current knowledge regarding the biochemical and molecular mechanisms of diatoms related to managing P deficiency in order to provide a wider insight into and understanding of their responses, as well as the metabolic pathways affected by the limitation of this nutrient.
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Cooper, Mark S., and Paul M. Stewart. "11β-Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Hypothalamus-Pituitary-Adrenal Axis, Metabolic Syndrome, and Inflammation." Molecular Endocrinology 23, no. 11 (November 1, 2009): 1934. http://dx.doi.org/10.1210/mend.23.11.9999.
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ABSTRACT Context 11β-Hydroxysteroid dehydrogenase (11β-HSD) enzymes are now appreciated to be important regulators of hormone action at a tissue level. 11β-HSD1 is widely expressed and increases glucocorticoid action through its unique ability to convert inactive glucocorticoids (cortisone in man, 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively). The enzyme has roles in the normal hypothalamus-pituitary-adrenal (HPA) axis, has been implicated in metabolic syndrome, and may modulate various aspects of the immune response. Evidence Acquisition A review of published, peer-reviewed medical literature (1990 to June 2009) on the physiology and pathophysiology of 11β-HSD1 was performed with an emphasis on HPA axis consequences, the metabolic syndrome, and the inflammatory response. Evidence Synthesis Studies of patients with genetic defects in 11β-HSD1 action show abnormal HPA axis responses with hyperandrogenism being a major consequence. The mechanisms underlying these abnormalities have been explored in mouse models with targeted deletion of components of the 11β-HSD1 system. A range of experimental studies emphasize the role of 11β-HSD1 in the metabolic syndrome and the potential for treatment with chemical inhibitors. An emerging area is the role of 11β-HSD1 in the inflammatory response. Conclusions 11β-HSD1 activity is an important component of the HPA axis and contributes to the metabolic syndrome and the normal immune response. Ongoing clinical observations and the development of selective inhibitors will further clarify the role of 11β-HSD1 in these areas.
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Jordá, Tania, and Sergi Puig. "Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae." Genes 11, no. 7 (July 15, 2020): 795. http://dx.doi.org/10.3390/genes11070795.
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Ergosterol is an essential component of fungal cell membranes that determines the fluidity, permeability and activity of membrane-associated proteins. Ergosterol biosynthesis is a complex and highly energy-consuming pathway that involves the participation of many enzymes. Deficiencies in sterol biosynthesis cause pleiotropic defects that limit cellular proliferation and adaptation to stress. Thereby, fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions. The regulation of ergosterol synthesis is achieved by overlapping mechanisms that include transcriptional expression, feedback inhibition of enzymes and changes in their subcellular localization. In the budding yeast Saccharomyces cerevisiae, the sterol regulatory element (SRE)-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ergosterol biosynthesis (ERG) gene expression. Here, we summarize the sterol biosynthesis, transport and detoxification systems of S. cerevisiae, as well as its adaptive response to sterol depletion, low oxygen, hyperosmotic stress and iron deficiency. Because of the large number of ERG genes and the crosstalk between different environmental signals and pathways, many aspects of ergosterol regulation are still unknown. The study of sterol metabolism and its regulation is highly relevant due to its wide applications in antifungal treatments, as well as in food and pharmaceutical industries.
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De Rango, Francesco, Paolina Crocco, Francesca Iannone, Adolfo Saiardi, Giuseppe Passarino, Serena Dato, and Giuseppina Rose. "Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity." Genes 10, no. 2 (February 8, 2019): 125. http://dx.doi.org/10.3390/genes10020125.
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Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival.
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Farha, Maya A., Tomasz L. Czarny, Cullen L. Myers, Liam J. Worrall, Shawn French, Deborah G. Conrady, Yang Wang, Eric Oldfield, Natalie C. J. Strynadka, and Eric D. Brown. "Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase." Proceedings of the National Academy of Sciences 112, no. 35 (August 17, 2015): 11048–53. http://dx.doi.org/10.1073/pnas.1511751112.
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Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery.
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Ingold, Edgar, and Hanns Ulrich Seitz. "Characterization and Properties of Different Glucosyltransferases Isolated from Suspension-Cultured Cells of Daucus carota." Zeitschrift für Naturforschung C 41, no. 4 (April 1, 1986): 409–20. http://dx.doi.org/10.1515/znc-1986-0407.
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Particulate enzymes (14,000 g pellet) from suspension-cultured carrot cells (Daucus carota L.) incorporated glucose from UDP-glucose and GDP-glucose into ethanol-insoluble products which were characterized as glucans or glucoprotein. Based on the test system to assay glucansynthe- tases I and II four different enzymatic activities could be distinguished on the basis of their substrate and divalent cation requirements, the influence of active substances such as nucleotides, nucleotide sugars, cellobiose, and in vivo inhibitors of cell wall glucan synthesis, their distribution in linear sucrose gradient and the nature of their products. The enzymatic activities which incorporated glucose from UDP-glucose or GDP-glucose at low substrate concentrations (10 -6 ᴍ) were both localized in membranes of a density of 1.129 g em-3 (Golgi membranes) and synthesized a β-1,4-glucan chain. Both showed similar properties in most of the characterization experiments. The glucosyltransferase that catalysed the formation of a β-1,3-glucan from UDP-glucose (0.48 mᴍ) was found in membranes which accumulated at a density of 1.170 g · cm-3 (plasma membrane) and differed in its properties from the Golgi-localized glucosyltransferase activities in many aspects. A soluble glucosyltransferase (175,000 × g supernatant) which was also active at low concentrations of UDP-glucose (10-6 ᴍ) but showed enhanced activity under conditions where the other glucosyltransferases were inactive incorporated glucose into a proteinase-sensitive product. In linear sucrose gradients this enzyme migrated to different gradient densities depending on conditions.
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Behl, Tapan, Ishnoor Kaur, Arun Kumar, Vineet Mehta, Gokhan Zengin, and Sandeep Arora. "Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy." Current Gene Therapy 20, no. 3 (October 9, 2020): 207–22. http://dx.doi.org/10.2174/1566523220999200817164051.
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: The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.
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Rincon, Gonzalo, Alma Islas-Trejo, Alejandro R. Castillo, Dale E. Bauman, Bruce J. German, and Juan F. Medrano. "Polymorphisms in genes in the SREBP1 signalling pathway and SCD are associated with milk fatty acid composition in Holstein cattle." Journal of Dairy Research 79, no. 1 (November 25, 2011): 66–75. http://dx.doi.org/10.1017/s002202991100080x.
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Genes in the sterol regulatory element-binding protein-1 (SREBP1) pathway play a central role in regulation of milk fat synthesis, especially the de-novo synthesis of saturated fatty acids. SCD, a SREBP-responsive gene, is the key enzyme in the synthesis of monounsaturated fatty acids in the mammary gland. In the present study, we discovered SNP in candidate genes associated with this signalling pathway and SCD to identify genetic markers that can be used for genetic and metabolically directed selection in cattle. We resequenced six candidate genes in the SREBP1 pathway (SREBP1, SCAP, INSIG1, INSIG2, MBTPS1, MBTPS2) and two genes for SCD (SCD1 and SCD5) and discovered 47 Tag SNP that were used in a marker-trait association study. Milk and blood samples were collected from Holstein cows in their 1st or 2nd parity at 100–150 days of lactation. Individual fatty acids from C4 to C20, saturated fatty acid (SFA) content, monounsaturated fatty acid content, polyunsaturated fatty acid content and desaturase indexes were measured and used to perform the asociation analysis. Polymorphisms in the SCD5 and INSIG2 genes were the most representative markers associated with SFA/unsaturated fatty acid (UFA) ratio in milk. The analysis of desaturation activity determined that markers in the SCD1 and SCD5 genes showed the most significant effects. DGAT1 K232A marker was included in the study to examine the effect of this marker on the variation of milk fatty acids in our Holstein population. The percentage of variance explained by DGAT1 in the analysis was only 6% of SFA/UFA ratio. Milk fat depression was observed in one of the dairy herds and in this particular dairy one SNP in the SREBP1 gene (rs41912290) accounted for 40% of the phenotypic variance. Our results provide detailed SNP information for key genes in the SREBP1 signalling pathway and SCD that can be used to change milk fat composition by marker-assisted breeding to meet consumer demands regarding human health, as well as furthering understanding of technological aspects of cows' milk.
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Thangavelu, Govindarajan, Asim Saha, Kazutoshi Aoyama, Cameron McDonald-Hyman, Yu-Chi Lee, Chrysothemis Brown, Angela Panoskaltsis-Mortari, et al. "Critical Roles of Retinoic Acid Signaling in Combating Acute Graft Versus Host Disease." Blood 128, no. 22 (December 2, 2016): 4534. http://dx.doi.org/10.1182/blood.v128.22.4534.4534.
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Abstract Retinoic acid (RA), a metabolite of vitamin A, modulates a variety of aspects of the immune system, primarily because of its diverse effects on a wide range of immune cells. Initiation of RA-mediated transcription requires the binding of RA to heterodimeric nuclear receptors composed of RA receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ). Although RA signaling is tolerogenic under steady state conditions, previous studies, including ours, have shown that RA can enhance pro-inflammatory responses in acute graft-versus-host disease (aGVHD) (Blood. 2013; 122(12): 2125). In that study, we demonstrated that donor T cells expressing a dominant negative RARα (DNRARα) markedly impaired GVHD lethality capacity. This paradoxical function in aGVHD was attributed to excessive RA production caused by the upregulation of RA-synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), in hematopoietic and non-hematopoietic cells. In the current study, we investigated genetic and translational approaches to ablate RA synthesis and signaling as a means to treat aGVHD. The 4 isoforms of the RALDH enzyme are differentially expressed in a variety of cell types. RALDH-2 is the predominant isoform in dendritic cells (DCs), whereas RALDH-1 levels were found to be higher in intestinal epithelial cells (IECs) during aGVHD. We hypothesized that conditional deletion of either RALDH-2 in host CD11c+ DCs, or RALDH-1 in host IECs using a Cre-Lox system would diminish RA synthesis and reduce aGVHD. Consistent with this hypothesis, ablation of RA synthesis by RALDH-2 in host CD11c+ DCs significantly reduced aGVHD (Figure 1A; p <0.0001) in a fully MHC mismatched BALB/c (H-2d) into C57BL/6 (B6, H-2b) mouse model of aGVHD. However, deletion of RALDH-1 in IECs failed to attenuate aGVHD (not shown), which could be attributed to the existence of other isoforms in these cells. To circumvent the potential contribution of multiple RA synthesizing isoforms, we generated mice over expressing CYP26A1, a key RA catabolizing enzyme. Over expression of CYP26A1 in host hematopoietic cells using CYP26A1stop/stop-VAV-Cre recipients significantly mitigated aGVHD (p<0.005; not shown), providing novel insights into the tissue-specific role of RA signaling in aGVHD. We further explored RA signaling in aGVHD using a translational approach. IRX4204 is a novel and highly specific RXR agonist currently in clinical trials for autoimmune diseases, which can sequester RXR receptors and phenocopies the genetic approach using DNRARα T cells and allowing translation into the clinic. We discovered that IRX4204 can enhance in vitro CD4+CD25+Foxp3+ Regulatory T cell (iTreg) generation from naïve CD4+Foxp3- precursors (Figure 1B), suggesting it might increase Treg in vivo, and therefore be therapeutically useful for aGVHD prevention. To determine the effects of IRX4204 in aGVHD, we used two fully MHC mismatched mouse models: (B6 (H-2b) into BALB/c (H-2d) and BALB/c (H-2d) into B6 (H-2b). Recipients treated with IRX4204 had significantly prolonged survival time (Figure 1C&D), reduced weight loss, and better clinical scores compared to vehicle-treated mice. IRX4204 also significantly reduced donor T cell proliferation, effector differentiation and a 2-4 fold reduced production of pro-inflammatory cytokine (IFN-γ, TNF-α). Despite up-regulating gut-homing receptors on donor T cells, intestinal (and liver) GVHD pathology was reduced, which was associated with higher IEC integrity, assessed by po FITC-dextran serum levels. Compared to controls, IRX4204-treated recipients had a higher frequency of Treg in the spleen, mesenteric lymph nodes (p <0.0001) and colon (p <0.001). To determine whether IRX4204 mitigated aGVHD by promoting peripheral Treg (pTreg) generation, we utilized Treg-depleted donor T cells from either wild type (WT) or Scurfy (Sc) mice in our B6 into BALB/c GVHD model. Sc mice have a FoxP3 gene deletion and therefore cannot produce pTreg. Interestingly, IRX4204 attenuated aGVHD only in recipients that were given WT T cells, indicating that the generation of pTregs was critical for IRX4204-mediated aGVHD protection. Overall, these data lay a strong foundation for the development of novel drug based therapies for aGVHD and other inflammatory disorders by ablating RA synthesis and signaling. Disclosures Chandraratna: Io Pharmaceuticals: Other: Employed by Io Pharmaceuticals and is a board member, holding the titles of title of President and Chief Scientific Officer, and has ownership interest in Io Pharmaceuticals. .
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Szymański, M., M. Deniziak, and J. Barciszewski. "The new aspects of aminoacyl-tRNA synthetases." Acta Biochimica Polonica 47, no. 3 (September 30, 2000): 821–34. http://dx.doi.org/10.18388/abp.2000_4000.
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Aminoacyl-tRNA synthetases (AARS) are essential proteins found in all living organisms. They form a diverse group of enzymes that ensure the fidelity of transfer of genetic information from the DNA into the protein. AARS catalyse the attachment of amino acids to transfer RNAs and thereby establish the rules of the genetic code by virtue of matching the nucleotide triplet of the anticodon with its cognate amino acid. Here we summarise the effects of recent studies on this interesting family of multifunctional enzymes.
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Hanaei, Sara, Sina Abdollahzade, Alireza Khoshnevisan, Christopher K. Kepler, and Nima Rezaei. "Genetic aspects of intervertebral disc degeneration." Reviews in the Neurosciences 26, no. 5 (October 1, 2015): 581–606. http://dx.doi.org/10.1515/revneuro-2014-0077.
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AbstractIntervertebral disc degeneration (IVDD) is one of the common causes of low back pain. Similar to many other multifactorial diseases, it is affected by environmental and genetic factors. Although not completely understood, genetic factors include a wide spectrum of variations, such as single nucleotide polymorphisms, which could play a significant role in the etiology of this disease. Besides, the interactions with environmental factors could make the role of genetic factors more complicated. Genetic variations in disc components could participate in developing degenerative disc disease through altering the normal homeostasis of discs. Gene polymorphisms in disc proteins (collagens I, II, III, IX, and XI), proteoglycans (aggrecan), cytokines (interleukins I, VI, and X), enzymes (matrix metalloproteinases II, III, and IX), and vitamin D receptor seem to play considerable roles in the pathology of this disease. There are also many other investigated genes that could somehow take part in the process. However, it seems that more studies are needed to clarify the exact role of genetics in IVDD.
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Morales, Laura E. "Gaucher's Disease: A Review." Annals of Pharmacotherapy 30, no. 4 (April 1996): 381–88. http://dx.doi.org/10.1177/106002809603000411.
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OBJECTIVE: To review the epidemiology, pathophysiology, clinical features, diagnosis, and treatment of Gaucher's disease, focusing on the role of enzyme replacement therapy. DATA SOURCES: a MEDLINE search (from 1984 to July 1995) of English-language literature pertaining to the treatment of Gaucher's disease was performed. Additional references were obtained by reviewing the references of pertinent articles identified through the search. Tertiary sources were also used. STUDY SELECTION AND DATA EXTRACTION: Articles with information on enzyme treatment were selected for review. Articles containing other interesting aspects of the disease or its treatment were also included. DATA SYNTHESIS: Gaucher's disease is the most common lipid storage disorder known and results from a genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme deficiency results in accumulation of glucocerebroside within the reticuloendothelial system. If may present with hepatosplenomegaly, bone marrow suppression, and bone lesions. The most common of the three subtypes, type 1, is non-neuronopathic. In the rare neuronopathic subtypes, type 2 or 3, there may also be nerve cell destruction within the central nervous system with acute brainstem dysfunction or progressive neurologic deterioration, respectively. In 1991, enzyme treatment became available with the marketing of alglucerase, a placentally derived modified form of glucocerebrosidase. In 1994, a recombinant DNA modified form of glucocerebrosidase, known as imiglucerase, was developed to replace alglucerase. Most published data on enzyme therapy are with alglucerase in patients with type 1 disease. A dosage regimen of 60 units/kg every 2 weeks for moderately to severely ill patients has been effective in reducing hepatosplenomegaly, improving anemia and thrombocytopenia, as well as improving weight gain and growth in children and increasing vigor and self-esteem in adults. Bone involvement is often slow to respond to therapy although pain is frequently improved. Controversy exists as to whether lower dosage regimens are as effective. The role of enzyme therapy in the rarer neuronopathic subtypes remains to be determined, but initial reports have been disappointing. CONCLUSIONS: Enzyme replacement therapy is available for the treatment of type 1 Gaucher's disease, resulting in clinical improvement with enhanced quality of life within the first year of treatment, although improvement in bone disease can take longer. Doses of 60 units/kg every 2 weeks are of clinical benefit to patients with moderate to severe disease. A number of lower dosage regimens have been evaluated in small groups of patients, with satisfactory clinical responses occurring in some of these patients.
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Nedoszytko, Bogusław, Edyta Reszka, Danuta Gutowska-Owsiak, Magdalena Trzeciak, Magdalena Lange, Justyna Jarczak, Marek Niedoszytko, et al. "Genetic and Epigenetic Aspects of Atopic Dermatitis." International Journal of Molecular Sciences 21, no. 18 (September 4, 2020): 6484. http://dx.doi.org/10.3390/ijms21186484.
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Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.
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Wani, Arshad Iqbal, Khalid J. Farooqi, Mir Iftikhar Bashir, Shahnaz Ahmad Mir, and Shariq Rashid Masoodi. "Mucopolysaccharidosis: Clinical and Radiological Aspects." JMS SKIMS 15, no. 1 (June 11, 2012): 54–56. http://dx.doi.org/10.33883/jms.v15i1.115.
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Mucopolysaccharidosis (MPS) refers to a group of genetic disorder characterized by excessive accumulation of mucopolysaccharides secondary to deficiencies in specific enzymes. It produces characteristic skeletal abnormalities collectively termed as “dysostosis multiplex”. Here we describe a young female child with classical radiological features of MPS on plain radiographs. JMS 2012;15(1):54-56.
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Pöschl, Gudrun, Felix Stickel, Xiang D. Wang, and Helmut K. Seitz. "Alcohol and cancer: genetic and nutritional aspects." Proceedings of the Nutrition Society 63, no. 1 (February 2004): 65–71. http://dx.doi.org/10.1079/pns2003323.
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Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcohol-induced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis.
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Serdiuk, V., and K. Maidenko. "Genetic Aspects of Primary Open-Angle Glaucoma." Ukrainian journal Ophthalmology, no. 2(13) (June 2021): 47–51. http://dx.doi.org/10.30702/ophthalmology30062021-13.2.47-51/681-07-037.
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Glaucoma is one of the widespread eye diseases causing visual disturbances and even blindness. Almost 15% of blindness worldwide is due to glaucoma. One of the factors of glaucoma development is heredity. Currently, identification and diagnosis of new glaucoma cases is achieved either by routine screening or examinations prompted by perceived risk. The factors associated with the pathogenesis of glaucoma include high intraocular pressure (IOP), aging, decreased blood flow and genetic factors. Traditional vision screening for disorders like primary open-angle glaucoma (POAG) is time-consuming and costly. POAG is the most common type of glaucoma which has no obvious abnormality in the eye that points to a cause. Although mutations in several genes, including myocilin, optineurin, and CYP1B1 are associated with the disease, these genes account for less than 10% of cases worldwide. The paper reviews genetic studies in POAG. The genetic basis for the development of glaucoma and a variety of its related syndromes is considered. CYP1B1 is a member of a family of cytochrome P450 genes known to encode enzymes that metabolize and detoxify both endogenous and exogenous molecules, although their activity is not limited to detoxification. The human CYP superfamily contains 57 functional genes and 58 pseudogenes. Two specific substrates of CYP1B1 (estradiols and retinoic acid) could contribute to ocular development and specifically to the development of the ocular anterior segment.
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Pomohaibo, V. M., L. D. Orlova, and N. A. Vlasenko. "Environmental DNA: ecological and genetic aspects." Ecology and Noospherology 27, no. 1-2 (March 29, 2016): 16–24. http://dx.doi.org/10.15421/031602.
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Attention to environmental DNA (eDNA) was motivated by problem of undesirable gene transfer possibility from genetically modified plants to wild bacteria and other organisms. First studies have already examined persistence of DNA from these plants in soil, and also in the samples of nearby groundwater and river for a few kilometers from the place of cultivating. In soil it persists long time enough – from a few days to a few years, and in water – from a few hours to a few days. eDNA excreted from different sources – frozen ice cores, sediments of lakes, soil, caves, water of lakes, rivers and oceans, contains genetic information about biodiversity of present and ancient organisms. Researches revealed an important fact: data of eDNA and other sources, for example pollen, macrofossils, living animals and plants, complement each other, showing more reliable information about the variety of species, than used separately. Therefore the analysis eDNA needs to be not of considered alternative method of ecological researches, but an additional to traditional methods. In the process of study of eDNA it is necessary to take into account five aspects at least: its origin, physical state, conversion, transport and technical challenges. The origin of eDNA remains studied not enough. From a few publications it is known that eDNA comes in different composition excretions, leaves, hair, peeling etc., or as a result of released plasmids and chromosomal DNA from living prokaryotes. There are also possible secondary sources of eDNA – dead bodies and excretions of predators, scavengers, detritivores and coprovores. On the amount of the genetic material, released by organisms in an environment, various ontogenetic, trophic and other factors can have considerably influence. eDNA can be presented in both intracellular and extracellular forms.. Over time intracellular eDNA releases outside by influence of different ecological factors – activity of microorganisms, presence of extracellular enzymes, mechanical destruction etc. In further extracellular eDNA can break in corpuscles of different sizes – mainly within the limits of 1–10 μm. It can be free, adsorbed by other substances or dissolved. At certain conditions the period of eDNA persistence can be very great – from a few hours (in water) to hundred thousands of years (in frozen ice cores). Ancient eDNA is very fragmented and chemically changed by various physical, chemical and biological factors of environment. Substantive eDNA amount is taken up by bacteria and protozoa. Here it quickly metabolizes, but some its fragments can be integrated in a local genome. eDNA is able to be transported to great distance (from a few meters to 10 kilometers) that can appreciably influence on the results of its research. Also the laboratory experiment has certain problems – design (equipment, sequence of operations and condition of it realization), realization of experiment, authenticity of it will depend on quality of equipment and reagents, competence and honesty of scientific personnel etc.), ability of skilled researcher to give interpretation of results. Data that given in our review testifies that the active study of eDNA only began, and further intensive efforts of environmentalists and geneticists are needed in direction of it research. The results of such researches will allow to create the effective methods of scientifically reasonable recreating nature application.
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Wünsch Filho, Victor, and Marco A. Zago. "Modern cancer epidemiological research: genetic polymorphisms and environment." Revista de Saúde Pública 39, no. 3 (June 2005): 490–97. http://dx.doi.org/10.1590/s0034-89102005000300023.
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Individual cancer susceptibility seems to be related to factors such as changes in oncogenes and tumor suppressor genes expression, and differences in the action of metabolic enzymes and DNA repair regulated by specific genes. Epidemiological studies on genetic polymorphisms of human xenobiotics metabolizing enzymes and cancer have revealed low relative risks. Research considering genetic polymorphisms prevalence jointly with environmental exposures could be relevant for a better understanding of cancer etiology and the mechanisms of carcinogenesis and also for new insights on cancer prognosis. This study reviews the approaches of molecular epidemiology in cancer research, stressing case-control and cohort designs involving genetic polymorphisms, and factors that could introduce bias and confounding in these studies. Similarly to classical epidemiological research, genetic polymorphisms requires considering aspects of precision and accuracy in the study design.
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Bennick, A. "Structural and Genetic Aspects of Proline-rich Proteins." Journal of Dental Research 66, no. 2 (February 1987): 457–61. http://dx.doi.org/10.1177/00220345870660021201.
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Considerable advances have been made in the genetics of salivary proline-rich proteins (PRP). The genes for acidic, basic, and glycosylated PRP have been cloned. They code for precursor proteins that all have an acidic N-terminal followed by proline-rich repeat sequences. Structural studies on secreted proteins have demonstrated that not only acidic but also some basic PRPs have this general structure. It is possible that mRNA for different PRP may have originated from a single gene by differential mRNA splicing, but post-translational cleavages of the primary translation product apparently also occur. In vitro translation of salivary gland mRNA results in a single precursor protein for acidic PRP. Such in vitro translated protein can be cleaved by salivary kallikrein, giving rise to two commonly secreted acidic PRPs, and kallikrein or kallikrein-like enzymes may be responsible for other post-translational cleavages of PRPs. Acidic as well as some basic PRPs are phosphorylated. A protein kinase has been demonstrated in salivary glands which phosphorylates the PRPs and other secreted salivary proteins in a cAMP and Ca2+-calmodulinindependent manner. Knowledge of the conformation of PRPs is limited. There is no conclusive evidence of polyproline-like structure in the proline-rich part of PRPs. Ca2+ binding studies on acidic PRPs indicate that there is interaction between the Ca2+ binding N-terminal end and the proline-rich C-terminal part. This interaction is relieved by modification of arginine side-chains. 1H, 32P, and 43Ca NMR studies have further elucidated the conformation of acidic PRPs in solution. Present evidence shows that salivary PRPs constitute a unique superfamily of proteins which pose a number of interesting questions concerning gene structure, pre- and post-translational modifications, and protein conformation.
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Neto, Roberval N. M., Edelvio de Barros Gomes, Lucas Weba-Soares, Léo R. L. Dias, Luís C. N. da Silva, and Rita de C. M. de Miranda. "Biotechnological Production of Statins: Metabolic Aspects and Genetic Approaches." Current Pharmaceutical Biotechnology 20, no. 15 (November 22, 2019): 1244–59. http://dx.doi.org/10.2174/1389201020666190718165746.
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Statins are drugs used for people with abnormal lipid levels (hyperlipidemia) and are among the best-selling medications in the United States. Thus, the aspects related to the production of these drugs are of extreme importance for the pharmaceutical industry. Herein, we provide a non-exhaustive review of fungal species used to produce statin and highlighted the major factors affecting the efficacy of this process. The current biotechnological approaches and the advances of a metabolic engineer to improve statins production are also emphasized. The biotechnological production of the main statins (lovastatin, pravastatin and simvastatin) uses different species of filamentous fungi, for example Aspergillus terreus. The statins production is influenced by different types of nutrients available in the medium such as the carbon and nitrogen sources, and several researches have focused their efforts to find the optimal cultivation conditions. Enzymes belonging to Lov class, play essential roles in statin production and have been targeted to genetic manipulations in order to improve the efficiency for Lovastatin and Simvastatin production. For instance, Escherichia coli strains expressing the LovD have been successfully used for lovastatin production. Other examples include the use of iRNA targeting LovF of A. terreus. Therefore, fungi are important allies in the fight against hyperlipidemias. Although many studies have been conducted, investigations on bioprocess optimization (using both native or genetic- modified strains) still necessary.
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Kim, T. Doohun, and Kyeong Kyu Kim. "Crystallographic Studies of Enzymes." Crystals 10, no. 1 (December 20, 2019): 6. http://dx.doi.org/10.3390/cryst10010006.
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Enzymes are biological catalysts, which work to accelerate chemical reactions at the molecular level in living organisms. They are major players in the control of biological processes such as replication, transcription, protein synthesis, metabolism, and signaling. Like inorganic catalysts, enzymes function by decreasing the activation energy of chemical reactions, thereby enhancing the rate of the reactions. Enzymes are widely used for chemical, food, pharmaceutical, medicinal, analytical, clinical, forensic, and environmental applications. Therefore, studies on their structure, mechanism, and function, using a wide range of experimental and computational methods, are necessary to understand better enzymes in biological processes. For this special issue, “Crystallographic Studies of Enzymes", we have collected research papers on enzymes with structural aspects and functional aspects; here we briefly discuss the contents of such research papers as follows, with the aim of suggesting new directions of investigation in the fields of enzyme research, protein engineering, and drug development.
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Petrone, Igor, Paula Sabbo Bernardo, Everton Cruz dos Santos, and Eliana Abdelhay. "MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review." Genes 12, no. 4 (April 17, 2021): 587. http://dx.doi.org/10.3390/genes12040587.
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Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.
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Kadyshev, V. V., S. A. Ryazhskaya, O. V. Khalanskaya, N. V. Zhurkova, and R. A. Zinchenko. "Clinical and genetic aspects of albinism." Russian Journal of Clinical Ophthalmology 21, no. 3 (2021): 175–80. http://dx.doi.org/10.32364/2311-7729-2021-21-3-175-180.
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Albinism is a clinically and genetically heterogeneous group of hereditary diseases whose pathogenesis is mediated by impaired synthesis of melanin which results in its partial or total loss. Reduced melatonin level clinically manifests as skin, hair, and ocular hypopigmentation. Ocular presentations include hypopigmentation/lack of pigmentation of eye fundus and iris, foveal hypoplasia, low vision, nystagmus and strabismus, photophobia, iris transillumination, and asymmetrical decussation of nerve fibers at the optic chiasm. However, albinism can be a part of more complex genetic syndromes, e.g., Hermansky-Pudlak syndrome or Chediak-Higashi syndrome. These disorders should be identified as early as possible to start therapy to prevent life-threatening conditions. Partial albinism with ocular, skin or hair hypopigmentation not associated with melanogenesis (e.g., Griscelli syndrome, Waardenburg syndrome, Aland Island eye disease, etc.) also occurs. Each case of albinism requires an accurate molecular genetic diagnosis to provide a personalized treatment approach, predict life expectancy and health status, and plan pregnancy. Keywords: albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, hypopigmentation, clinical polymorphism, genetic heterogeneity. For citation: Kadyshev V.V., Ryazhskaya S.A., Khalanskaya O.V. et al. Clinical and genetic aspects of albinism. Russian Journal of Clinical Ophthalmology. 2021;21(3):175–180 (in Russ.). DOI: 10.32364/2311-7729-2021-21-3-175-180.
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Schulze, Jenny Jakobsson, Mattias Lorentzon, Claes Ohlsson, Jonas Lundmark, Hyung-Keun Roh, Anders Rane, and Lena Ekström. "Genetic aspects of epitestosterone formation and androgen disposition: influence of polymorphisms in CYP17 and UGT2B enzymes." Pharmacogenetics and Genomics 18, no. 6 (June 2008): 477–85. http://dx.doi.org/10.1097/fpc.0b013e3282fad38a.
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Liu, Xiaobing, Bingjie Tu, Qiuying Zhang, and Stephen J. Herbert. "Physiological and molecular aspects of pod shattering resistance in crops." Czech Journal of Genetics and Plant Breeding 55, No. 3 (June 17, 2019): 87–92. http://dx.doi.org/10.17221/104/2018-cjgpb.
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Pod shattering resistance is a trait acquired by crops in the process of evolution. Manipulation of physiological and molecular processes is fundamental for the improvement of shattering resistance in crops. In this review we discuss several enzymes, key hormones and their possible roles or relationships involved in pod shattering, and highlight responsible genes, quantitative traits loci (QTLs) and their implications for increased pod shattering resistance. Cell wall degrading enzymes, particularly β-glucanases and endopolygalacturonases play an important role in the process of pod dehiscence. It is not clear how and to what extent a specific hormone regulates the dehiscence zone differentiation and the dehiscence process is not clear. Resistance to shattering is highly heritable and is not controlled by a single gene. Several QTLs associated to dehiscence have been identified in crops, while the underlying genetic functions of these QTLs deserve further investigation. Further physiological analyses of the pod wall will help to understand better the pod dehiscence.
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Abete-Luzi, Patricia, Tetsunari Fukushige, Sijung Yun, Michael W. Krause, and David M. Eisenmann. "New Roles for the Heterochronic Transcription Factor LIN-29 in Cuticle Maintenance and Lipid Metabolism at the Larval-to-Adult Transition in Caenorhabditis elegans." Genetics 214, no. 3 (January 23, 2020): 669–90. http://dx.doi.org/10.1534/genetics.119.302860.
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Temporal regulation of gene expression is a crucial aspect of metazoan development. In the roundworm Caenorhabditis elegans, the heterochronic pathway controls multiple developmental events in a time-specific manner. The most downstream effector of this pathway, the zinc-finger transcription factor LIN-29, acts in the last larval stage (L4) to regulate elements of the larval-to-adult switch. Here, we explore new LIN-29 targets and their implications for this developmental transition. We used RNA-sequencing to identify genes differentially expressed between animals misexpressing LIN-29 at an early time point and control animals. Among 230 LIN-29-activated genes, we found that genes encoding cuticle collagens were overrepresented. Interestingly, expression of lin-29 and some of these collagens was increased in adults with cuticle damage, suggesting a previously unknown function for LIN-29 in adult cuticle maintenance. On the other hand, genes involved in fat metabolism were enriched among 350 LIN-29-downregulated targets. We used mass spectrometry to assay lipid content in animals overexpressing LIN-29 and observed reduced fatty acid levels. Many LIN-29-repressed genes are normally expressed in the intestine, suggesting cell-nonautonomous regulation. We identified several LIN-29 upregulated genes encoding signaling molecules that may act as mediators in the regulation of intestinally expressed genes encoding fat metabolic enzymes and vitellogenins. Overall, our results support the model of LIN-29 as a major regulator of adult cuticle synthesis and integrity, and as the trigger for metabolic changes that take place at the important transition from rapid growth during larval life to slower growth and offspring production during adulthood.
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Reue, Karen, Jessica M. Lee, and Laurent Vergnes. "Diet1 Is a Regulator of Fibroblast Growth Factor 15/19-Dependent Bile Acid Synthesis." Digestive Diseases 33, no. 3 (2015): 307–13. http://dx.doi.org/10.1159/000371649.
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Background: A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, farnesoid X receptor is activated and induces transcription of fibroblast growth factor (FGF)15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production. Key Messages: Mice with a Diet1-null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, Diet1-deficient mice constitutively convert cholesterol to bile acids and are resistant to diet-induced hypercholesterolemia and atherosclerosis. Diet1 affects FGF15/19 production at the posttranscriptional level, and the proteins appear to have overlapping subcellular localization in enterocytes. Diet1 appears to be a control point for the production of FGF15/19 in enterocytes, and thus a regulator of bile acid and lipid homeostasis. Studies to evaluate the role of common and rare DIET1 genetic variants in human health and disease are warranted. Conclusions: Further elucidation of the Diet1-FGF15/19 interaction will provide new insights into the intricate regulatory mechanisms underlying bile acid metabolism.
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Баймиев, Ан Х., Е. А. Гильванова, П. Ю. Мильман, Р. Т. Матниязов, and Ал Х. Баймиев. "Genetic engineering of cyclomaltodextrin glucanotransferases." Biomics 13, no. 2 (2021): 138–52. http://dx.doi.org/10.31301/2221-6197.bmcs.2021-10.
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Studies of cyclic oligosaccharides from six, seven and eight glucose residues, designated as alpha-, beta- and gamma-cyclodextrins, respectively, and everything related to them have been going on for 130 years. In this review, the history of the study of these molecules is briefly considered. The interest in cyclodextrins is caused by their ability to form inclusion complexes with a number of organic and inorganic compounds, radically changing some of their properties. This is widely used in the pharmaceutical, cosmetic and food industries, and beta-cyclodextrin is even registered as a food additive E459. Cyclodextrins are obtained from starch under the action of cyclodextringlucanotransferase (CGTase) enzymes, a characteristic feature of which is their non-strict specificity in relation to the types of oligosaccharides produced. The main producers of these enzymes are a group of bacteria of the order Bacillales, which unites several families (Paenibacillaceae, Bacillaceae, Thermoactynomicetaceae, etc.), but in last years CGTases have been found in a wide range of bacteria and archaea. The genetic engineering of CGTases began in the middle of 1980s, after the CGTase gene from Paenibacillus macerans (formerly Bacillus macerans) was cloned and sequenced for the first time, and during this period rather noticeable progress was made in understanding the organization and functioning of these enzymes, including using X-ray diffraction analysis. With the help of site-directed mutagenesis, error-prone PCR, as well as by creating chimeric forms of these enzymes, certain successes have been achieved in recent decades in changing (improving) the specificity of their action. Suitable leader peptides are used to increase the synthesis and secretion of genetically engineered CGTases, and various heterologous producers are also proposed, including the bacteria Escherichia coli, B.subtilis, Lactococcus lactis and the methylotrophic yeast Koagataella phaffii.
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Tavasoli, Mahtab, Sarah Lahire, Taryn Reid, Maren Brodovsky, and Christopher R. McMaster. "Genetic diseases of the Kennedy pathways for membrane synthesis." Journal of Biological Chemistry 295, no. 51 (October 22, 2020): 17877–86. http://dx.doi.org/10.1074/jbc.rev120.013529.
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The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.
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Hastings, I. M. "Germline selection: population genetic aspects of the sexual/asexual life cycle." Genetics 129, no. 4 (December 1, 1991): 1167–76. http://dx.doi.org/10.1093/genetics/129.4.1167.
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Abstract Population geneticists make a distinction between sexual and asexual organisms depending on whether individuals inherit genes from one or two parents. When individual genes are considered, this distinction becomes less satisfactory for multicellular sexual organisms. Individual genes pass through numerous asexual mitotic cell divisions in the germline prior to meiosis and sexual recombination. The processes of mitotic mutation, mitotic crossing over, and mitotic gene conversion create genotypic diversity between diploid cells in the germline. Genes expressed in the germline whose products affect cell viability (such as many "housekeeping" enzymes) may be subjected to natural selection acting on this variability resulting in a non-Mendelian output of gametes. Such genes will be governed by the population genetics of the sexual/asexual life cycle rather than the conventional sexual/Mendelian life cycle. A model is developed to investigate some properties of the sexual/asexual life cycle. When appropriate parameter values were included in the model, it was found that mutation rates per locus per gamete may vary by a factor of up to 100 if selection acts in the germline. Sexual/asexual populations appear able to evolve to a genotype of higher fitness despite intervening genotypes of lower fitness, reducing the problems of underdominance and Wright's adaptive landscape encountered by purely sexual populations. As might be expected this ability is chiefly determined by the number of asexual mitotic cell divisions within the germline. The evolutionary consequences of "housekeeping" loci being governed by the dynamics of the sexual/asexual life cycle are considered.
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Terruzzi, Ileana, Pamela Senesi, Anna Montesano, Antonio La Torre, Giampietro Alberti, Stefano Benedini, Andrea Caumo, Isabella Fermo, and Livio Luzi. "Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes." Physiological Genomics 43, no. 16 (August 2011): 965–73. http://dx.doi.org/10.1152/physiolgenomics.00040.2010.
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Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine β-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group ( P = 0.0001, P = 0.018, and P = 0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate (Myf-6), and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC) = Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC = Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass.
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Cunningham, Francis X. "Regulation of carotenoid synthesis and accumulation in plants." Pure and Applied Chemistry 74, no. 8 (January 1, 2002): 1409–17. http://dx.doi.org/10.1351/pac200274081409.
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Although genes that encode most enzymes of the carotenoid pathway in higher plants have been identified, the regulatory mechanisms that govern the synthesis and accumulation of carotenoid pigments are still obscure. Recent findings relevant to two aspects of carotenoid pathway control are reviewed: availability of substrate and pathway branching. Experimental approaches that are likely to enhance our understanding of carotenoid pathway regulation are also described.
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Shi, Yuguang, and Dong Cheng. "Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism." American Journal of Physiology-Endocrinology and Metabolism 297, no. 1 (July 2009): E10—E18. http://dx.doi.org/10.1152/ajpendo.90949.2008.
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Monoacyglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze two consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT enzymes that differ in catalytic properties, subcellular localization, tissue distribution, and physiological functions. MGAT and DGAT enzymes play fundamental roles in the metabolism of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiological functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT enzymes and the development of chemical inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT enzymes by synthetic compounds may provide novel treatment for obesity and its related metabolic complications.
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Rao, Mala B., Aparna M. Tanksale, Mohini S. Ghatge, and Vasanti V. Deshpande. "Molecular and Biotechnological Aspects of Microbial Proteases." Microbiology and Molecular Biology Reviews 62, no. 3 (September 1, 1998): 597–635. http://dx.doi.org/10.1128/mmbr.62.3.597-635.1998.
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SUMMARY Proteases represent the class of enzymes which occupy a pivotal position with respect to their physiological roles as well as their commercial applications. They perform both degradative and synthetic functions. Since they are physiologically necessary for living organisms, proteases occur ubiquitously in a wide diversity of sources such as plants, animals, and microorganisms. Microbes are an attractive source of proteases owing to the limited space required for their cultivation and their ready susceptibility to genetic manipulation. Proteases are divided into exo- and endopeptidases based on their action at or away from the termini, respectively. They are also classified as serine proteases, aspartic proteases, cysteine proteases, and metalloproteases depending on the nature of the functional group at the active site. Proteases play a critical role in many physiological and pathophysiological processes. Based on their classification, four different types of catalytic mechanisms are operative. Proteases find extensive applications in the food and dairy industries. Alkaline proteases hold a great potential for application in the detergent and leather industries due to the increasing trend to develop environmentally friendly technologies. There is a renaissance of interest in using proteolytic enzymes as targets for developing therapeutic agents. Protease genes from several bacteria, fungi, and viruses have been cloned and sequenced with the prime aims of (i) overproduction of the enzyme by gene amplification, (ii) delineation of the role of the enzyme in pathogenecity, and (iii) alteration in enzyme properties to suit its commercial application. Protein engineering techniques have been exploited to obtain proteases which show unique specificity and/or enhanced stability at high temperature or pH or in the presence of detergents and to understand the structure-function relationships of the enzyme. Protein sequences of acidic, alkaline, and neutral proteases from diverse origins have been analyzed with the aim of studying their evolutionary relationships. Despite the extensive research on several aspects of proteases, there is a paucity of knowledge about the roles that govern the diverse specificity of these enzymes. Deciphering these secrets would enable us to exploit proteases for their applications in biotechnology.
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Makar, I. A., V. V. Havrylyak, and G. M. Sedilo. "Genetic and biochemical aspects of the synthesis of keratin by hair follicles." Cytology and Genetics 41, no. 1 (February 2007): 65–68. http://dx.doi.org/10.3103/s0095452707010094.
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Khavinson, Vladimir, Natalia Linkova, Ekaterina Kozhevnikova, and Svetlana Trofimova. "EDR Peptide: Possible Mechanism of Gene Expression and Protein Synthesis Regulation Involved in the Pathogenesis of Alzheimer’s Disease." Molecules 26, no. 1 (December 31, 2020): 159. http://dx.doi.org/10.3390/molecules26010159.
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The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer’s (AD) and Huntington’s diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.
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Kladar, Nebojša, Jasminka Mrđanović, Goran Anačkov, Slavica Šolajić, Neda Gavarić, Branislava Srđenović, and Biljana Božin. "Hypericum perforatum: Synthesis of Active Principles during Flowering and Fruitification—Novel Aspects of Biological Potential." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/2865610.
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St. John’s wort is a widely used medicinal plant. The quality of herbal drug, which is in most of the cases collected from nature, varies. Therefore, the aim of the present study was detailed chemical characterization of Hypericum perforatum subsp. perforatum samples collected in close time intervals during flowering and fruitification with the purpose to state the phenological stage characterized by maximum levels of active principles. The antioxidant potential and potential to inhibit biologically important enzymes, as well as the cytotoxicity and genotoxicity of the sample collected during the full flowering period, were evaluated. Data showed that the optimal period for the achieving of maximum level of active principles is the phenophase between floral budding and flowering stage. Significant antioxidant potential and the ability to inhibit biologically important enzymes (especially α-glucosidase) were recorded. The extract exhibited no genotoxicity in subcytotoxic concentrations, while increased cytotoxicity recorded in cotreatment with bleomycin on malignant cell lines was especially significant.
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Palmer, C. V., J. C. Bythell, and B. L. Willis. "Enzyme activity demonstrates multiple pathways of innate immunity in Indo-Pacific anthozoans." Proceedings of the Royal Society B: Biological Sciences 279, no. 1743 (July 18, 2012): 3879–87. http://dx.doi.org/10.1098/rspb.2011.2487.
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Coral reefs are threatened by increasing levels of coral disease and the functional loss of obligate algal symbionts (bleaching). Levels of immunity relate directly to susceptibility to these threats; however, our understanding of fundamental aspects of coral immunology is lacking. We show that three melanin-synthesis pathway components (mono-phenoloxidase, ortho -diphenoloxidase (tyrosinase-type pathway) and para -diphenoloxidase (laccase-type pathway)) are present in both their active (phenoloxidase, PO) and inactive (prophenoloxidase, PPO) forms across a diverse range of 22 species of healthy Indo-Pacific anthozoans. We also demonstrate transglutaminase activity of the coagulation cascade for, to our knowledge, the first time in a coral. Melanin-synthesis enzyme activities varied among taxa, although they were generally lowest in the coral family Acroporidae and highest in the Poritidae and Oculinidae. Inactive tyrosinase-type activity (PPO) and active laccase-type activity (PO) correlate with taxonomic patterns in disease resistance, whereas the converse pattern in activity levels correlates with bleaching resistance. Overall, we demonstrate the presence of several melanin-synthesis pathways in Indo-Pacific corals, co-regulation among some pathway components, and highlight their potential roles in coral health.
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Kieser, Karen J., Catherine Baranowski, Michael C. Chao, Jarukit E. Long, Christopher M. Sassetti, Matthew K. Waldor, James C. Sacchettini, Thomas R. Ioerger, and Eric J. Rubin. "Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility." Proceedings of the National Academy of Sciences 112, no. 42 (October 5, 2015): 13087–92. http://dx.doi.org/10.1073/pnas.1514135112.
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Peptidoglycan (PG), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. PG synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen Mycobacterium tuberculosis (Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized, we carried out whole-genome transposon mutagenesis screens in Mtb strains deleted for ponA1, ponA2, and ldtB, major PG synthetic enzymes. We identified distinct factors required to sustain bacterial growth in the absence of each of these enzymes. We find that even the homologs PonA1 and PonA2 have unique sets of genetic interactions, suggesting there are distinct PG synthesis pathways in Mtb. Either PonA1 or PonA2 is required for growth of Mtb, but both genetically interact with LdtB, which has its own distinct genetic network. We further provide evidence that each interaction network is differentially susceptible to antibiotics. Thus, Mtb uses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities.