Journal articles: 'Proteins Enantiomers'

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Cooper, George, and Andro C. Rios. "Enantiomer excesses of rare and common sugar derivatives in carbonaceous meteorites." Proceedings of the National Academy of Sciences 113, no. 24 (May 31, 2016): E3322—E3331. http://dx.doi.org/10.1073/pnas.1603030113.

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Biological polymers such as nucleic acids and proteins are constructed of only one—the d or l—of the two possible nonsuperimposable mirror images (enantiomers) of selected organic compounds. However, before the advent of life, it is generally assumed that chemical reactions produced 50:50 (racemic) mixtures of enantiomers, as evidenced by common abiotic laboratory syntheses. Carbonaceous meteorites contain clues to prebiotic chemistry because they preserve a record of some of the Solar System’s earliest (∼4.5 Gy) chemical and physical processes. In multiple carbonaceous meteorites, we show that both rare and common sugar monoacids (aldonic acids) contain significant excesses of the d enantiomer, whereas other (comparable) sugar acids and sugar alcohols are racemic. Although the proposed origins of such excesses are still tentative, the findings imply that meteoritic compounds and/or the processes that operated on meteoritic precursors may have played an ancient role in the enantiomer composition of life’s carbohydrate-related biopolymers.

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Suar, Mrutyunjay, Andrea Hauser, Thomas Poiger, Hans-Rudolf Buser, Markus D. Müller, Charu Dogra, Vishakha Raina, et al. "Enantioselective Transformation of α-Hexachlorocyclohexane by the Dehydrochlorinases LinA1 and LinA2 from the Soil Bacterium Sphingomonas paucimobilis B90A." Applied and Environmental Microbiology 71, no. 12 (December 2005): 8514–18. http://dx.doi.org/10.1128/aem.71.12.8514-8518.2005.

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ABSTRACT Sphingomonas paucimobilis B90A contains two variants, LinA1 and LinA2, of a dehydrochlorinase that catalyzes the first and second steps in the metabolism of hexachlorocyclohexanes (R. Kumari, S. Subudhi, M. Suar, G. Dhingra, V. Raina, C. Dogra, S. Lal, J. R. van der Meer, C. Holliger, and R. Lal, Appl. Environ. Microbiol. 68:6021-6028, 2002). On the amino acid level, LinA1 and LinA2 were 88% identical to each other, and LinA2 was 100% identical to LinA of S. paucimobilis UT26. Incubation of chiral α-hexachlorocyclohexane (α-HCH) with Escherichia coli BL21 expressing functional LinA1 and LinA2 S-glutathione transferase fusion proteins showed that LinA1 preferentially converted the (+) enantiomer, whereas LinA2 preferred the (−) enantiomer. Concurrent formation and subsequent dissipation of β-pentachlorocyclohexene enantiomers was also observed in these experiments, indicating that there was enantioselective formation and/or dissipation of these enantiomers. LinA1 preferentially formed (3S,4S,5R,6R)-1,3,4,5,6-pentachlorocyclohexene, and LinA2 preferentially formed (3R,4R,5S,6S)-1,3,4,5,6-pentachlorocyclohexene. Because enantioselectivity was not observed in incubations with whole cells of S. paucimobilis B90A, we concluded that LinA1 and LinA2 are equally active in this organism. The enantioselective transformation of chiral α-HCH by LinA1 and LinA2 provides the first evidence of the molecular basis for the changed enantiomer composition of α-HCH in many natural environments. Enantioselective degradation may be one of the key processes determining enantiomer composition, especially when strains that contain only one of the linA genes, such as S. paucimobilis UT26, prevail.

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Hiep, Bui Tung, Fran�ois Gimenez, Vu Khanh, Nguyen Kim Hung, Alain Thuillier, Robert Farinotti, and Christine Fernandez. "Binding of chlorpheniramine enantiomers to human plasma proteins." Chirality 11, no. 5-6 (1999): 501–4. http://dx.doi.org/10.1002/(sici)1520-636x(1999)11:5/6<501::aid-chir24>3.0.co;2-k.

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Martin, Jackie L., Jerrold Meinwald, Peter Radford, Zhi Liu, Mary Louise M. Graf, and Lance R. Pohl. "Stereoselective Metabolism of Halothane Enantiomers to Trifluoroacetylated Liver Proteins." Drug Metabolism Reviews 27, no. 1-2 (January 1995): 179–89. http://dx.doi.org/10.3109/03602539509029822.

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Vostrikova, Natal’ya L., Oksana A. Kuznetsova, Valentina B. Krylova, and Andrey V. Kulikovskii. "PREREQUISITES FOR THE FORMATION OF D - ENANTIOMERS OF AMINO ACIDS OF ANIMAL PROTEINS IN THE MANUFACTURING PROCESS OF MEAT PRODUCTS." Theory and practice of meat processing 4, no. 1 (April 5, 2019): 30–36. http://dx.doi.org/10.21323/2414-438x-2019-4-1-30-36.

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The paper presents studies on the presence or formation of d - enantiomers of amino acids in animal tissues or organs, in meat products during its production processes. It is shown that the process of epimerization of L - amino acid residues with the formation of D-enantiomers affect the reduction of the properties of food products, including the formation of oncoassociated subsequent effects on the human body.Modern control of the quantitative and qualitative composition of d-enantiomers of amino acids in food products, monitoring for stratification of the increased risk of toxic compounds in food are becoming an urgent medical and social problem. The studies planned in this paper are aimed at developing approaches to the creation of food products that reduce the oncogenic alimentary load on human health by solving the problem of technological modification of production, eliminating or minimizing post - translational modifications in proteins that contribute to the formation of d-enantiomers of amino acids. These studies will create a scientific and technological database associated with the risk assessment of carcinogenesis in protein matrices of animal origin. Based on the presented analysis, the task of developing and testing a method to control the accumulation of D-isomers in the course of various technological processes of meat production is extremely popular.

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Meierhenrich, Uwe J. "Amino Acids and the Asymmetry of Life." European Review 21, no. 2 (April 30, 2013): 190–99. http://dx.doi.org/10.1017/s106279871200035x.

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‘How did life start on Earth?’ and ‘Why were left-handed amino acids selected for the architecture of proteins?’ A new attempt to answer these questions of high public and interdisciplinary scientific interest will be provided by this review. It will describe most recent experimental data on how the basic and molecular building blocks of life, amino acids, formed in a prebiotic setting. Most amino acids are chiral, that is that they cannot be superimposed with their mirror image molecules (enantiomers). In processes triggering the origin of life on Earth, the equal occurrence, i.e. the parity between left-handed amino acids and their right-handed mirror images, was violated. In the case of amino acids, the balance was tipped to the left – as a result of which life's proteins today exclusively implement the left-handed form of amino acids, called l-amino acid enantiomers. Neither plants, nor animals, including humans, make use of d-amino acids for the molecular architecture of their proteins (enzymes). This review addresses the molecular asymmetry of amino acids in living organisms, namely the preference for left-handedness. What was the cause for the violation of molecular parity of amino acids in the emergence of life on Earth? All the fascinating models proposed by physicists, chemists, and biologists will be vividly presented including the scientific conflicts. Special emphasis will be given to amino acid enantiomers that were subjected to chiral photons. The interaction between racemic molecules and chiral photons was shown to produce an enantiomeric enrichment that will be discussed in the context of absolute asymmetric synthesis. The concluding paragraphs will describe the attempt to verify any of those models with the chirality-module of the Rosetta mission. This European space mission contains probe Philae that was launched on board the Rosetta spacecraft with the aim of landing on the icy surface of comet 67P/Churyumov-Gerasimenko and analysing whether chiral organic compounds are present that could have been brought to the Earth by comet impacts.

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Leal, Walter Soares. "Molecules and macromolecules involved in chemical communication of scarab beetles." Pure and Applied Chemistry 73, no. 3 (January 1, 2001): 613–16. http://dx.doi.org/10.1351/pac200173030613.

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Chemical communication involves the production and release of specific chemicals (pheromones and other semiochemicals) by the emitter, and the detection and olfactory processing of these signals leading to appropriate behavioral responses in the receiver. In contrast to most of the scarab species investigated to date, the Japanese and Osaka beetles have the ability to detect the allospecific pheromone, which plays a pivotal role in the isolation mechanism between these two species. Each species produces a single enantiomer of japonilure [(Z)-5-(dec1-enyl)oxacyclopentan-2-one], but they have evolved the ability to detect both enantiomers, one as an attractant and the other as a behavioral antagonist (stop signal). There is growing evidence in the literature that the inordinate sensitivity and selectivity of the insect olfactory system is achieved by a combination of various olfactory-specific proteins, namely, odorant-binding proteins (OBPs), odorant receptors (ORs), and odorant-degrading enzymes. The relationship between the pheromone structures and the primary sequences of the proteins suggest that OBPs play a part in the selectivity of the olfactory system in scarab beetles by "filtering" chemical signals during the early olfactory processing (perireceptor events). Nevertheless, it is unlikely that pheromone-binding proteins are "chiral filters" as the Japanese and Osaka beetles each possess only one single binding protein. Upon interaction with negatively charged membranes, OBPs undergo conformational changes that may lead to the release of the ligands.

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Steimbach, Raphael R., Gergely Tihanyi, Magalie N. E. Géraldy, Alicja Wzorek, Aubry K. Miller, and Karel D. Klika. "Can an Intermediate Rate of Nitrogen Inversion Affect Drug Efficacy?" Symmetry 13, no. 9 (September 20, 2021): 1753. http://dx.doi.org/10.3390/sym13091753.

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Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug–protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation.

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9

Pinnelli, Govardhana R., Mailyn Terrado, N. Kirk Hillier, David R. Lance, and Erika Plettner. "Synthesis of Isotopically Labelled Disparlure Enantiomers and Application to the Study of Enantiomer Discrimination in Gypsy Moth Pheromone-Binding Proteins." European Journal of Organic Chemistry 2019, no. 40 (October 18, 2019): 6807–21. http://dx.doi.org/10.1002/ejoc.201901164.

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10

Plettner, Erika, Josef Lazar, Erin G. Prestwich, and Glenn D. Prestwich. "Discrimination of Pheromone Enantiomers by Two Pheromone Binding Proteins from the Gypsy MothLymantriadispar†." Biochemistry 39, no. 30 (August 2000): 8953–62. http://dx.doi.org/10.1021/bi000461x.

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11

Martinelli, Ilenia, Daniele Tomassoni, Proshanta Roy, Lorenzo Di Cesare Mannelli, Francesco Amenta, and Seyed Khosrow Tayebati. "Antioxidant Properties of Alpha-Lipoic (Thioctic) Acid Treatment on Renal and Heart Parenchyma in a Rat Model of Hypertension." Antioxidants 10, no. 7 (June 23, 2021): 1006. http://dx.doi.org/10.3390/antiox10071006.

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Renal and cardiac impairments are frequent events in the presence of hypertension. Organ damage is mainly linked to oxidative stress due to high blood pressure and may be reduced by antioxidant supplementation. Alpha-lipoic acid (ALA) is one of most effective antioxidants. It is widely used as a nutritional supplement in a racemic mixture (+/–), even though the (+)-enantiomer is biologically active. This study was designed to investigate the effect of treatment with (+/–)-ALA and its enantiomers on renal and heart parenchyma in spontaneously hypertensive rats (SHR), using immunochemical and immunohistochemical techniques. The results confirmed that the oxidative mechanisms of organ alterations, due to hypertension, and characterized by glomerular and tubular lesions, left ventricular hypertrophy, and fibrosis but not by apoptosis were accompanied by proteins’ and nucleic acids’ oxidation. We found greater effectiveness of (+)-ALA compared to (+/−)-ALA in reducing oxidative stress, cardiac and renal damages in SHR. To conclude, these data propose (+)-ALA as one of the more appropriate antioxidant molecules to prevent renal and cardiac alterations associated with hypertension.

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12

Brullot, Ward, Maarten K. Vanbel, Tom Swusten, and Thierry Verbiest. "Resolving enantiomers using the optical angular momentum of twisted light." Science Advances 2, no. 3 (March 2016): e1501349. http://dx.doi.org/10.1126/sciadv.1501349.

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Circular dichroism and optical rotation are crucial for the characterization of chiral molecules and are of importance to the study of pharmaceutical drugs, proteins, DNA, and many others. These techniques are based on the different interactions of enantiomers with circularly polarized components of plane wave light that carries spin angular momentum (SAM). For light carrying orbital angular momentum (OAM), for example, twisted or helical light, the consensus is that it cannot engage with the chirality of a molecular system as previous studies failed to demonstrate an interaction between optical OAM and chiral molecules. Using unique nanoparticle aggregates, we prove that optical OAM can engage with materials’ chirality and discriminate between enantiomers. Further, theoretical results show that compared to circular dichroism, mainly based on magnetic dipole contributions, the OAM analog helical dichroism (HD) is critically dependent on fundamentally different chiral electric quadrupole contributions. Our work opens new venues to study chirality and can find application in sensing and chiral spectroscopy.

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13

Armstrong, Daniel W., Randy Menges, and Irving W. Wainer. "Use of Centrifugal Partition Chromatography and Proteins in The Preparative Separation of Amino Acid Enantiomers." Journal of Liquid Chromatography 13, no. 18 (November 1990): 3571–81. http://dx.doi.org/10.1080/01483919008049556.

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14

Sun, Jia-an, De-zhi Kong, Ya-qin Zhen, Qing Li, Wei Zhang, Jiang-hua Zhang, Zhi-wei Yin, and Lei-ming Ren. "Stereoselective binding of doxazosin enantiomers to plasma proteins from rats, dogs and humans in vitro." Acta Pharmacologica Sinica 34, no. 12 (November 18, 2013): 1568–74. http://dx.doi.org/10.1038/aps.2013.120.

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15

Millot, M. C. "Separation of drug enantiomers by liquid chromatography and capillary electrophoresis, using immobilized proteins as chiral selectors." Journal of Chromatography B 797, no. 1-2 (November 2003): 131–59. http://dx.doi.org/10.1016/j.jchromb.2003.08.035.

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16

Lachmann, B., and C. Noe. "KAPILLARELEKTROPHORETISCHE BESTIMMUNG VON KOHLENHYDRAT-ENANTI0MEREN." Scientia Pharmaceutica 69, no. 4 (December 28, 2001): 299–314. http://dx.doi.org/10.3797/scipharm.aut-01-201.

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Capillary electrophoresis is a versatile analytical technique for the determination of a very widespread range of compounds. Many applications for the separation of different pharmaceuticals, ions, herbicides and biomolecules such as DNA, proteins and peptides have been published over the last decade. A comparatively new field is the separation and determination of carbohydrates bycapillary electrophoresis, especially the assignment of absolute configuration. These methods will also gain importance in the field of pharmaceutical carbohydrate analysis. In this review a short overview ofthe different methods and separation procedures is given and some applications for the separation of sugar enantiomers are described in more detail.

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Sun, Xiu Hua, Chang Lu Gao, and Li Qun Gu. "Synthetic Glass Nanopore for Single Molecule Detection." Applied Mechanics and Materials 229-231 (November 2012): 197–200. http://dx.doi.org/10.4028/www.scientific.net/amm.229-231.197.

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The molecular-scale pore structure, called nanopore, interacting with target molecules in its functionalized lumen, can produce characteristic changes in the pore conductance, which allows us to identify single molecules and simultaneously quantify each target species in the mixture. Nanopore sensors have been created for tremendous biomedical detections, with targets ranging from metal ions, drug compounds and cellular second messengers, to proteins and DNAs. Here we will review our recent discoveries with a lab-in-hand glass nanopore: single-molecule discrimination of chiral enantiomers with a trapped cyclodextrin, sensing of bioterrorist agent ricin and site-directed capturing a single nanoparticle.

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Kobayashi, Jyumpei. "d-Amino Acids and Lactic Acid Bacteria." Microorganisms 7, no. 12 (December 12, 2019): 690. http://dx.doi.org/10.3390/microorganisms7120690.

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Proteins are composed of l-amino acids except for glycine, which bears no asymmetric carbon atom. Accordingly, researchers have studied the function and metabolism of l-amino acids in living organisms but have paid less attention to the presence and roles of their d-enantiomers. However, with the recent developments in analytical techniques, the presence of various d-amino acids in the cells of various organisms and the importance of their roles have been revealed. For example, d-serine (d-Ser) and d-aspartate (d-Asp) act as neurotransmitters and hormone-like substances, respectively, in humans, whereas some kinds of d-amino acids act as a biofilm disassembly factor in bacteria. Interestingly, lactic acid bacteria produce various kinds of d-amino acids during fermentation, and many d-amino acids taste sweet, compared with the corresponding l-enantiomers. The influence of d-amino acids on human health and beauty has been reported in recent years. These facts suggest that the d-amino acids produced by lactic acid bacteria are important in terms of the taste and function of lactic-acid-fermented foods. Against this background, unique d-amino-acid-metabolizing enzymes have been searched for and observed in lactic acid bacteria. This review summarizes and introduces the importance of various d-amino acids in this regard.

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Gilbert, R. L., C. J. Blunt, D. R. Harper, D. J. Jeffries, and R. A. J. Mcllhinney. "Effect of Inhibitors of Protein Myristoylation on Varicella-Zoster Virus Replication." Antiviral Chemistry and Chemotherapy 5, no. 3 (June 1994): 182–86. http://dx.doi.org/10.1177/095632029400500307.

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Inhibitors of N-myristoyltransferase (NMT) have been shown to inhibit retrovirus replication, notably that of the human immunodeficiency virus (HIV), where the absence of protein myristoylation inhibits viral replication. The authors have assayed 14 compounds derived from myristic acid for activity against varicella-zoster virus (human herpesvirus 3; VZV) by plaque reduction assay. Seven showed cytotoxicity and of the others, two failed to inhibit VZV replication. One of these was N-myristoylglycinaldiethylacetal (GoA), which has been reported to be active against HIV. 12-(methoxy) dodecanoic acid (13-oxamyristic acid), which has also been reported to inhibit HIV replication, was found to inhibit VZV replication but was cytotoxic at high concentrations. The greatest inhibitory effect without apparent toxicity was induced by 2-hydroxytetradecanoic acid and its enantiomers. The results of these assays provide further evidence that inhibitors of NMT have potential as antiviral agents against the many viruses with myristoylated proteins.

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Hackler, László, Márió Gyuris, Orsolya Huzián, Róbert Alföldi, Gábor J. Szebeni, Ramóna Madácsi, Levente Knapp, Iván Kanizsai, and László G. Puskás. "Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent." Molecules 24, no. 23 (November 23, 2019): 4269. http://dx.doi.org/10.3390/molecules24234269.

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Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer’s disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.

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Bayer, Ernst, Hartmut Frank, Jürgen Gerhardt, and Graeme Nicholson. "Capillary Gas Chromatographic Analysis of Amino Acids by Enantiomer Labeling." Journal of AOAC INTERNATIONAL 70, no. 2 (March 1, 1987): 234–40. http://dx.doi.org/10.1093/jaoac/70.2.234.

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Abstract The optical isomers of amino acids can be easily separated by gas chromatography using capillary columns coated with the chiral polysiloxane peptide, Chirasil-Val. Quantitative trace amino acid analysis in complex mixtures such as biological fluids, sea water, or protein hydrolysates can be achieved by enantiomer labeling: The D-amino acid enantiomers, which do not occur naturally, are added to the sample prior to analysis as internal standards. Because the D-enantiomers show the same physical and chemical properties as the natural L-enantiomers, they are ideal standard references. In routine analysis, the derivatization is achieved with a new automated derivatization robot. The D-standard serves as overall internal standard for the whole analytical procedure from sample enrichment to derivatization, chromatography, and response of the detector.

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Kitagawa, Fumihiko, Masato Kamiya, Yukihiro Okamoto, Hiromi Taji, Satomi Onoue, Yoshiko Tsuda, and Koji Otsuka. "Electrophoretic analysis of proteins and enantiomers using capillaries modified by a successive multiple ionic-polymer layer (SMIL) coating technique." Analytical and Bioanalytical Chemistry 386, no. 3 (May 16, 2006): 594–601. http://dx.doi.org/10.1007/s00216-006-0438-x.

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McDaniel, Jessica M., Kenyon G. Daniel, Fred Luhder, Sheng Wei, Richard Tanner, Danielle Grams, Alan F. List, and P. K. Epling-Burnette. "Virtual and Physical Analysis of the Proximal T Cell Signalosome Reveals PP2A Inhibition Is Important for Co-Stimulatory Function of Immunomodulatory (IMiD) Drugs." Blood 116, no. 21 (November 19, 2010): 281. http://dx.doi.org/10.1182/blood.v116.21.281.281.

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Abstract Abstract 281 Lenalidomide generates high rates of transfusion independence and complete cytogenetic response in del(5q) MDS patients by selective clonal suppression. This family of immunomodulatory drugs (IMiDs) including lenalidomide (CC5013, Revlimid®) and pomalidomide (CC4047, Actimid®) are thalidomide analogues that also induce T cell receptor (TCR) co-stimulation, as well as augment NK and NKT cells by an unknown mechanism of action. Signaling by the T cell receptor (TCR) involves activation of a multi-subunit complex known as the Proximal Signalosome that orchestrates the ordered sequential events leading to phosphorylation of Src-family kinase members Lck and Fyn, phosphorylation of ZAP-70/Syk protein tyrosine kinases, recruitment of SLP-76, Grb-2, and Vav1. IMiDs operate through the B7-CD28 pathway, which provides co-stimulation and enhancement to the Signalosome pathway. To determine the molecular target, we evaluated the activation status of proteins involved in the TCR/CD28 Signalosome after lenalidomide treatment using a murine CD28-/- thymoma cell line transfected with full-length, wild type CD28 or a mutant (tailless) CD28 molecule lacking the intracellular signaling domain (Dennehy et al, 2007, J. of Immunology). We found that lenalidomide augments phosphorylation components downstream of CD28 in WT, but not in tailless mutant cells, suggesting that the intracytoplasmic domain of CD28 is necessary for drug response. We have previously shown that lenalidomide inhibits the activity of two haplodeficient phosphatases on chromosome 5q, Protein Phosphatase 2A (PP2A) and Cdc25c, located within the commonly deleted region (CDR). PP2Ac is known to bind to CD28 and is hypothesized to inhibit T cell co-stimulation. Therefore, it is plausible that lenalidomide and other IMiDs inhibit PP2A in T cells to augment proximal T cell signals. We examined this using molecular modeling and virtual screening. The application GLIDE (Schrödinger, L.L.C.) was used to estimate the free energy of binding for thalidomide, lenalidomide, and pomalidomide to the PP2A-ca heterodimer. The PP2A crystal structure (PDB 3K7V) was analyzed by SiteMap (Schrödinger, L.L.C.) to identify potential small-molecule binding sites. SiteMap identified the catalytic site which was then used for our binding simulations. The IMiD compounds and a known PP2A inhibitor, Fostriecin, were prepared for docking using LigPrep (Schrödinger, L.L.C.) which creates 3D geometry for the structures, provides alternative tautomers, ionization states (for pH values between 5.0 and 9.0), alternative ring conformations, and diastereomers. Free energies of binding and poses for the molecules suggest that both the R and S enantiomers of all three immunomodulatory drugs bind to the same position within the catalytic pocket of the c subunit of the PP2A heterodimer and thereby inhibit phosphatase activity. The S enantiomers of both lenalidomide and pomalidomide have better binding poses and energies (-5.80 kcal/mol and -6.06 kcal/mol respectively) than S thalidomide which has one hydrogen bond, instead of two, and a worse binding free energy than its enantiomer (-5.34 kcal/mol vs. -6.38 kcal/mol) (Figure 1). This increase in binding energy, when coupled with the change in binding pose suggests that S thalidomide would be an inferior inhibitor. The R enantiomers of all three drugs bind with nearly identical posing and binding free energy. Therefore, we hypothesized that, as a racemate, thalidomide may have reduced inhibitory potency compared to the other IMiDs. This was tested in vitro using hemaglutinin (HA)-tagged PP2A immunoprecipitated from stably transfected ad293 cells in a Malachite Green phosphatase assay. All of the drugs showed inhibition of phosphatase activity compared to control but interestingly, PP2A treated with 10μ M of lenalidomide and pomalidomide showed 40.4%±1.93 and 42.6%±0.29 decreased activity respectively compared with thalidomide (24.6%±7.5), which validated the modeling predictions. Together, these results suggest that IMiDs inhibit the enzymatic activity of PP2A, which augments TCR/CD28 Signalosome activity. Disclosures: No relevant conflicts of interest to declare.

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Tanaka, Yoshihide, and Shigeru Terabe. "Partial separation zone technique for the separation of enantiomers by affinity electrokinetic chromatography with proteins as chiral pseudo-stationary phases." Journal of Chromatography A 694, no. 1 (March 1995): 277–84. http://dx.doi.org/10.1016/0021-9673(94)00790-g.

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Ponomarenko, Nina S., Oleksandr Kokhan, Phani R. Pokkuluri, Karen L. Mulfort, and David M. Tiede. "Examination of abiotic cofactor assembly in photosynthetic biomimetics: site-specific stereoselectivity in the conjugation of a ruthenium(II) tris(bipyridine) photosensitizer to a multi-heme protein." Photosynthesis Research 143, no. 2 (January 10, 2020): 99–113. http://dx.doi.org/10.1007/s11120-019-00697-8.

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AbstractTo understand design principles for assembling photosynthetic biohybrids that incorporate precisely-controlled sites for electron injection into redox enzyme cofactor arrays, we investigated the influence of chirality in assembly of the photosensitizer ruthenium(II)bis(2,2′-bipyridine)(4-bromomethyl-4′-methyl-2,2′-bipyridine), Ru(bpy)2(Br-bpy), when covalently conjugated to cysteine residues introduced by site-directed mutagenesis in the triheme periplasmic cytochrome A (PpcA) as a model biohybrid system. For two investigated conjugates that show ultrafast electron transfer, A23C-Ru and K29C-Ru, analysis by circular dichroism spectroscopy, CD, demonstrated site-specific chiral discrimination as a factor emerging from the close association between [Ru(bpy)3]2+ and heme cofactors. CD analysis showed the A23C-Ru and K29C-Ru conjugates to have distinct, but opposite, stereoselectivity for the Λ and Δ-Ru(bpy)2(Br-bpy) enantiomers, with enantiomeric excesses of 33.1% and 65.6%, respectively. In contrast, Ru(bpy)2(Br-bpy) conjugation to a protein site with high flexibility, represented by the E39C-Ru construct, exhibited a nearly negligible chiral selectivity, measured by an enantiomeric excess of 4.2% for the Λ enantiomer. Molecular dynamics simulations showed that site-specific stereoselectivity reflects steric constraints at the conjugating sites and that a high degree of chiral selectivity correlates to reduced structural disorder for [Ru(bpy)3]2+ in the linked assembly. This work identifies chiral discrimination as means to achieve site-specific, precise geometric positioning of introduced photosensitizers relative to the heme cofactors in manner that mimics the tuning of cofactors in photosynthesis.

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Keszthelyi, L. "Origin of the homochirality of biomolecules." Quarterly Reviews of Biophysics 28, no. 4 (November 1995): 473–507. http://dx.doi.org/10.1017/s0033583500003309.

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Molecules built up from a given set of atoms may differ in their three-dimensional structure. They may have one or more asymmetric centres that serve as reference points for the steric distribution of the atoms. Carbon atoms, common to all biomolecules, are often such centres. For example, the Cα atom between the carboxyl and amino groups in amino acids is an asymmetric centre: looking ON ward (i.e. from the carbOxyl to the amiNo group, with the Cα oriented so that it is above the carboxyl and amino groups) the radical characterizing the amino acid may be to the right (D-molecules) or to the left (L-molecules). Nineteen of the 20 amino acids occurring in proteins have such a structure (the exception is glycine, where the radical is a hydrogen atom). These pairs of molecules cannot be brought into coincidence with their own mirror image, as is the situation with our hands. The phenomenon has therefore been named handedness, or chirality, from the Greek word cheir, meaning hand. The two forms of the chiral molecules are called enantiomers or antipodes. They differ in rotating the plane of the polarized light either to the right or to the left. The sense of rotation depends on the wavelength of the measuring light, but at a given wavelength it is always opposite for a pair of enantiomers. Chirality may also occur when achiral molecules form chiral substances during crystallization (for example, quartz forms D-quartz or Lquartz). A detailed theoretical treatment of molecular chirality is given by Barron (1991).

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Blindheim, Fredrik, Mari Hansen, Sigvart Evjen, Wei Zhu, and Elisabeth Jacobsen. "Chemoenzymatic Synthesis of Synthes as Precursors for Enantiopure Clenbuterol and Other β2 Agonists." Catalysts 8, no. 11 (November 4, 2018): 516. http://dx.doi.org/10.3390/catal8110516.

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Clenbuterol is a β2-agonist used in the veterinary treatment of asthma in several countries. The drug is listed on the World Antidoping Agency’s prohibited list due to its effect on increased protein synthesis in the body. However, racemic clenbuterol has recently been shown to reduce the risk of Parkinson’s disease. In order to reveal which one (or both) of the enantiomers that cause this effect, pure enantiomers need to be separately studied. (R)-1-(4-Amino-3,5-dichlorophenyl)-2-bromoethan-1-ol has been synthesised in 93% enantiomeric excess (ee) by asymmetric reduction of the corresponding ketone catalysed by a ketoreductase and nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor in dimethyl sulfoxide (DMSO). (S)-N-(2,6-Dichloro-4-(1-hydroxyethyl)phenyl)acetamide has been synthesised in >98% ee by the same system. Both synthons are potential precursors for clenbuterol enantiomers.

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Mizutani, Tadashi, and Shigeyuki Yagi. "Linear tetrapyrroles as functional pigments in chemistry and biology." Journal of Porphyrins and Phthalocyanines 08, no. 03 (March 2004): 226–37. http://dx.doi.org/10.1142/s1088424604000210.

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1,19,21,24-tetrahydro-1,19-bilindione is the framework of pigments frequently found in nature, which includes biliverdin IX α, phytochromobilin and phycocyanobilin. 1,19-bilindiones have unique features such as (1) photochemical and thermal cis-trans isomerization, (2) excited energy transfer, (3) chiroptical properties due to the cyclic helical conformation, (4) redox activity, (5) coordination to various metals, and (6) reconstitution to proteins. 1,19-bilindione can adopt a number of conformations since it has exocyclic three double bonds and three single bonds that are rotatable thermally and photochemically. In solution, biliverdin and phycocyanobilin adopt a cyclic helical ZZZ, syn, syn, syn conformation, but other conformations are stabilized depending on the experimental conditions and substituents on the bilin framework. The conformational changes in 1,19-bilindiones are related to the biological functions of a photoreceptor protein, phytochrome. Structural and conformational studies of bilindiones are summarized both in solution and in protein. The conformational changes of bilins can be used for other functions such as a chirality sensor. The bilindiones and the zinc complexes of bilindiones can be employed as a chirality sensor due to the helically chiral structure and the dynamics of racemization of enantiomers. In this paper, we discuss the conformational equilibria and dynamics of bilindiones and its implications in photobiology and materials science.

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Peace, Robert W., and G. Sarwar Gilani. "Chromatographic Determination of Amino Acids in Foods." Journal of AOAC INTERNATIONAL 88, no. 3 (May 1, 2005): 877–87. http://dx.doi.org/10.1093/jaoac/88.3.877.

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Abstract Amino acids in foods exist in a free form or bound in peptides, proteins, or nonpeptide bonded polymers. Naturally occurring L-amino acids are required for protein synthesis and are precursors for essential molecules, such as co-enzymes and nucleic acids. Nonprotein amino acids may also occur in animal tissues as metabolic intermediates or have other important functions. The development of bacterially derived food proteins, genetically modified foods, and new methods of food processing; the production of amino acids for food fortification; and the introduction of new plant food sources have meant that protein amino acids and amino acid enantiomers in foods can have both nutritional and safety implications for humans. There is, therefore, a need for the rapid and accurate determination of amino acids in foods. Determination of the total amino acid content of foods requires protein hydrolysis by various means that must take into account variations in stability of individual amino acids and resistance of different peptide bonds to the hydrolysis procedures. Modern methods for separation and quantitation of free amino acids either before or after protein hydrolysis include ion exchange chromatography, high performance liquid chromatography (LC), gas chromatography, and capillary electrophoresis. Chemical derivatization of amino acids may be required to change them into forms amenable to separation by the various chromatographic methods or to create derivatives with properties, such as fluorescence, that improve their detection. Official methods for hydrolysis and analysis of amino acids in foods for nutritional purposes have been established. LC is currently the most widely used analytical technique, although there is a need for collaborative testing of methods available. Newer developments in chromatographic methodology and detector technology have reduced sample and reagent requirements and improved identification, resolution, and sensitivity of amino acid analyses of food samples.

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Menéndez-Perdomo, Ivette M., and Peter J. Facchini. "Isolation and characterization of two O-methyltransferases involved in benzylisoquinoline alkaloid biosynthesis in sacred lotus (Nelumbo nucifera)." Journal of Biological Chemistry 295, no. 6 (December 30, 2019): 1598–612. http://dx.doi.org/10.1074/jbc.ra119.011547.

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Benzylisoquinoline alkaloids (BIAs) are a major class of plant metabolites with many pharmacological benefits. Sacred lotus (Nelumbo nucifera) is an ancient aquatic plant of medicinal value because of antiviral and immunomodulatory activities linked to its constituent BIAs. Although more than 30 BIAs belonging to the 1-benzylisoquinoline, aporphine, and bisbenzylisoquinoline structural subclasses and displaying a predominant R-enantiomeric conformation have been isolated from N. nucifera, its BIA biosynthetic genes and enzymes remain unknown. Herein, we report the isolation and biochemical characterization of two O-methyltransferases (OMTs) involved in BIA biosynthesis in sacred lotus. Five homologous genes, designated NnOMT1–5 and encoding polypeptides sharing >40% amino acid sequence identity, were expressed in Escherichia coli. Functional characterization of the purified recombinant proteins revealed that NnOMT1 is a regiospecific 1-benzylisoquinoline 6-O-methyltransferase (6OMT) accepting both R- and S-substrates, whereas NnOMT5 is mainly a 7-O-methyltransferase (7OMT), with relatively minor 6OMT activity and a strong stereospecific preference for S-enantiomers. Available aporphines were not accepted as substrates by either enzyme, suggesting that O-methylation precedes BIA formation from 1-benzylisoquinoline intermediates. Km values for NnOMT1 and NnOMT5 were 20 and 13 μm for (R,S)-norcoclaurine and (S)-N-methylcoclaurine, respectively, similar to those for OMTs from other BIA-producing plants. Organ-based correlations of alkaloid content, OMT activity in crude extracts, and OMT gene expression supported physiological roles for NnOMT1 and NnOMT5 in BIA metabolism, occurring primarily in young leaves and embryos of sacred lotus. In summary, our work identifies two OMTs involved in BIA metabolism in the medicinal plant N. nucifera.

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Krom, Bastiaan P., Ronald Aardema, and Juke S. Lolkema. "Bacillus subtilis YxkJ Is a Secondary Transporter of the 2-Hydroxycarboxylate Transporter Family That Transports l-Malate and Citrate." Journal of Bacteriology 183, no. 20 (October 15, 2001): 5862–69. http://dx.doi.org/10.1128/jb.183.20.5862-5869.2001.

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ABSTRACT The genome of Bacillus subtilis contains two genes that code for membrane proteins that belong to the 2-hydroxycarboxylate transporter family. Here we report the functional characterization of one of the two, yxkJ, which codes for a transporter protein named CimHbs. The gene was cloned and expressed inEscherichia coli and complemented the citrate-negative phenotype of wild-type E. coli and the malate-negative phenotype of the E. coli strain JRG4008, which is defective in malate uptake. Subsequent uptake studies in whole cells expressing CimHbs clearly demonstrated the citrate and malate transport activity of the protein. Immunoblot analysis showed that CimHbs is a 48-kDa protein that is well expressed in E. coli. Studies with right-side-out membrane vesicles demonstrated that CimHbs is an electroneutral proton-solute symporter. No indications were found for the involvement of Na+ ions in the transport process. Inhibition of the uptake catalyzed by CimHbs by divalent metal ions, together with the lack of effect on transport by the chelator EDTA, showed that CimHbs translocates the free citrate and malate anions. Among a large set of substrates tested, only malate, citramalate, and citrate competitively inhibited citrate transport catalyzed by CimHbs. The transporter is strictly stereoselective, recognizing only the S enantiomers of malate and citramalate. Remarkably, though citramalate binds to the transporter, it is not translocated.

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Müller, Tina A., Thomas Fleischmann, Jan Roelof van der Meer, and Hans-Peter E. Kohler. "Purification and Characterization of Two Enantioselective α-Ketoglutarate-Dependent Dioxygenases, RdpA and SdpA, from Sphingomonas herbicidovorans MH." Applied and Environmental Microbiology 72, no. 7 (July 2006): 4853–61. http://dx.doi.org/10.1128/aem.02758-05.

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ABSTRACT α-Ketoglutarate-dependent (R)-dichlorprop dioxygenase (RdpA) and α-ketoglutarate-dependent (S)-dichlorprop dioxygenase (SdpA), which are involved in the degradation of phenoxyalkanoic acid herbicides in Sphingomonas herbicidovorans MH, were expressed and purified as His6-tagged fusion proteins from Escherichia coli BL21(DE3)(pLysS). RdpA and SdpA belong to subgroup II of the α-ketoglutarate-dependent dioxygenases and share the specific motif HXDX24TX131HX10R. Amino acids His-111, Asp-113, and His-270 and amino acids His-102, Asp-104, and His 257 comprise the 2-His-1-carboxylate facial triads and were predicted to be involved in iron binding in RdpA and SdpA, respectively. RdpA exclusively transformed the (R) enantiomers of mecoprop [2-(4-chloro-2-methylphenoxy)propanoic acid] and dichlorprop [2-(2,4-dichlorophenoxy)propanoic acid], whereas SdpA was specific for the (S) enantiomers. The apparent Km values were 99 μM for (R)-mecoprop, 164 μM for (R)-dichlorprop, and 3 μM for α-ketoglutarate for RdpA and 132 μM for (S)-mecoprop, 495 μM for (S)-dichlorprop, and 20 μM for α-ketoglutarate for SdpA. Both enzymes had high apparent Km values for oxygen; these values were 159 μM for SdpA and >230 μM for RdpA, whose activity was linearly dependent on oxygen at the concentration range measured. Both enzymes had narrow cosubstrate specificity; only 2-oxoadipate was able to replace α-ketoglutarate, and the rates were substantially diminished. Ferrous iron was necessary for activity of the enzymes, and other divalent cations could not replace it. Although the results of growth experiments suggest that strain MH harbors a specific 2,4-dichlorophenoxyacetic acid-converting enzyme, tfdA-, tfdAα-, or cadAB-like genes were not discovered in a screening analysis in which heterologous hybridization and PCR were used.

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A.S., Knyazeva, Vostrikova N.L., Kulikovskii A.V., and Utyanov D.A. "Features of the extraction of D‑enantiomers of amino acids from the meat matrix for subsequent analysis using HPLC–MS/MS." Vsyo o myase, no. 5 (October 30, 2020): 50–52. http://dx.doi.org/10.21323/2071-2499-2020-5-50-52.

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The article is devoted to the study of the processes of epimerization of L-amino acid residues with the formation of D-enantiomers, which affect the onco-associated properties of food products. A method for the chromatographic separation of optically active D- and L-amino acids using a chiral column has been developed. Measurements of the quantitative content of analytes were carried out using a diode array detector, followed by mass spectrometric confirmation. Methodological approaches to sample preparation are presented. It was revealed that during acid hydrolysis, leucine racemization from D-form to L-form. A procedure has been developed for enzymatic hydrolysis of samples by a complex of proteolytic enzymes, followed by purification of the hydrolyzate by solid-phase extraction. The degree of extraction, matrix effects, and the quantitative detection limit of the technique were determined. The data on post-translational modifications in the structure of proteins and peptides under the influence of technological operations and enzymatic processes in the production of meat products are presented.

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Ageeva, Aleksandra A., Ilya M. Magin, Alexander B. Doktorov, Victor F. Plyusnin, Polina S. Kuznetsova, Alexander A. Stepanov, Alexander A. Alekseev, Nikolay E. Polyakov, and Tatyana V. Leshina. "Role of Chiral Configuration in the Photoinduced Interaction of D- and L-Tryptophan with Optical Isomers of Ketoprofen in Linked Systems." International Journal of Molecular Sciences 22, no. 12 (June 8, 2021): 6198. http://dx.doi.org/10.3390/ijms22126198.

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The study of the L- and D-amino acid properties in proteins and peptides has attracted considerable attention in recent years, as the replacement of even one L-amino acid by its D-analogue due to aging of the body is resulted in a number of pathological conditions, including Alzheimer’s and Parkinson’s diseases. A recent trend is using short model systems to study the peculiarities of proteins with D-amino acids. In this report, the comparison of the excited states quenching of L- and D-tryptophan (Trp) in a model donor–acceptor dyad with (R)- and (S)-ketoprofen (KP-Trp) was carried out by photochemically induced dynamic nuclear polarization (CIDNP) and fluorescence spectroscopy. Quenching of the Trp excited states, which occurs via two mechanisms: prevailing resonance energy transfer (RET) and electron transfer (ET), indeed demonstrates some peculiarities for all three studied configurations of the dyad: (R,S)-, (S,R)-, and (S,S)-. Thus, the ET efficiency is identical for (S,R)- and (R,S)-enantiomers, while RET differs by 1.6 times. For (S,S)-, the CIDNP coefficient is almost an order of magnitude greater than for (R,S)- and (S,R)-. To understand the source of this difference, hyperpolarization of (S,S)-and (R,S)- has been calculated using theory involving the electron dipole–dipole interaction in the secular equation.

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Bindra, Ranjit, Parker L. Sulkowski, Christopher D. Corso, Peter Glazer, and Brian M. Shuch. "Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11586. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11586.

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11586 Background: 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (aKG)-dependent dioxygenases. The former is an oncometabolite induced by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML). Methods: Our group recently reported that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies that directly implicate two aKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. Results: Using the methodology and preliminary data obtained above as a basis for further inquiry, here we have extended these findings to several related gene mutations, which similarly induce profound synthetic lethality with PARP inhibitors in these tumors, and our data suggest a similar mechanism of action via which HR is suppressed. Finally, we provide additional evidence that suppression of 2HG production with small molecule inhibitors of mutant IDH1/2 function does not lead to any detectable decreases in cell growth or viability in several unique models. Conclusions: Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with inhibitors blocking the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors later this year.

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Berkecz, Róbert, Gábor Németi, Antal Péter, and István Ilisz. "Liquid Chromatographic Enantioseparations Utilizing Chiral Stationary Phases Based on Crown Ethers and Cyclofructans." Molecules 26, no. 15 (July 31, 2021): 4648. http://dx.doi.org/10.3390/molecules26154648.

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Natural compounds can exist in different forms, where molecules possessing chirality play an essential role in living organisms. Currently, one of the most important tasks of modern analytical chemistry is the enantioseparation of chiral compounds, in particular, the enantiomers of compounds having biological and/or pharmaceutical activity. Whether the task is to analyze environmental or food samples or to develop an assay for drug control, well-reproducible, highly sensitive, stereoselective, and robust methods are required. High-performance liquid chromatography best meets these conditions. Nevertheless, in many cases, gas chromatography, supercritical fluid chromatography, or capillary electrophoresis can also offer a suitable solution. Amino acids, proteins, cyclodextrins, derivatized polysaccharides, macrocyclic glycopeptides, and ion exchangers can serve as efficient selectors in liquid chromatography, and they are quite frequently applied and reviewed. Crown ethers and cyclofructans possessing similar structural characteristics and selectivity in the enantiodiscrimination of different amine compounds are discussed less frequently. This review collects information on enantioseparations achieved recently with the use of chiral stationary phases based on crown ethers or cyclofructans, focusing on liquid chromatographic applications.

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Bystrov, Vladimir, Alla Sidorova, Aleksey Lutsenko, Denis Shpigun, Ekaterina Malyshko, Alla Nuraeva, Pavel Zelenovskiy, Svitlana Kopyl, and Andrei Kholkin. "Modeling of Self-Assembled Peptide Nanotubes and Determination of Their Chirality Sign Based on Dipole Moment Calculations." Nanomaterials 11, no. 9 (September 16, 2021): 2415. http://dx.doi.org/10.3390/nano11092415.

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The chirality quantification is of great importance in structural biology, where the differences in proteins twisting can provide essentially different physiological effects. However, this aspect of the chirality is still poorly studied for helix-like supramolecular structures. In this work, a method for chirality quantification based on the calculation of scalar triple products of dipole moments is suggested. As a model structure, self-assembled nanotubes of diphenylalanine (FF) made of L- and D-enantiomers were considered. The dipole moments of FF molecules were calculated using semi-empirical quantum-chemical method PM3 and the Amber force field method. The obtained results do not depend on the used simulation and calculation method, and show that the D-FF nanotubes are twisted tighter than L-FF. Moreover, the type of chirality of the helix-like nanotube is opposite to that of the initial individual molecule that is in line with the chirality alternation rule general for different levels of hierarchical organization of molecular systems. The proposed method can be applied to study other helix-like supramolecular structures.

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Im, Seung Hyuk, Dam Hyeok Im, Su Jeong Park, Justin Jihong Chung, Youngmee Jung, and Soo Hyun Kim. "Stereocomplex Polylactide for Drug Delivery and Biomedical Applications: A Review." Molecules 26, no. 10 (May 11, 2021): 2846. http://dx.doi.org/10.3390/molecules26102846.

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Polylactide (PLA) is among the most common biodegradable polymers, with applications in various fields, such as renewable and biomedical industries. PLA features poly(D-lactic acid) (PDLA) and poly(L-lactic acid) (PLLA) enantiomers, which form stereocomplex crystals through racemic blending. PLA emerged as a promising material owing to its sustainable, eco-friendly, and fully biodegradable properties. Nevertheless, PLA still has a low applicability for drug delivery as a carrier and scaffold. Stereocomplex PLA (sc-PLA) exhibits substantially improved mechanical and physical strength compared to the homopolymer, overcoming these limitations. Recently, numerous studies have reported the use of sc-PLA as a drug carrier through encapsulation of various drugs, proteins, and secondary molecules by various processes including micelle formation, self-assembly, emulsion, and inkjet printing. However, concerns such as low loading capacity, weak stability of hydrophilic contents, and non-sustainable release behavior remain. This review focuses on various strategies to overcome the current challenges of sc-PLA in drug delivery systems and biomedical applications in three critical fields, namely anti-cancer therapy, tissue engineering, and anti-microbial activity. Furthermore, the excellent potential of sc-PLA as a next-generation polymeric material is discussed.

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Hudson, Cook, Grimes, Muller, Adams, and Wandinger-Ness. "Dual Actions of Ketorolac in Metastatic Ovarian Cancer." Cancers 11, no. 8 (July 24, 2019): 1049. http://dx.doi.org/10.3390/cancers11081049.

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Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.

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Csapá, János, Zsuzsanna Csapó-Kiss, László Wágner, Tibor Tálos, Truman G. Martin, Staffan Folestad, Anna Tivesten, and Sándor Némethy. "Hydrolysis of proteins performed at high temperatures and for short times with reduced racemization, in order to determine the enantiomers of d- and l-amino acids." Analytica Chimica Acta 339, no. 1-2 (February 1997): 99–107. http://dx.doi.org/10.1016/s0003-2670(96)00452-7.

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Malina, Jaroslav, Marie Vojtiskova, Viktor Brabec, Connie I. Diakos, and Trevor W. Hambley. "DNA adducts of the enantiomers of the Pt(II) complexes of the ahaz ligand (ahaz=3-aminohexahydroazepine) and recognition of these adducts by HMG domain proteins." Biochemical and Biophysical Research Communications 332, no. 4 (July 2005): 1034–41. http://dx.doi.org/10.1016/j.bbrc.2005.05.047.

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Hochberg, David, and Josep Ribó. "Entropic Analysis of Mirror Symmetry Breaking in Chiral Hypercycles." Life 9, no. 1 (March 15, 2019): 28. http://dx.doi.org/10.3390/life9010028.

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Replicators are fundamental to the origin of life and evolvability. Biology exhibits homochirality: only one of two enantiomers is used in proteins and nucleic acids. Thermodynamic studies of chemical replicators able to lead to homochirality shed valuable light on the origin of homochirality and life in conformity with the underlying mechanisms and constraints. In line with this framework, enantioselective hypercyclic replicators may lead to spontaneous mirror symmetry breaking (SMSB) without the need for additional heterochiral inhibition reactions, which can be an obstacle for the emergence of evolutionary selection properties. We analyze the entropy production of a two-replicator system subject to homochiral cross-catalysis which can undergo SMSB in an open-flow reactor. The entropy exchange with the environment is provided by the input and output matter flows, and is essential for balancing the entropy production at the non-equilibrium stationary states. The partial entropy contributions, associated with the individual elementary flux modes, as defined by stoichiometric network analysis (SNA), describe how the system’s internal currents evolve, maintaining the balance between entropy production and exchange, while minimizing the entropy production after the symmetry breaking transition. We validate the General Evolution Criterion, stating that the change in the chemical affinities proceeds in a way as to lower the value of the entropy production.

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Scholten, Ulrich, Alejandro Castillejo Merchán, and Klaus Bernauer. "Electron-transfer‐mediated binding of optically active cobalt(III) complexes to horse heart cytochrome c." Journal of The Royal Society Interface 2, no. 2 (February 10, 2005): 109–12. http://dx.doi.org/10.1098/rsif.2004.0023.

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Optically active cobalt(II) complexes are used as reducing agents in the electron-transfer reaction involving horse heart cytochrome c . Analysis of the circular dichroism (CD) spectra of reaction products indicates that the corresponding cobalt(III) species of both enantiomers of [Co II (alamp)] (H 2 alamp= N , N ′-[(pyridine-2,6-diyl)bis(methylene)]-bis[alanine]) are partly attached to the protein during electron transfer by coordination to an imidazole unit of one of the histidine residues. His-26 and His-33 are both solvent exposed, and the results suggest that one of these histidine residues acts as a bridge in the electron transfer to and from the haem iron of cytochrome c . The reaction is enantioselective: the ratio of the relative reactivity at 15 °C is 2.9 in favour of the R , R -enantiomer. A small induced CD activity in the haem chromophore reveals that some structural changes in the protein occur consecutively with the binding of the cobalt(III) complex.

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Zhang, Jianhua, Jianjun Sui, Chi Bun Ching, and Wei Ning Chen. "Protein profile in neuroblastoma cells incubated withS- andR-enantiomers of ibuprofen by iTRAQ-coupled 2-D LC-MS/MS analysis: Possible action of induced proteins on Alzheimer's disease." PROTEOMICS 8, no. 8 (April 2008): 1595–607. http://dx.doi.org/10.1002/pmic.200700556.

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Lamka, J., V. Krizova, V. Cvilink, M. Savlik, J. Velik, L. Duchacek, B. Szotakova, and L. Skalova. "A single adulticide dose of albendazole induces cytochromes P4501A in mouflon (Ovis musimon) with dicrocoeliosis." Veterinární Medicína 52, No. 8 (January 7, 2008): 343–52. http://dx.doi.org/10.17221/1873-vetmed.

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Contact handling with wild or semi-domesticated animals requires limiting animal stress to minimum. In this respect, single administration of drug should be preferred in contact therapy of mouflon (<i>Ovis musimon</i>) infected by lancet fluke (<i>Dicrocoelium dendriticum</i>). We tested single administration of albendazole (ABZ) (30 mg/kg of body weight) in a form of oral suspension and investigated to reach anthelmintic effects and to modulate biotransformation enzymes in liver and small intestine. Two weeks after ABZ administration coprology and necropsy findings document the adulticide effect in liver. The activities of éight biotransformation enzymes and ABZ biotransformation were tested in hepatic and intestinal subcellular fractions from control and ABZ treated animals. The highest inductive effect of ABZ was detected on cytochromes P4501A (CYP1A) activities. Increased amount of CYP1A proteins was confirmed using western blotting. In hepatic and intestinal microsomes, velocity of albendazole sulfoxide (ABZSO) formation was unaffected, but a shift in ratio of individual ABZSO enantiomers was observed. The second step of ABZ biotransformation corresponding to the formation of the pharmacologically inactive albendazole sulfone, was significantly accelerated both in liver and intestine of ABZ treated animals. The increase of ABZ deactivation could facilitate the development of anthelmintic resistance in parasites. Although single ABZ dose is therapeutically effective, its potential to induce CYP1A should be taken in account for controling helmithoses.

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Safrany, Stephen T., Deborah A. Sawyer, Stefan R. Nahorski, and Barry V. L. Potter. "SyntheticD- andL-enantiomers of 2,2-difluoro-2-deoxy-myo-inositol 1,4,5-trisphosphate interact differently withmyo-inositol 1,4,5-trisphosphate binding proteins: Identification of a potent small molecule 3-kinase inhibitor." Chirality 4, no. 7 (1992): 415–22. http://dx.doi.org/10.1002/chir.530040703.

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47

Wu, Zachary, S. B. Jennifer Kan, Russell D. Lewis, Bruce J. Wittmann, and Frances H. Arnold. "Machine learning-assisted directed protein evolution with combinatorial libraries." Proceedings of the National Academy of Sciences 116, no. 18 (April 12, 2019): 8852–58. http://dx.doi.org/10.1073/pnas.1901979116.

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To reduce experimental effort associated with directed protein evolution and to explore the sequence space encoded by mutating multiple positions simultaneously, we incorporate machine learning into the directed evolution workflow. Combinatorial sequence space can be quite expensive to sample experimentally, but machine-learning models trained on tested variants provide a fast method for testing sequence space computationally. We validated this approach on a large published empirical fitness landscape for human GB1 binding protein, demonstrating that machine learning-guided directed evolution finds variants with higher fitness than those found by other directed evolution approaches. We then provide an example application in evolving an enzyme to produce each of the two possible product enantiomers (i.e., stereodivergence) of a new-to-nature carbene Si–H insertion reaction. The approach predicted libraries enriched in functional enzymes and fixed seven mutations in two rounds of evolution to identify variants for selective catalysis with 93% and 79% ee (enantiomeric excess). By greatly increasing throughput with in silico modeling, machine learning enhances the quality and diversity of sequence solutions for a protein engineering problem.

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48

Velíšek, J., M. Doležal, C. Crews, and T. Dvořák. "Optical isomers of chloropropanediols: mechanisms of their formation and decomposition in protein hydrolysates." Czech Journal of Food Sciences 20, No. 5 (November 19, 2011): 161–70. http://dx.doi.org/10.17221/3527-cjfs.

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Protein hydrolysates produced by hydrochloric acid hydrolysis were analysed for 3-chloropropane-1,2-diol and its enantiomers. It was found that (R)-3-chloropropane-1,2-diol and (S)-3-chloropropane-1,2-diol were present in the hydrolysates in equimolar concentrations. Model experiments with glycerol, triolein and soy lecithin heated with hydrochloric acid in solution showed that these materials were precursors of 3-chloropropane-1,2-diol and 2-chloropropane-1,3-diol and, as expected, yielded racemic 3-chloropropane-1,2-diol. Yields of 3-chloropropane-1,2-diols decreased in the order triolein > lecithin > glycerol. The mechanisms of 3-chloropropane-1,2-diol enantiomers formation during the production of protein hydrolysates are presented and discussed as well as the reaction pathways of their decomposition in alkaline media via the corresponding intermediates, (R)- and (S)-glycidol, respectively. Both epoxides are hydrolysed to glycerol and form a variety of products with hydrolysate constituents.  

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49

Peña-Montes, Carolina, María Elena Mondragón-Tintor, José Augusto Castro-Rodríguez, Ismael Bustos-Jaimes, Arturo Navarro-Ocaña, and Amelia Farrés. "Immobilization and Biochemical Properties of the Enantioselective Recombinant NStcI Esterase of Aspergillus nidulans." Enzyme Research 2013 (May 27, 2013): 1–11. http://dx.doi.org/10.1155/2013/928913.

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The recombinant NStcI A. nidulans esterase was adsorbed on Accurel MP1000, where protein yield and immobilization efficiency were 42.48% and 81.94%, respectively. Storage stability test at 4°C and RT showed 100% of residual activity after 40 days at both temperatures. The biocatalyst retains more than 70% of its initial activity after 3 cycles of repeated use. Biochemical properties of this new biocatalyst were obtained. Maximum activity was achieved at pH 11 and 30°C, while the best stability was observed with the pH between 9 and 11 at 40°C. NStcI thermostability was increased after immobilization, as it retained 47.5% of its initial activity after 1 h at 60°C, while the free enzyme under the same conditions displayed no activity. NStcI preserved 70% of its initial activity in 100% hexane after 72 h. Enzymatic kinetic resolution of (R,S)-1-phenylethanol was chosen as model reaction, using vinyl acetate as acyl donor. After optimization of reaction parameters, the highest possible conversion (42%) was reached at 37°C, aw of 0.07, and 120 h of bioconversion in hexane with an enantiomeric excess of 71.7%. NStcI has selectivity for (R)-enantiomer. The obtained E value (31.3) is in the range considered useful to resolve enantiomeric mixtures.

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50

Zipper, Christian, Monika Bunk, Alexander J. B. Zehnder, and Hans-Peter E. Kohler. "Enantioselective Uptake and Degradation of the Chiral Herbicide Dichlorprop [(RS)-2-(2,4-Dichlorophenoxy)propanoic acid] by Sphingomonas herbicidovorans MH." Journal of Bacteriology 180, no. 13 (July 1, 1998): 3368–74. http://dx.doi.org/10.1128/jb.180.13.3368-3374.1998.

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ABSTRACT Sphingomonas herbicidovorans MH was able to completely degrade both enantiomers of the chiral herbicide dichlorprop [(RS)-2-(2,4-dichlorophenoxy)propanoic acid], with preferential degradation of the (S) enantiomer over the (R) enantiomer. These results are in agreement with the recently reported enantioselective degradation of mecoprop [(RS)-2-(4-chloro-2-methylphenoxy)propanoic acid] by this bacterium (C. Zipper, K. Nickel, W. Angst, and H.-P. E. Kohler, Appl. Environ. Microbiol. 62:4318–4322, 1996). Uptake of (R)-dichlorprop, (S)-dichlorprop, and 2,4-D (2,4-dichlorophenoxyacetic acid) was inducible. Initial uptake rates of cells grown on the respective substrate showed substrate saturation kinetics with apparent affinity constants (Kt ) of 108, 93, and 117 μM and maximal velocities (V max) of 19, 10, and 21 nmol min−1 mg of protein−1 for (R)-dichlorprop, (S)-dichlorprop, and 2,4-D, respectively. Transport of (R)-dichlorprop, (S)-dichlorprop, and 2,4-D was completely inhibited by various uncouplers and by nigericin but was only marginally inhibited by valinomycin and by the ATPase inhibitorN,N′-dicyclohexylcarbodiimine. Experiments on the substrate specificity of the putative transport systems revealed that (R)-dichlorprop uptake was inhibited by (R)-mecoprop but not by (S)-mecoprop, (S)-dichlorprop, or 2,4-D. On the other hand, the (S)-dichlorprop transport was inhibited by (S)-mecoprop but not by (R)-mecoprop, (R)-dichlorprop, or 2,4-D. These results provide evidence that the first step in the degradation of dichlorprop, mecoprop, and 2,4-D by S. herbicidovorans is active transport and that three inducible, proton gradient-driven uptake systems exist: one for (R)-dichlorprop and (R)-mecoprop, another for (S)-dichlorprop and (S)-mecoprop, and a third for 2,4-D.

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Journal articles on the topic 'Proteins Enantiomers'

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