Articles de revues : « S-Fatty acylation »

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Percher, Avital, Srinivasan Ramakrishnan, Emmanuelle Thinon, Xiaoqiu Yuan, Jacob S. Yount et Howard C. Hang. « Mass-tag labeling reveals site-specific and endogenous levels of protein S-fatty acylation ». Proceedings of the National Academy of Sciences 113, n^o 16 (4 avril 2016) : 4302–7. http://dx.doi.org/10.1073/pnas.1602244113.

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Fatty acylation of cysteine residues provides spatial and temporal control of protein function in cells and regulates important biological pathways in eukaryotes. Although recent methods have improved the detection and proteomic analysis of cysteine fatty (S-fatty) acylated proteins, understanding how specific sites and quantitative levels of this posttranslational modification modulate cellular pathways are still challenging. To analyze the endogenous levels of protein S-fatty acylation in cells, we developed a mass-tag labeling method based on hydroxylamine-sensitivity of thioesters and selective maleimide-modification of cysteines, termed acyl-PEG exchange (APE). We demonstrate that APE enables sensitive detection of protein S-acylation levels and is broadly applicable to different classes of S-palmitoylated membrane proteins. Using APE, we show that endogenous interferon-induced transmembrane protein 3 is S-fatty acylated on three cysteine residues and site-specific modification of highly conserved cysteines are crucial for the antiviral activity of this IFN-stimulated immune effector. APE therefore provides a general and sensitive method for analyzing the endogenous levels of protein S-fatty acylation and should facilitate quantitative studies of this regulated and dynamic lipid modification in biological systems.

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Kordyukova, Larisa V., Marina V. Serebryakova, Vladislav V. Khrustalev et Michael Veit. « Differential S-acylation of Enveloped Viruses ». Protein & ; Peptide Letters 26, n^o 8 (11 septembre 2019) : 588–600. http://dx.doi.org/10.2174/0929866526666190603082521.

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Post-translational modifications often regulate protein functioning. Covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage (known as protein palmitoylation or S-acylation) affects protein trafficking, protein-protein and protein-membrane interactions. This post-translational modification is coupled to membrane fusion or virus assembly and may affect viral replication in vitro and thus also virus pathogenesis in vivo. In this review we outline modern methods to study S-acylation of viral proteins and to characterize palmitoylproteomes of virus infected cells. The palmitoylation site predictor CSS-palm is critically tested against the Class I enveloped virus proteins. We further focus on identifying the S-acylation sites directly within acyl-peptides and the specific fatty acid (e.g, palmitate, stearate) bound to them using MALDI-TOF MS-based approaches. The fatty acid heterogeneity/ selectivity issue attracts now more attention since the recently published 3D-structures of two DHHC-acyl-transferases gave a hint how this might be achieved.

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Hemsley, Piers A. « S-acylation in plants : an expanding field ». Biochemical Society Transactions 48, n^o 2 (2 avril 2020) : 529–36. http://dx.doi.org/10.1042/bst20190703.

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S-acylation is a common yet poorly understood fatty acid-based post-translational modification of proteins in all eukaryotes, including plants. While exact roles for S-acylation in protein function are largely unknown the reversibility of S-acylation indicates that it is likely able to play a regulatory role. As more studies reveal the roles of S-acylation within the cell it is becoming apparent that how S-acylation affects proteins is conceptually different from other reversible modifications such as phosphorylation or ubiquitination; a new mind-set is therefore required to fully integrate these data into our knowledge of plant biology. This review aims to highlight recent advances made in the function and enzymology of S-acylation in plants, highlights current and emerging technologies for its study and suggests future avenues for investigation.

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Birner-Gruenberger, Ruth, et Rolf Breinbauer. « Tracking Protein S-Fatty Acylation with Proteomics ». ChemBioChem 17, n^o 16 (8 juillet 2016) : 1488–90. http://dx.doi.org/10.1002/cbic.201600314.

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Manhertz-Patterson, Rojae, et G. Ekin Atilla-Gokcumen. « S-acylation in apoptotic and non-apoptotic cell death : a central regulator of membrane dynamics and protein function ». Biochemical Society Transactions 53, n^o 02 (avril 2025) : 487–96. https://doi.org/10.1042/bst20253012.

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Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.

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Ticho, Alexander L., Pooja Malhotra, Christopher R. Manzella, Pradeep K. Dudeja, Seema Saksena, Ravinder K. Gill et Waddah A. Alrefai. « S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells ». Journal of Biological Chemistry 295, n^o 14 (18 février 2020) : 4488–97. http://dx.doi.org/10.1074/jbc.ra119.011032.

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The ileal apical sodium-dependent bile acid transporter (ASBT) is crucial for the enterohepatic circulation of bile acids. ASBT function is rapidly regulated by several posttranslational modifications. One reversible posttranslational modification is S-acylation, involving the covalent attachment of fatty acids to cysteine residues in proteins. However, whether S-acylation affects ASBT function and membrane expression has not been determined. Using the acyl resin-assisted capture method, we found that the majority of ASBT (∼80%) was S-acylated in ileal brush border membrane vesicles from human organ donors, as well as in HEK293 cells stably transfected with ASBT (2BT cells). Metabolic labeling with alkyne–palmitic acid (100 μm for 15 h) also showed that ASBT is S-acylated in 2BT cells. Incubation with the acyltransferase inhibitor 2-bromopalmitate (25 μm for 15 h) significantly reduced ASBT S-acylation, function, and levels on the plasma membrane. Treatment of 2BT cells with saturated palmitic acid (100 μm for 15 h) increased ASBT function, whereas treatment with unsaturated oleic acid significantly reduced ASBT function. Metabolic labeling with alkyne–oleic acid (100 μm for 15 h) revealed that oleic acid attaches to ASBT, suggesting that unsaturated fatty acids may decrease ASBT's function via a direct covalent interaction with ASBT. We also identified Cys-314 as a potential S-acylation site. In conclusion, these results provide evidence that S-acylation is involved in the modulation of ASBT function. These findings underscore the potential for unsaturated fatty acids to reduce ASBT function, which may be useful in disorders in which bile acid toxicity is implicated.

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Chen, Baoen, Jixiao Niu, Johannes Kreuzer, Baohui Zheng, Gopala K. Jarugumilli, Wilhelm Haas et Xu Wu. « Auto-fatty acylation of transcription factor RFX3 regulates ciliogenesis ». Proceedings of the National Academy of Sciences 115, n^o 36 (20 août 2018) : E8403—E8412. http://dx.doi.org/10.1073/pnas.1800949115.

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Defects in cilia have been associated with an expanding human disease spectrum known as ciliopathies. Regulatory Factor X 3 (RFX3) is one of the major transcription factors required for ciliogenesis and cilia functions. In addition, RFX3 regulates pancreatic islet cell differentiation and mature β-cell functions. However, how RFX3 protein is regulated at the posttranslational level remains poorly understood. Using chemical reporters of protein fatty acylation and mass spectrometry analysis, here we show that RFX3 transcriptional activity is regulated by S-fatty acylation at a highly conserved cysteine residue in the dimerization domain. Surprisingly, RFX3 undergoes enzyme-independent, “self-catalyzed” auto-fatty acylation and displays preferences for 18-carbon stearic acid and oleic acid. The fatty acylation-deficient mutant of RFX3 shows decreased homodimerization; fails to promote ciliary gene expression, ciliogenesis, and elongation; and impairs Hedgehog signaling. Our findings reveal a regulation of RFX3 transcription factor and link fatty acid metabolism and protein lipidation to the regulation of ciliogenesis.

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Lemonidis, Kimon, Oforiwa A. Gorleku, Maria C. Sanchez-Perez, Christopher Grefen et Luke H. Chamberlain. « The Golgi S-acylation machinery comprises zDHHC enzymes with major differences in substrate affinity and S-acylation activity ». Molecular Biology of the Cell 25, n^o 24 (décembre 2014) : 3870–83. http://dx.doi.org/10.1091/mbc.e14-06-1169.

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S-acylation, the attachment of fatty acids onto cysteine residues, regulates protein trafficking and function and is mediated by a family of zDHHC enzymes. The S-acylation of peripheral membrane proteins has been proposed to occur at the Golgi, catalyzed by an S-acylation machinery that displays little substrate specificity. To advance understanding of how S-acylation of peripheral membrane proteins is handled by Golgi zDHHC enzymes, we investigated interactions between a subset of four Golgi zDHHC enzymes and two S-acylated proteins—synaptosomal-associated protein 25 (SNAP25) and cysteine-string protein (CSP). Our results uncover major differences in substrate recognition and S-acylation by these zDHHC enzymes. The ankyrin-repeat domains of zDHHC17 and zDHHC13 mediated strong and selective interactions with SNAP25/CSP, whereas binding of zDHHC3 and zDHHC7 to these proteins was barely detectable. Despite this, zDHHC3/zDHHC7 could S-acylate SNAP25/CSP more efficiently than zDHHC17, whereas zDHHC13 lacked S-acylation activity toward these proteins. Overall the results of this study support a model in which dynamic intracellular localization of peripheral membrane proteins is achieved by highly selective recruitment by a subset of zDHHC enzymes at the Golgi, combined with highly efficient S-acylation by other Golgi zDHHC enzymes.

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Shipston, Michael J. « Ion channel regulation by protein S-acylation ». Journal of General Physiology 143, n^o 6 (12 mai 2014) : 659–78. http://dx.doi.org/10.1085/jgp.201411176.

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Protein S-acylation, the reversible covalent fatty-acid modification of cysteine residues, has emerged as a dynamic posttranslational modification (PTM) that controls the diversity, life cycle, and physiological function of numerous ligand- and voltage-gated ion channels. S-acylation is enzymatically mediated by a diverse family of acyltransferases (zDHHCs) and is reversed by acylthioesterases. However, for most ion channels, the dynamics and subcellular localization at which S-acylation and deacylation cycles occur are not known. S-acylation can control the two fundamental determinants of ion channel function: (1) the number of channels resident in a membrane and (2) the activity of the channel at the membrane. It controls the former by regulating channel trafficking and the latter by controlling channel kinetics and modulation by other PTMs. Ion channel function may be modulated by S-acylation of both pore-forming and regulatory subunits as well as through control of adapter, signaling, and scaffolding proteins in ion channel complexes. Importantly, cross-talk of S-acylation with other PTMs of both cysteine residues by themselves and neighboring sites of phosphorylation is an emerging concept in the control of ion channel physiology. In this review, I discuss the fundamentals of protein S-acylation and the tools available to investigate ion channel S-acylation. The mechanisms and role of S-acylation in controlling diverse stages of the ion channel life cycle and its effect on ion channel function are highlighted. Finally, I discuss future goals and challenges for the field to understand both the mechanistic basis for S-acylation control of ion channels and the functional consequence and implications for understanding the physiological function of ion channel S-acylation in health and disease.

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Li, Yumeng, Shushu Wang, Yanchi Chen, Manjia Li, Xiaoshu Dong, Howard C. Hang et Tao Peng. « Site-specific chemical fatty-acylation for gain-of-function analysis of protein S-palmitoylation in live cells ». Chemical Communications 56, n^o 89 (2020) : 13880–83. http://dx.doi.org/10.1039/d0cc06073a.

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Zhang, Lian, Karyn Foster, Qiuju Li et Jeffrey R. Martens. « S-acylation regulates Kv1.5 channel surface expression ». American Journal of Physiology-Cell Physiology 293, n^o 1 (juillet 2007) : C152—C161. http://dx.doi.org/10.1152/ajpcell.00480.2006.

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The number of ion channels expressed on the cell surface shapes the complex electrical response of excitable cells. An imbalance in the ratio of inward and outward conducting channels is unfavorable and often detrimental. For example, over- or underexpression of voltage-gated K+ (Kv) channels can be cytotoxic and in some cases lead to disease. In this study, we demonstrated a novel role for S-acylation in Kv1.5 cell surface expression. In transfected fibroblasts, biochemical evidence showed that Kv1.5 is posttranslationally modified on both the NH2 and COOH termini via hydroxylamine-sensitive thioester bonds. Pharmacological inhibition of S-acylation, but not myristoylation, significantly decreased Kv1.5 expression and resulted in accumulation of channel protein in intracellular compartments and targeting for degradation. Channel protein degradation was rescued by treatment with proteasome inhibitors. Time course experiments revealed that S-acylation occurred in the biosynthetic pathway of nascent channel protein and showed that newly synthesized Kv1.5 protein, but not protein expressed on the cell surface, is sensitive to inhibitors of thioacylation. Sensitivity to inhibitors of S-acylation was governed by COOH-terminal, but not NH2-terminal, cysteines. Surprisingly, although intracellular cysteines were required for S-acylation, mutation of these residues resulted in an increase in Kv1.5 cell surface channel expression, suggesting that screening of free cysteines by fatty acylation is an important regulatory step in the quality control pathway. Together, these results show that S-acylation can regulate steady-state expression of Kv1.5.

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Rana, Mitra S., Chul-Jin Lee et Anirban Banerjee. « The molecular mechanism of DHHC protein acyltransferases ». Biochemical Society Transactions 47, n^o 1 (17 décembre 2018) : 157–67. http://dx.doi.org/10.1042/bst20180429.

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Abstract Protein S-acylation is a reversible lipidic posttranslational modification where a fatty acid chain is covalently linked to cysteine residues by a thioester linkage. A family of integral membrane enzymes known as DHHC protein acyltransferases (DHHC-PATs) catalyze this reaction. With the rapid development of the techniques used for identifying lipidated proteins, the repertoire of S-acylated proteins continues to increase. This, in turn, highlights the important roles that S-acylation plays in human physiology and disease. Recently, the first molecular structures of DHHC-PATs were determined using X-ray crystallography. This review will comment on the insights gained on the molecular mechanism of S-acylation from these structures in combination with a wealth of biochemical data generated by researchers in the field.

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Wells, Carlos Montez, Emily Carol Coleman, Rabeta Yeasmin, Zoe Lynn Harrison, Mallesh Kurakula, Daniel L. Baker, Joel David Bumgardner, Tomoko Fujiwara et Jessica Amber Jennings. « Synthesis and Characterization of 2-Decenoic Acid Modified Chitosan for Infection Prevention and Tissue Engineering ». Marine Drugs 19, n^o 10 (29 septembre 2021) : 556. http://dx.doi.org/10.3390/md19100556.

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Chitosan nanofiber membranes are recognized as functional antimicrobial materials, as they can effectively provide a barrier that guides tissue growth and supports healing. Methods to stabilize nanofibers in aqueous solutions include acylation with fatty acids. Modification with fatty acids that also have antimicrobial and biofilm-resistant properties may be particularly beneficial in tissue regeneration applications. This study investigated the ability to customize the fatty acid attachment by acyl chlorides to include antimicrobial 2-decenoic acid. Synthesis of 2-decenoyl chloride was followed by acylation of electrospun chitosan membranes in pyridine. Physicochemical properties were characterized through scanning electron microscopy, FTIR, contact angle, and thermogravimetric analysis. The ability of membranes to resist biofilm formation by S. aureus and P. aeruginosa was evaluated by direct inoculation. Cytocompatibility was evaluated by adding membranes to cultures of NIH3T3 fibroblast cells. Acylation with chlorides stabilized nanofibers in aqueous media without significant swelling of fibers and increased hydrophobicity of the membranes. Acyl-modified membranes reduced both S. aureus and P.aeruginosa bacterial biofilm formation on membrane while also supporting fibroblast growth. Acylated chitosan membranes may be useful as wound dressings, guided regeneration scaffolds, local drug delivery, or filtration.

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Salaun, Christine, Carolina Locatelli, Filip Zmuda, Juan Cabrera González et Luke H. Chamberlain. « Accessory proteins of the zDHHC family of S-acylation enzymes ». Journal of Cell Science 133, n^o 22 (15 novembre 2020) : jcs251819. http://dx.doi.org/10.1242/jcs.251819.

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ABSTRACTAlmost two decades have passed since seminal work in Saccharomyces cerevisiae identified zinc finger DHHC domain-containing (zDHHC) enzymes as S-acyltransferases. These enzymes are ubiquitous in the eukarya domain, with 23 distinct zDHHC-encoding genes in the human genome. zDHHC enzymes mediate the bulk of S-acylation (also known as palmitoylation) reactions in cells, transferring acyl chains to cysteine thiolates, and in so-doing affecting the stability, localisation and function of several thousand proteins. Studies using purified components have shown that the minimal requirements for S-acylation are an appropriate zDHHC enzyme–substrate pair and fatty acyl-CoA. However, additional proteins including GCP16 (also known as Golga7), Golga7b, huntingtin and selenoprotein K, have been suggested to regulate the activity, stability and trafficking of certain zDHHC enzymes. In this Review, we discuss the role of these accessory proteins as essential components of the cellular S-acylation system.

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Garst, Emma H., Tandrila Das et Howard C. Hang. « Chemical approaches for investigating site-specific protein S-fatty acylation ». Current Opinion in Chemical Biology 65 (décembre 2021) : 109–17. http://dx.doi.org/10.1016/j.cbpa.2021.06.004.

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Gu, Si, Xinghua Nie, Amal George, Kyle Tyler, Yu Xing, Ling Qin et Baoxiu Qi. « Bioinformatics and Expression Profiling of the DHHC-CRD S-Acyltransferases Reveal Their Roles in Growth and Stress Response in Woodland Strawberry (Fragaria vesca) ». Plants 14, n^o 1 (4 janvier 2025) : 127. https://doi.org/10.3390/plants14010127.

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Protein S-acyl transferases (PATs) are a family of enzymes that catalyze protein S-acylation, a post-translational lipid modification involved in protein membrane targeting, trafficking, stability, and protein–protein interaction. S-acylation plays important roles in plant growth, development, and stress responses. Here, we report the genome-wide analysis of the PAT family genes in the woodland strawberry (Fragaria vesca), a model plant for studying the economically important Rosaceae family. In total, 21 ‘Asp-His-His-Cys’ Cys Rich Domain (DHHC-CRD)-containing sequences were identified, named here as FvPAT1-21. Expression profiling by reverse transcription quantitative PCR (RT-qPCR) showed that all the 21 FvPATs were expressed ubiquitously in seedlings and different tissues from adult plants, with notably high levels present in vegetative tissues and young fruits. Treating seedlings with hormones indole-3-acetic acid (IAA), abscisic acid (ABA), and salicylic acid (SA) rapidly increased the transcription of most FvPATs. A complementation assay in yeast PAT mutant akr1 and auto-S-acylation assay of one FvPAT (FvPAT19) confirmed its enzyme activity where the Cys in the DHHC motif was required. An AlphaFold prediction of the DHHC and the mutated DHHC155S of FvPAT19 provided further proof of the importance of C155 in fatty acid binding. Together, our data clearly demonstrated that S-acylation catalyzed by FvPATs plays important roles in growth, development, and stress signaling in strawberries. These preliminary results could contribute to further research to understand S-acylation in strawberries and plants in general.

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Baker, R. Roy, et H. Y. Chang. « The acylation of 1-acyl-sn-glycero-3-phosphate by neuronal nuclei and microsomal fractions of immature rabbit cerebral cortex ». Biochemistry and Cell Biology 68, n^o 3 (1 mars 1990) : 641–47. http://dx.doi.org/10.1139/o90-091.

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The acylation of 1-acyl-sn-glycero-3-phosphate to form phosphatidic acid was studied using a neuronal nuclear fraction N1 and microsomal fractions P3, R (rough), S (smooth), and P (neuronal microsomes from nerve cell bodies) isolated from cerebral cortices of 15-day-old rabbits. The assays contained this lysophospholipid, ATP, CoA, MgCl2, NaF, dithiothreitol, and radioactive palmitate, oleate, or arachidonate. Of the subfractions, N1 and R had the highest specific activities (expressed per micromole phospholipid in the fraction). The rates with oleate were two to four times the values seen for phosphatidic acid formation from sn-[3H]glycero-3-phosphate and oleoyl-CoA. Using oleate or palmitate, fraction R had superior specific rates to N1 at low lysophosphatidic acid concentrations. With increasing lysophospholipid concentrations the specific rates of N1 and R came closer together and maintained at least a twofold superiority over fraction P. Fraction S had the lowest specific rates of phosphatidic acid formation. Fractions N1, R, and P showed a preference for palmitate and oleate over arachidonate, particularly at low concentrations of lysophosphatidic acid. For N1 and R, the preference was also more marked at higher concentrations of fatty acid. Thus a selectivity for saturated and monounsaturated fatty acids was shown in the formation of phosphatidic acid, as was a concentration of acylating activity in the neuronal nucleus and the rough endoplasmic reticulum.Key words: 1-acyl-sn-glycero-3-phosphate, acylation, neuronal nuclei, microsomes, cerebral cortex.

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Zmuda, Filip, et Luke H. Chamberlain. « Regulatory effects of post-translational modifications on zDHHC S-acyltransferases ». Journal of Biological Chemistry 295, n^o 43 (17 août 2020) : 14640–52. http://dx.doi.org/10.1074/jbc.rev120.014717.

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The human zDHHC S-acyltransferase family comprises 23 enzymes that mediate the S-acylation of a multitude of cellular proteins, including channels, receptors, transporters, signaling molecules, scaffolds, and chaperones. This reversible post-transitional modification (PTM) involves the attachment of a fatty acyl chain, usually derived from palmitoyl-CoA, to specific cysteine residues on target proteins, which affects their stability, localization, and function. These outcomes are essential to control many processes, including synaptic transmission and plasticity, cell growth and differentiation, and infectivity of viruses and other pathogens. Given the physiological importance of S-acylation, it is unsurprising that perturbations in this process, including mutations in ZDHHC genes, have been linked to different neurological pathologies and cancers, and there is growing interest in zDHHC enzymes as novel drug targets. Although zDHHC enzymes control a diverse array of cellular processes and are associated with major disorders, our understanding of these enzymes is surprisingly incomplete, particularly with regard to the regulatory mechanisms controlling these enzymes. However, there is growing evidence highlighting the role of different PTMs in this process. In this review, we discuss how PTMs, including phosphorylation, S-acylation, and ubiquitination, affect the stability, localization, and function of zDHHC enzymes and speculate on possible effects of PTMs that have emerged from larger screening studies. Developing a better understanding of the regulatory effects of PTMs on zDHHC enzymes will provide new insight into the intracellular dynamics of S-acylation and may also highlight novel approaches to modulate S-acylation for clinical gain.

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FRANZOT, Sarah P., et Tamara L. DOERING. « Inositol acylation of glycosylphosphatidylinositols in the pathogenic fungus Cryptococcus neoformansz and the model yeast Saccharomyces cerevisiae ». Biochemical Journal 340, n^o 1 (10 mai 1999) : 25–32. http://dx.doi.org/10.1042/bj3400025.

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Cryptococcus neoformans, an opportunistic fungus responsible for life-threatening infection in immunocompromised patients, is able to synthesize glycosylphosphatidylinositol (GPI) structures. Radiolabelling experiments in vitro with the use of a cryptococcal cell-free system showed that the pathway begins as in other eukaryotes, with the addition of N-acetylglucosamine to phosphatidylinositol, followed by deacetylation of the sugar residue. The third step, acylation of the inositol ring, seemed to involve a fatty acid other than palmitate, in contrast with previous findings in Saccharomyces cerevisiae and mammalian GPI pathways. A systematic study of inositol acylation in C. neoformans and S. cerevisiae showed that both organisms used a variety of fatty acids in this step; these were transferred directly from acyl-CoA to inositol without modification. However, the specificity of fatty acid utilization was quite distinct in the two fungi, with the pathogen being substantially more restrictive. In mammalian cells fatty acids added exogenously as acyl-CoAs are not transferred directly to inositol. These results suggest significant differences in the GPI biosynthetic pathway between mammalian and C. neoformans cells that could represent targets for anti-cryptococcal therapy.

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Greaves, Jennifer, Kevin R. Munro, Stuart C. Davidson, Matthieu Riviere, Justyna Wojno, Terry K. Smith, Nicholas C. O. Tomkinson et Luke H. Chamberlain. « Molecular basis of fatty acid selectivity in the zDHHC family of S-acyltransferases revealed by click chemistry ». Proceedings of the National Academy of Sciences 114, n^o 8 (6 février 2017) : E1365—E1374. http://dx.doi.org/10.1073/pnas.1612254114.

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S-acylation is a major posttranslational modification, catalyzed by the zinc finger DHHC domain containing (zDHHC) enzyme family. S-acylated proteins can be modified by different fatty acids; however, very little is known about how zDHHC enzymes contribute to acyl chain heterogeneity. Here, we used fatty acid-azide/alkyne labeling of mammalian cells, showing their transformation into acyl-CoAs and subsequent click chemistry-based detection, to demonstrate that zDHHC enzymes have marked differences in their fatty acid selectivity. This difference in selectivity was apparent even for highly related enzymes, such as zDHHC3 and zDHHC7, which displayed a marked difference in their ability to use C18:0 acyl-CoA as a substrate. Furthermore, we identified isoleucine-182 in transmembrane domain 3 of zDHHC3 as a key determinant in limiting the use of longer chain acyl-CoAs by this enzyme. This study uncovered differences in the fatty acid selectivity profiles of cellular zDHHC enzymes and mapped molecular determinants governing this selectivity.

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Panina, Irina, Nikolay Krylov, Mohamed Rasheed Gadalla, Elena Aliper, Larisa Kordyukova, Michael Veit, Anton Chugunov et Roman Efremov. « Molecular Dynamics of DHHC20 Acyltransferase Suggests Principles of Lipid and Protein Substrate Selectivity ». International Journal of Molecular Sciences 23, n^o 9 (3 mai 2022) : 5091. http://dx.doi.org/10.3390/ijms23095091.

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Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two steps: the autoacylation is followed by the acyl chain transfer onto protein substrates. The crystal structure of human DHHC20 (hDHHC20), an enzyme involved in the acylation of S-protein of SARS-CoV-2, revealed that the acyl chain may be inserted into a hydrophobic cavity formed by four transmembrane (TM) α-helices. To test this model, we used molecular dynamics of membrane-embedded hDHHC20 and its mutants either in the absence or presence of various acyl-CoAs. We found that among a range of acyl chain lengths probed only C16 adopts a conformation suitable for hDHHC20 autoacylation. This specificity is altered if the small or bulky residues at the cavity’s ceiling are exchanged, e.g., the V185G mutant obtains strong preferences for binding C18. Surprisingly, an unusual hydrophilic ridge was found in TM helix 4 of hDHHC20, and the responsive hydrophilic patch supposedly involved in association was found in the 3D model of the S-protein TM-domain trimer. Finally, the exchange of critical Thr and Ser residues in the spike led to a significant decrease in its S-acylation. Our data allow further development of peptide/lipid-based inhibitors of hDHHC20 that might impede replication of Corona- and other enveloped viruses.

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Guertin, Denise, Lucie Grisé-Miron et Denis Riendeau. « Identification of a 51-kilodalton polypeptide fatty acyl chain acceptor in soluble extracts from mouse cardiac tissue ». Biochemistry and Cell Biology 64, n^o 12 (1 décembre 1986) : 1249–55. http://dx.doi.org/10.1139/o86-164.

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We have identified a protein in the soluble fraction from mouse cardiac tissue extracts which is rapidly and selectively acylated by myristyl CoA. This protein was partially purified by anion-exchange chromatography and gel filtration, and the acylation reaction was measured using [3H]myristyl CoA as substrate, followed by sodium dodecyl sulfate – polyacrylamide gel electrophoresis to resolve [3H]fatty acyl polypeptides. The [3H]acyl protein migrated as heterogenous bands corresponding to relative masses (Mrs) of 42 000–51 000 under nonreducing conditions or as a single polypeptide of Mr 51 000 in the presence of reducing agents. Fatty acyl chain incorporation into protein was very rapid and already maximum after 30 s of incubation, whereas no acylation was detected using heat-denatured samples or when the reaction was stopped immediately after initiation. Only the acyl CoA served as fatty acyl chain donor. No incorporation into protein occurred when myristyl CoA was substituted by myristic acid, ATP, and CoA. A time-dependent reduction in the level of [3H]fatty acyl polypeptide was observed upon addition of excess unlabeled myristyl CoA, indicating the ability of the labeled acyl moiety of the protein to turn over during incubation. The saturated C10:0, C14:0, and C16:0 acyl CoAs were more effective to chase the label from the [3H]acyl polypeptide than the C18:0 and C18:1 acyl CoAs. These results provide evidence for a 51-kilodalton polypeptide which serves as an acceptor for fatty acyl chains and could represent an important intermediate in fatty acyl chain transfer reactions in cardiac tissue.

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van't Hof, Wouter, et Ronald G. Crystal. « Fatty Acid Modification of the Coxsackievirus and Adenovirus Receptor ». Journal of Virology 76, n^o 12 (15 juin 2002) : 6382–86. http://dx.doi.org/10.1128/jvi.76.12.6382-6386.2002.

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ABSTRACT Membrane-proximal cysteines 259 and 260 in the cytoplasmic tail of the coxsackievirus and adenovirus receptor (CAR) are known to be essential for the tumor suppression activity of CAR. We demonstrate that these residues provide an S-acylation motif for modification of CAR with the fatty acid palmitate. Substitution of alanine for cysteines 259 and 260 results in the additional localization of CAR in perinuclear compartments with no effect on the efficiency of adenovirus infection. The results indicate that palmitylation is important for stable plasma membrane expression and biological activity of CAR but is not critical for adenovirus receptor performance.

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Thorp, Edward B., Joseph A. Boscarino, Hillary L. Logan, Jeffrey T. Goletz et Thomas M. Gallagher. « Palmitoylations on Murine Coronavirus Spike Proteins Are Essential for Virion Assembly and Infectivity ». Journal of Virology 80, n^o 3 (1 février 2006) : 1280–89. http://dx.doi.org/10.1128/jvi.80.3.1280-1289.2006.

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ABSTRACT Coronavirus spike (S) proteins are palmitoylated at several cysteine residues clustered near their transmembrane-spanning domains. This is achieved by cellular palmitoyl acyltransferases (PATs), which can modify newly synthesized S proteins before they are assembled into virion envelopes at the intermediate compartment of the exocytic pathway. To address the importance of these fatty acylations to coronavirus infection, we exposed infected cells to 2-bromopalmitate (2-BP), a specific PAT inhibitor. 2-BP profoundly reduced the specific infectivities of murine coronaviruses at very low, nontoxic doses that were inert to alphavirus and rhabdovirus infections. 2-BP effected only two- to fivefold reductions in S palmitoylation, yet this correlated with reduced S complexing with virion membrane (M) proteins and consequent exclusion of S from virions. At defined 2-BP doses, underpalmitoylated S proteins instead trafficked to infected cell surfaces and elicited cell-cell membrane fusions, suggesting that the acyl chain adducts are more critical to virion assembly than to S-induced syncytial developments. These studies involving pharmacologic inhibition of S protein palmitoylation were complemented with molecular genetic analyses in which cysteine acylation substrates were mutated. Notably, some mutations (C1347F and C1348S) did not interfere with S incorporation into virions, indicating that only a subset of the cysteine-rich region provides the essential S-assembly functions. However, the C1347F/C1348S mutant viruses exhibited relatively low specific infectivities, similar to virions secreted from 2-BP-treated cultures. Our collective results indicate that the palmitate adducts on coronavirus S proteins are necessary in assembly and also in positioning the assembled envelope proteins for maximal infectivity.

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Schneiter, Roger, Cesar E. Guerra, Manfred Lampl, Verena Tatzer, Günther Zellnig, Hannah L. Klein et Sepp D. Kohlwein. « A Novel Cold-Sensitive Allele of the Rate-Limiting Enzyme of Fatty Acid Synthesis, Acetyl Coenzyme A Carboxylase, Affects the Morphology of the Yeast Vacuole through Acylation of Vac8p ». Molecular and Cellular Biology 20, n^o 9 (1 mai 2000) : 2984–95. http://dx.doi.org/10.1128/mcb.20.9.2984-2995.2000.

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ABSTRACT The yeast vacuole functions both as a degradative organelle and as a storage depot for small molecules and ions. Vacuoles are dynamic reticular structures that appear to alternately fuse and fragment as a function of growth stage and environment. Vac8p, an armadillo repeat-containing protein, has previously been shown to function both in vacuolar inheritance and in protein targeting from the cytoplasm to the vacuole. Both myristoylation and palmitoylation of Vac8p are required for its efficient localization to the vacuolar membrane (Y.-X. Wang, N. L. Catlett, and L. S. Weisman, J. Cell Biol. 140:1063–1074, 1998). We report that mutants with conditional defects in the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase (ACC1), display unusually multilobed vacuoles, similar to those observed in vac8 mutant cells. This vacuolar phenotype of acc1 mutant cells was shown biochemically to be accompanied by a reduced acylation of Vac8p which was alleviated by fatty acid supplementation. Consistent with the proposed defect of acc1 mutant cells in acylation of Vac8p, vacuolar membrane localization of Vac8p was impaired upon shiftingacc1 mutant cells to nonpermissive condition. The function of Vac8p in protein targeting, on the other hand, was not affected under these conditions. These observations link fatty acid synthesis and availability to direct morphological alterations of an organellar membrane.

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Kwiterovich, Peter O., Mahnaz Motevalli, Michae Miller, Paul S. Bachorik, Stephanie D. Kafonek, Subroto Chatterjee, Tern Beaty et Donna Virgil. « Further insights into the pathophysiology of hyperapobetalipoproteinemia : role of basic proteins I, II, III ». Clinical Chemistry 37, n^o 3 (1 mars 1991) : 317–26. http://dx.doi.org/10.1093/clinchem/37.3.317.

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Abstract Hyperapobetalipoproteinemia (hyperapoB), a familial lipoprotein disorder characterized by an increase in small, dense, low-density lipoprotein (LDL) particles, is strongly associated with coronary artery disease. There are two metabolic defects in hyperapoB: an increased synthesis of a very-low-density lipoprotein in liver, resulting in an overproduction of LDL, and a delayed clearance of post-prandial triglyceride and free fatty acids. To date, defects in the apolipoprotein B gene do not appear to explain the hyperapoB phenotype. Defect(s) in the uptake or intracellular metabolism of free fatty acids have been found in cells from hyperapoB patients. Three basic proteins (BPs)--BP I (Mr 14,000, pI 9.10), BP II (Mr 27,500, pI 8.48), and BP III (Mr 55,000, pI 8.73)--were isolated from normal human serum. Compared with normal fibroblasts, cultured hyperapoB fibroblasts incubated with BP I, which appears to be the same protein as acylation-stimulating protein (ASP), showed 50% less stimulation of triglyceride acylation and cholesterol esterification, whereas BP II markedly stimulated cholesteryl ester formation, and BP III caused no difference in response vs normal fibroblasts. However, in cultured normal human monocyte macrophages, BP III, but not BP I or BP II, stimulated cholesteryl esterification two- to threefold. BP I, BP II, and BP III may provide new insights into normal metabolism of lipids, lipoproteins, and free fatty acids and the pathophysiology of hyperapoB.

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Hurst, C. H., et P. A. Hemsley. « Current perspective on protein S-acylation in plants : more than just a fatty anchor ? » Journal of Experimental Botany 66, n^o 6 (27 février 2015) : 1599–606. http://dx.doi.org/10.1093/jxb/erv053.

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Shimohigashi, Yasuyuki, Shin Ono, Hiroshi Sakamoto, Haruko Yoshitomi, Michinori Waki et Motonori Ohno. « Inactivation of Gramicidin S by Acylation of Two Ornithine Residues with Higher Fatty Acids ». Chemistry Letters 22, n^o 4 (avril 1993) : 671–72. http://dx.doi.org/10.1246/cl.1993.671.

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Fraser, Niall J., Jacqueline Howie, Krzysztof J. Wypijewski et William Fuller. « Therapeutic targeting of protein S-acylation for the treatment of disease ». Biochemical Society Transactions 48, n^o 1 (24 décembre 2019) : 281–90. http://dx.doi.org/10.1042/bst20190707.

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The post-translational modification protein S-acylation (commonly known as palmitoylation) plays a critical role in regulating a wide range of biological processes including cell growth, cardiac contractility, synaptic plasticity, endocytosis, vesicle trafficking, membrane transport and biased-receptor signalling. As a consequence, zDHHC-protein acyl transferases (zDHHC-PATs), enzymes that catalyse the addition of fatty acid groups to specific cysteine residues on target proteins, and acyl proteins thioesterases, proteins that hydrolyse thioester linkages, are important pharmaceutical targets. At present, no therapeutic drugs have been developed that act by changing the palmitoylation status of specific target proteins. Here, we consider the role that palmitoylation plays in the development of diseases such as cancer and detail possible strategies for selectively manipulating the palmitoylation status of specific target proteins, a necessary first step towards developing clinically useful molecules for the treatment of disease.

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Malhotra, Pooja, Nathan Calzadilla, Shane Comiskey, Seema Saksena, Pradeep K. Dudeja, Ravinder K. Gill et Waddah A. Alrefai. « Sa1679 : NOVEL EVIDENCE FOR S-ACYLATION OF NPC1L1 TO FATTY ACIDS IN INTESTINAL EPITHELIAL CELLS ». Gastroenterology 162, n^o 7 (mai 2022) : S—462. http://dx.doi.org/10.1016/s0016-5085(22)61100-4.

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Veit, Michael, et Stefanie Siche. « S-acylation of influenza virus proteins : Are enzymes for fatty acid attachment promising drug targets ? » Vaccine 33, n^o 49 (décembre 2015) : 7002–7. http://dx.doi.org/10.1016/j.vaccine.2015.08.095.

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Dong, Linjie, Jianjian Li, Lun Li, Tingting Li et Hongying Zhong. « Comparative analysis of S-fatty acylation of gel-separated proteins by stable isotope–coded fatty acid transmethylation and mass spectrometry ». Nature Protocols 6, n^o 9 (18 août 2011) : 1377–90. http://dx.doi.org/10.1038/nprot.2011.358.

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Zhang, Minze, Xiaoliang Han, Klaus Osterrieder et Michael Veit. « Palmitoylation of the envelope membrane proteins GP5 and M of porcine reproductive and respiratory syndrome virus is essential for virus growth ». PLOS Pathogens 17, n^o 4 (23 avril 2021) : e1009554. http://dx.doi.org/10.1371/journal.ppat.1009554.

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Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped positive-strand RNA virus in the Arteiviridae family, is a major pathogen affecting pigs worldwide. The membrane (glyco)proteins GP5 and M form a disulfide-linked dimer, which is a major component of virions. GP5/M are required for virus budding, which occurs at membranes of the exocytic pathway. Both GP5 and M feature a short ectodomain, three transmembrane regions, and a long cytoplasmic tail, which contains three and two conserved cysteines, respectively, in close proximity to the transmembrane span. We report here that GP5 and M of PRRSV-1 and -2 strains are palmitoylated at the cysteines, regardless of whether the proteins are expressed individually or in PRRSV-infected cells. To completely prevent S-acylation, all cysteines in GP5 and M have to be exchanged. If individual cysteines in GP5 or M were substituted, palmitoylation was reduced, and some cysteines proved more important for efficient palmitoylation than others. Neither infectious virus nor genome-containing particles could be rescued if all three cysteines present in GP5 or both present in M were replaced in a PRRSV-2 strain, indicating that acylation is essential for virus growth. Viruses lacking one or two acylation sites in M or GP5 could be rescued but grew to significantly lower titers. GP5 and M lacking acylation sites form dimers and GP5 acquires Endo-H resistant carbohydrates in the Golgi apparatus suggesting that trafficking of the membrane proteins to budding sites is not disturbed. Likewise, GP5 lacking two acylation sites is efficiently incorporated into virus particles and these viruses exhibit no reduction in cell entry. We speculate that multiple fatty acids attached to GP5 and M in the endoplasmic reticulum are required for clustering of GP5/M dimers at Golgi membranes and constitute an essential prerequisite for virus assembly.

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Mundy, D. I., et G. Warren. « Mitosis and inhibition of intracellular transport stimulate palmitoylation of a 62-kD protein. » Journal of Cell Biology 116, n^o 1 (1 janvier 1992) : 135–46. http://dx.doi.org/10.1083/jcb.116.1.135.

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Recent studies suggest that a cycle of acylation/deacylation is involved in the vesicular transport of proteins between intracellular compartments at both the budding and the fusion stage (Glick, B. S., and J. E. Rothman. 1987. Nature (Lond.). 326:309-312). Since a number of cellular processes requiring vesicular transport are inhibited during mitosis, we examined the fatty acylation of proteins in interphase and mitotic cells. We have identified a major palmitoylated protein with an apparent molecular weight of 62,000 (p62), whose level of acylation increases 5-10-fold during mitosis. Acylation was reversible and p62 was no longer palmitoylated in cells that have exited mitosis and entered G1. p62 is tightly bound to the cytoplasmic side of membranes, since it was sensitive to digestion with proteases in the absence of detergent and was not removed by treatment with 1 M KCl. p62 is removed from membranes by nonionic detergents or concentrations of urea greater than 4 M. The localization of p62 by subcellular fractionation is consistent with it being in the cis-Golgi or the cis-Golgi network. A palmitoylated protein of the same molecular weight was also observed in interphase cells treated with inhibitors of intracellular transport, such as brefeldin A, monensin, carbonylcyanide m-chlorophenylhydrazone, or aluminum fluoride. The protein palmitoylated in the presence of brefeldin A was shown to be the same as that palmitoylated during mitosis using partial proteolysis. Digestion with two enzymes, alkaline protease and endoprotease lys-C, generated the same 3H-palmitate-labeled peptide fragments from p62 from mitotic or brefeldin A-treated cells. We suggest that the acylation and deacylation of p62 may be important in vesicular transport and that this process may be regulated during mitosis.

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Brown, Robert W. B., Aabha I. Sharma, Miguel Rey Villanueva, Xiaomo Li, Ouma Onguka, Leeor Zilbermintz, Helen Nguyen et al. « Trypanosoma brucei Acyl-Protein Thioesterase-like (TbAPT-L) Is a Lipase with Esterase Activity for Short and Medium-Chain Fatty Acids but Has No Depalmitoylation Activity ». Pathogens 11, n^o 11 (27 octobre 2022) : 1245. http://dx.doi.org/10.3390/pathogens11111245.

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Dynamic post-translational modifications allow the rapid, specific, and tunable regulation of protein functions in eukaryotic cells. S-acylation is the only reversible lipid modification of proteins, in which a fatty acid, usually palmitate, is covalently attached to a cysteine residue of a protein by a zDHHC palmitoyl acyltransferase enzyme. Depalmitoylation is required for acylation homeostasis and is catalyzed by an enzyme from the alpha/beta hydrolase family of proteins usually acyl-protein thioesterase (APT1). The enzyme responsible for depalmitoylation in Trypanosoma brucei parasites is currently unknown. We demonstrate depalmitoylation activity in live bloodstream and procyclic form trypanosomes sensitive to dose-dependent inhibition with the depalmitoylation inhibitor, palmostatin B. We identified a homologue of human APT1 in Trypanosoma brucei which we named TbAPT-like (TbAPT-L). Epitope-tagging of TbAPT-L at N- and C- termini indicated a cytoplasmic localization. Knockdown or over-expression of TbAPT-L in bloodstream forms led to robust changes in TbAPT-L mRNA and protein expression but had no effect on parasite growth in vitro, or cellular depalmitoylation activity. Esterase activity in cell lysates was also unchanged when TbAPT-L was modulated. Unexpectedly, recombinant TbAPT-L possesses esterase activity with specificity for short- and medium-chain fatty acid substrates, leading to the conclusion, TbAPT-L is a lipase, not a depalmitoylase.

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Ramos-Vega, Ana Laura, Yadira Dávila-Martínez, Christian Sohlenkamp, Sandra Contreras-Martínez, Sergio Encarnación, Otto Geiger et Isabel M. López-Lara. « SMb20651 is another acyl carrier protein from Sinorhizobium meliloti ». Microbiology 155, n^o 1 (1 janvier 2009) : 257–67. http://dx.doi.org/10.1099/mic.0.022079-0.

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Acyl carrier proteins (ACPs) are small acidic proteins that carry growing acyl chains during fatty acid or polyketide synthesis. In rhizobia, there are four different and well-characterized ACPs: AcpP, NodF, AcpXL and RkpF. The genome sequence of Sinorhizobium meliloti 1021 reveals two additional ORFs that possibly encode additional ACPs. One of these, smb20651, is located on the plasmid pSymB as part of an operon. The genes of the operon encode a putative asparagine synthetase (AsnB), the predicted ACP (SMb20651), a putative long-chain fatty acyl-CoA ligase (SMb20650) and a putative ammonium-dependent NAD+ synthetase (NadE1). When SMb20651 was overexpressed in Escherichia coli, [3H]β-alanine, a biosynthetic building block of 4′-phosphopantetheine, was incorporated into the protein in vivo. The purified SMb20651 was modified with 4′-phosphopantetheine in the presence of S. meliloti holo-ACP synthase (AcpS). Also, holo-SMb20651 was modified in vitro with a malonyl group by malonyl CoA-ACP transacylase. In E. coli, coexpression of SMb20651 together with other proteins such as AcpS and SMb20650 led to the formation of additional forms of SMb20651. In this bacterium, acylation of SMb20651 with C12 : 0 or C18 : 0 fatty acids was detected, demonstrating that this protein is involved in fatty acid biosynthesis or transfer. Expression of SMb20651 was detected in S. meliloti as holo-SMb20651 and acyl-SMb20651.

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LOCKWOOD, Nathan A., Judith R. HASEMAN, Matthew V. TIRRELL et Kevin H. MAYO. « Acylation of SC4 dodecapeptide increases bactericidal potency against Gram-positive bacteria, including drug-resistant strains ». Biochemical Journal 378, n^o 1 (15 février 2004) : 93–103. http://dx.doi.org/10.1042/bj20031393.

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We have conjugated dodecyl and octadecyl fatty acids to the N-terminus of SC4, a potently bactericidal, helix-forming peptide 12-mer (KLFKRHLKWKII), and examined the bactericidal activities of the resultant SC4 ‘peptide-amphiphile’ molecules. SC4 peptide-amphiphiles showed up to a 30-fold increase in bactericidal activity against Gram-positive strains (Staphylococcus aureus, Streptococcus pyogenes and Bacillus anthracis), including S. aureus strains resistant to conventional antibiotics, but little or no increase in bactericidal activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Fatty acid conjugation improved endotoxin (lipopolysaccharide) neutralization by 3- to 6-fold. Although acylation somewhat increased lysis of human erythrocytes, it did not increase lysis of endothelial cells, and the haemolytic effects occurred at concentrations 10- to 100-fold higher than those required for bacterial cell lysis. For insight into the mechanism of action of SC4 peptide-amphiphiles, CD, NMR and fluorescence spectroscopy studies were performed in micelle and liposome models of eukaryotic and bacterial cell membranes. CD indicated that SC4 peptide-amphiphiles had the strongest helical tendencies in liposomes mimicking bacterial membranes, and strong membrane integration of the SC4 peptide-amphiphiles was observed using tryptophan fluorescence spectroscopy under these conditions; results that correlated with the increased bactericidal activities of SC4 peptide-amphiphiles. NMR structural analysis in micelles demonstrated that the two-thirds of the peptide closest to the fatty acid tail exhibited a helical conformation, with the positively-charged side of the amphipathic helix interacting more with the model membrane surface. These results indicate that conjugation of a fatty acid chain to the SC4 peptide enhances membrane interactions, stabilizes helical structure in the membrane-bound state and increases bactericidal potency.

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Fujiyama, A., S. Tsunasawa, F. Tamanoi et F. Sakiyama. « S-farnesylation and methyl esterification of C-terminal domain of yeast RAS2 protein prior to fatty acid acylation. » Journal of Biological Chemistry 266, n^o 27 (septembre 1991) : 17926–31. http://dx.doi.org/10.1016/s0021-9258(18)55216-9.

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Panina, Irina S., Nikolay A. Krylov, Anton O. Chugunov, Roman G. Efremov et Larisa V. Kordyukova. « The Mechanism of Selective Recognition of Lipid Substrate by hDHHC20 Enzyme ». International Journal of Molecular Sciences 23, n^o 23 (26 novembre 2022) : 14791. http://dx.doi.org/10.3390/ijms232314791.

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S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying an Asp-His-His-Cys catalytic motif) in two stages: (1) acyl-CoA-mediated autoacylation of the enzyme; and (2) further transfer of the acyl chain to a protein substrate. Despite the availability of a 3D-structure of human acyltransferase (hDHHC20), the molecular aspects of lipid selectivity of DHHC-acyltransferases remain unclear. In this paper, using molecular dynamics (MD) simulations, we studied membrane-bound hDHHC20 right before the acylation by C12-, C14-, C16-, C18-, and C20-CoA substrates. We found that: (1) regardless of the chain length, its terminal methyl group always reaches the “ceiling” of the enzyme’s cavity; (2) only for C16, an optimal “reactivity” (assessed by a simple geometric criterion) permits the autoacylation; (3) in MD, some key interactions between an acyl-CoA and a protein differ from those in the reference crystal structure of the C16-CoA-hDHHS20 mutant complex (probably, because this structure corresponds to a non-native dimer). These features of specific recognition of full-size acyl-CoA substrates support our previous hypothesis of “geometric and physicochemical selectivity” derived for simplified acyl-CoA analogues.

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Hopper, Shaun, et James Meador-Woodruff. « T181. PROTEIN ACYL-THIOESTERASE ENZYME ACTIVITY IN THE POSTMORTEM DORSOLATERAL PREFRONTAL CORTEX IN SCHIZOPHRENIA ». Schizophrenia Bulletin 46, Supplement_1 (avril 2020) : S300—S301. http://dx.doi.org/10.1093/schbul/sbaa029.741.

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Abstract Background The role protein trafficking and localization is a recent target of investigation in schizophrenia pathophysiology. An important mediator of protein trafficking is S-acylation, also known as S-palmitoylation, which is the reversible attachment of long chain fatty acids to cysteine residues. S-acylation is a dynamic post-translational modification that modulates hydrophobicity of proteins, regulating their membrane association and subcellular localization. Notably, we have previously reported a proteome-wide decrease in S-acylated protein levels in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. One potential mechanism of decreased S-acylation is increased removal of acyl groups from proteins by protein acyl-thioesterase enzymes (PATs). Here we describe the optimization of an assay to measure the activity of the PAT family of enzymes in human postmortem cortical tissue and use the assay to address our hypothesis that PAT activity is increased in the DLPFC of subjects with schizophrenia. Methods To determine PAT activity, tissue homogenate was incubated with 4-methylumbelliferyl-6-thio-palmitate-β-D-glucopyranoside (4MU-Gluc-Palm) and 1U of exogenous β-glucosidase (to hydrolyze the 4MU-Gluc reaction intermediary). Released 4MU was excited at 360 ± 40 nm and fluorescent emission was measured, per minute, at 460 ± 40 nm. To determine the relationship between initial reaction rate and amount of enzyme, the initial reaction rate using 300 µM 4MU-Gluc-Palm was measured in homogenate containing 1 – 10 µg of total protein from the DLPFC of a subject with no history of psychiatric illness. The PAT activity of DLPFC homogenate boiled for 30 min and total protein homogenate from lymphocytes were measured as negative and positive control reactions, respectively. To estimate the maximum reaction rate (Vmax) and the concentration of 4MU-Gluc-Palm which achieved ½ Vmax (Km; a measure of enzyme-substrate affinity) the initial reaction rate was calculated in the presence of 0 – 200 µM 4MU-Gluc-Palm and the Michaelis-Menten equation was fit to plots of concentration vs. initial rate. Reactions were performed on 2.5 µg total protein homogenate from the DLPFC of 24 subjects with schizophrenia and 24 non-psychiatrically ill subjects. Results A fluorescent signal, which increases with time to a plateau upon substrate depletion, is detectable in total protein homogenate from DLPFC and lymphocytes, but not boiled DLPFC homogenate. In the DLPFC the initial reaction rate is linear with total protein amount [r2 = .99; p = .007], demonstrating that the reaction is sensitive to varying amounts of enzyme in a 10-fold range. When compared between schizophrenia and control subjects, neither Vmax [t(46) = 0.756; p = .45] nor Km [t(46) = 0.780; p = .44] were statistically significantly different. Discussion Here we have demonstrated that PAT activity is measurable in human cortical tissue homogenate. Additionally, we have found no difference in the Vmax or Km of the combined PAT enzyme group in schizophrenia, providing no evidence to support our hypothesis that total PAT activity is increased in subjects with schizophrenia. This suggests that the proteome-wide decrease in S-acylated proteins in schizophrenia is caused by another mechanism, possibly increased expression or function of one or more of the specific PATs, leading to substrate specific changes in S-acylation, or a decrease in activity the acyl protein transferase enzymes, which attach acyl groups to proteins.

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L Wood, Paul, Aaron Phillipps, Randall L Woltjer, Jeffrey A Kaye et Joseph F Quinn. « Increased Lysophosphatidyleth-anolamine and Diacylglycerol levels in Alzheimer’s Disease Plasma ». JSM Alzheimer’s Disease and Related Dementia 1, n^o 1 (27 avril 2014) : 1–4. http://dx.doi.org/10.47739/2378-9565.alzheimersdisease.1001.

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Background: Previous studies have demonstrated deficits in biosynthesis of plasmalogens and sphingolipids in Alzheimer ’s Disease (AD). Objective: We undertook an analysis of alternate biomarkers of lipid synthesis, metabolism, and remodeling “Lands” cycle in the plasma of control and cognitively impaired patients based upon their Mini-Mental State Examination (MMSE) scores. Methods: Plasma levels of 600 lipids were measured utilizing a high-resolution mass spectrometric shotgun analysis platform. Results: The lyso metabolites of phosphatidylethanolamines and phosphatidylglycerols, along with diacyglycerols were all elevated in the plasma of patients with cognitive impairment.There were no significant differences in the plasma levels of fatty acids metabolized by peroxisomes. Conclusion: The increased levels of lysolipids and diacylglycerols in theplasma of all patient groups suggest that lipid remodeling is dysfunctional early in the AD disease process. It remains to be determined if this involves increased phospholipase A2 activity, decreased acyltransferase activity, or decreased cellular uptake of lysophospholipids for subsequent acylation.

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Fernandes, P. R., et M. J. Dewey. « Genetic control of erythrocyte volume regulation : effect of a single gene (rol) on cation metabolism ». American Journal of Physiology-Cell Physiology 267, n^o 1 (1 juillet 1994) : C211—C219. http://dx.doi.org/10.1152/ajpcell.1994.267.1.c211.

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In laboratory mice we previously defined a gene, rol (resistance to osmotic lysis), based on its effect on erythrocyte osmotic fragility. Here we report a physiological characterization of rol gene action utilizing congenic strains developed for the purpose; these two strains have a common genetic background and differ only by the two alleles of rol, susceptible (rols) or resistant (rolr). In comparison to rols/s erythrocytes, rolr/r cells have a reduced mean cell volume, a higher mean corpuscular hemoglobin concentration and hemolytic volume, and respond differently to swelling induced by ion influx. Rolr/r erythrocytes also have reduced cell water and K, which are associated with a threefold higher activity of the Na-K-Cl cotransporter (measured as ouabain-resistant, bumetanide-sensitive 86Rb influx) and 30% higher Na pump activity. Apart from differences in ion transport and water content, the content of 2,3-diphosphoglycerate (2,3-DPG) in rolr/r cells is 15% lower than in rols/s ones. Analyses of membrane structural components revealed no rol-associated differences in their phospholipid or fatty acid content, nor were strain differences evident among the membrane and cytoskeletal proteins and their posttranslational modifications (phosphorylation and fatty acylation). Rol is not the structural gene for either the alpha- or the beta-chain of hemoglobin and has no effect on erythrocyte production or destruction. The concerted effect of rol variation on erythrocyte volume, water and cation content, cation cotransport, and 2,3-DPG levels is similar in many ways to the variation observed among individual humans for the same characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

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Clements, Jenna, Changmin Peng, Thanh Tu Ho, Hening Lin et Edward Seto. « Abstract 2395 HDAC11's de-fatty acylation of SF3B2 could provide new understanding of RNA splicing regulation and Liver Cancer progression ». Journal of Biological Chemistry 300, n^o 3 (mars 2024) : 107087. http://dx.doi.org/10.1016/j.jbc.2024.107087.

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Katzman, Rebecca B., et Richard Longnecker. « LMP2A Does Not Require Palmitoylation To Localize to Buoyant Complexes or for Function ». Journal of Virology 78, n^o 20 (15 octobre 2004) : 10878–87. http://dx.doi.org/10.1128/jvi.78.20.10878-10887.2004.

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ABSTRACT Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is expressed constitutively in lipid rafts in latently infected B lymphocytes. Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids selective for specific protein association. Lipid rafts have been shown to be necessary for B-cell receptor (BCR) signal transduction. LMP2A prevents BCR recruitment to lipid rafts, thereby abrogating BCR function. As LMP2A is palmitoylated, whether this fatty acid modification is necessary for LMP2A to localize to lipid rafts and for protein function was investigated. LMP2A palmitoylation was confirmed in latently infected B cells. LMP2A was found to be palmitoylated on multiple cysteines only by S acylation. An LMP2A mutant that was not palmitoylated was identified and functioned similar to wild-type LMP2A; unmodified LMP2A localized to lipid rafts, was tyrosine phosphorylated, was associated with LMP2A-associated proteins, was ubiquitinated, and was able to block calcium mobilization following BCR cross-linking. Therefore, palmitoylation of LMP2A is not required for LMP2A targeting to buoyant complexes or for function.

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van Gastel, Nick, Nithya Balasundaram, Aysegül Erdem, Azeem Sharda, Veerle Daniels, Phillip Chea, Fleur Leguay et al. « 3004 – ACUTE MYELOID LEUKEMIA CELLS REQUIRE 18-CARBON LONG FATTY ACIDS FOR PROTEIN S-ACYLATION TO MAINTAIN MITOCHONDRIAL ACTIVITY AND METABOLIC PLASTICITY ». Experimental Hematology 137 (août 2024) : 104292. http://dx.doi.org/10.1016/j.exphem.2024.104292.

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Vaca-Garcia, C., et M. E. Borredon. « Solvent-free fatty acylation of cellulose and lignocellulosic wastes. Part 2 : reactions with fatty acids1The first paper of this series is : Thiebaud, S., Borredon, M.E., 1995. Solvent-free wood esterification with fatty acid chlorides. Bioresour. Technol., 52, 169–173.1 ». Bioresource Technology 70, n^o 2 (novembre 1999) : 135–42. http://dx.doi.org/10.1016/s0960-8524(99)00034-6.

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Faraj, May, et Katherine Cianflone. « Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP ». American Journal of Physiology-Endocrinology and Metabolism 287, n^o 1 (juillet 2004) : E150—E159. http://dx.doi.org/10.1152/ajpendo.00398.2003.

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Acylation-stimulating protein (ASP) is a lipogenic hormone secreted by white adipose tissue (WAT). Male C3 knockout (KO; C3−/−) ASP-deficient mice have delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The objective of this study was to examine the mechanism(s) by which ASP deficiency induces differences in postprandial TG clearance and body composition in male KO mice. Except for increased 3H-labeled nonesterified fatty acid (NEFA) trapping in brown adipose tissue (BAT) of KO mice ( P = 0.02), there were no intrinsic tissue differences between wild-type (WT) and KO mice in 3H-NEFA or [14C]glucose oxidation, TG synthesis or lipolysis in WAT, muscle, or liver. There were no differences in WAT or skeletal muscle hydrolysis, uptake, and storage of [3H]triolein substrate [in situ lipoprotein lipase (LPL) activity]. ASP, however, increased in situ LPL activity in WAT (+64.8%, P = 0.02) but decreased it in muscle (−35.0%, P = 0.0002). In addition, after prelabeling WAT with [3H]oleate and [14C]glucose, ASP increased 3H-lipid retention, [3H]TG synthesis, and [3H]TG-to-[14C]TG ratio, whereas it decreased 3H-NEFA release, indicating increased NEFA trapping in WAT. Conversely, in muscle, ASP induced effects opposite to those in WAT and increased lipolysis, indicating reduced NEFA trapping within muscle by ASP ( P < 0.05 for all parameters). In conclusion, novel data in this study suggest that 1) there is little intrinsic difference between KO and WT tissue in the parameters examined and 2) ASP differentially regulates in situ LPL activity and NEFA trapping in WAT and skeletal muscle, which may promote optimal insulin sensitivity in vivo.

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Dulęba, Jacek, Tomasz Siódmiak et Michał Piotr Marszałł. « Amano Lipase PS from Burkholderia cepacia- Evaluation of the Effect of Substrates and Reaction Media on the Catalytic Activity ». Current Organic Chemistry 24, n^o 7 (3 juin 2020) : 798–807. http://dx.doi.org/10.2174/1385272824666200408092305.

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: Lipases in the native or immobilized form have commonly been used as catalysts in the chemical and pharmaceutical industry. One of the widely available enzyme catalysts on the market is lipase from Burkholderia cepacia (BCLs), previously called Pseudomonas cepacia (PCLs). This enzyme is applied, among others, in the stereoselective acylation of molecules to achieve chiral pure enantiomers of drugs or their building blocks. In this study, Amano lipase PS (APS-BCL), which is a commercial lipase from Burkholderia cepacia (BC) was tested. The lipolytic activity of APS-BCL by hydrolysis of vegetable oils and enantioselective activity of APS-BCL by the kinetic resolution of (R,S)-1-phenylethanol with using isopropenyl acetate as an acyl donor were evaluated. An effect of reaction media with different logP values (t-butyl methyl ether, dichloromethane, diisopropyl ether, toluene, cyclohexane, n-hexane, isooctane and n-heptane) on the enantioselective activity of lipase was also studied. The high value of the enantiomeric ratio (E =308.5) with the utilization of isopropenyl acetate was achieved. Whereas, the best reaction medium turned out to be diisopropyl ether, C =47.9%, eep =98%, ees =90%, after 24 h of incubation. Moreover, the influence of ω6/ω9 polyunsaturated fatty acids (PUFAs) ratio in commercial (peanut, camelina, rape, pumpkin seed, walnut, sesame, avocado, rice, corn, black cumin, hemp, safflower, grape seed) oils was investigated for the lipase activity. For the first time, the cut-off limit of ω6/ω9 ratio was proposed. The ratio equal to or higher than 2.3 allows achieving higher lipolytic activity.

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Deng, Xile, Wenna Zheng, Qingcai Zhan, Yanan Deng, Yong Zhou et Lianyang Bai. « New Lead Discovery of Herbicide Safener for Metolachlor Based on a Scaffold-Hopping Strategy ». Molecules 25, n^o 21 (28 octobre 2020) : 4986. http://dx.doi.org/10.3390/molecules25214986.

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The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of the existing herbicides in the field. Sanshools, which are well known as spices, are N-alkyl substituted compounds extracted from the Zanthoxylum species and have several essential physiological and pharmacological functions. Sanshools display excellent safener activity for the herbicide metolachlor in rice seedlings. However, the high cost of sanshools extraction and difficulties in the synthesis of their complicated chemical structures limit their utilization in agricultural fields. Thus, the present study designed and synthesized various N-alkyl amide derivatives via the scaffold-hopping strategy to solve the challenge of complicated structures and find novel potential safeners for the herbicide metolachlor. In total, 33 N-alkyl amide derivatives (2a–k, 3a–k, and 4a–k) were synthesized using amines and saturated and unsaturated fatty acids as starting materials through acylation and condensation. The identity of all the target compounds was well confirmed by 1H-NMR, 13C-NMR, and high-resolution mass spectrometry (HRMS). The primary evaluation of safener activities for the compounds by the agar method indicated that most of the target compounds could protect rice seedlings from injury caused by metolachlor. Notably, compounds 2k and 4k displayed excellent herbicide safener activities on plant height and demonstrated relatively similar activities to the commercialized compound dichlormid. Moreover, we showed that compounds 2k and 4k had higher glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO) activities in rice seedlings, compared to the metolachlor treatment. In particular, 2k and 4k are safer for aquatic organisms than dichlormid. Results from the current work exhibit that compounds 2k and 4k have excellent crop safener activities toward rice and can, thus, be promising candidates for further structural optimization in rice protection.

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González Montoro, Ayelén, Rodrigo Quiroga et Javier Valdez Taubas. « Zinc co-ordination by the DHHC cysteine-rich domain of the palmitoyltransferase Swf1 ». Biochemical Journal 454, n^o 3 (29 août 2013) : 427–35. http://dx.doi.org/10.1042/bj20121693.

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S-acylation, commonly known as palmitoylation, is a widespread post-translational modification of proteins that consists of the thioesterification of one or more cysteine residues with fatty acids. This modification is catalysed by a family of PATs (palmitoyltransferases), characterized by the presence of a 50-residue long DHHC-CRD (Asp-His-His-Cys cysteine-rich domain). To gain knowledge on the structure–function relationships of these proteins, we carried out a random-mutagenesis assay designed to uncover essential amino acids in Swf1, the yeast PAT responsible for the palmitoylation of SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) proteins. We identified 21 novel loss-of-function mutations, which are mostly localized within the DHHC-CRD. Modelling of the tertiary structure of the Swf1 DHHC domain suggests that it could fold as a zinc-finger domain, co-ordinating two zinc atoms in a CCHC arrangement. All residues predicted to be involved in the co-ordination of zinc were found to be essential for Swf1 function in the screen. Moreover, these mutations result in unstable proteins, in agreement with a structural role for these zinc fingers. The conservation of amino acids predicted to form each zinc-binding pocket suggests a shared function, as the selective pressure to maintain them is lost upon mutation of one of them. A Swf1 orthologue that lacks one of the zinc-binding pockets is able to complement a yeast swf1∆ strain, possibly because a similar fold can be stabilized by hydrogen bonds instead of zinc co-ordination. Finally, we show directly that recombinant Swf1 DHHC-CRD is able to bind zinc. Sequence analyses of DHHC domains allowed us to present models of the zinc-binding properties for all PATs.

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