Статті в журналах: "S-Acylation"

1

Chamberlain, Luke H., and Michael J. Shipston. "The Physiology of Protein S-acylation." Physiological Reviews 95, no. 2 (April 2015): 341–76. http://dx.doi.org/10.1152/physrev.00032.2014.

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Protein S-acylation, the only fully reversible posttranslational lipid modification of proteins, is emerging as a ubiquitous mechanism to control the properties and function of a diverse array of proteins and consequently physiological processes. S-acylation results from the enzymatic addition of long-chain lipids, most typically palmitate, onto intracellular cysteine residues of soluble and transmembrane proteins via a labile thioester linkage. Addition of lipid results in increases in protein hydrophobicity that can impact on protein structure, assembly, maturation, trafficking, and function. The recent explosion in global S-acylation (palmitoyl) proteomic profiling as a result of improved biochemical tools to assay S-acylation, in conjunction with the recent identification of enzymes that control protein S-acylation and de-acylation, has opened a new vista into the physiological function of S-acylation. This review introduces key features of S-acylation and tools to interrogate this process, and highlights the eclectic array of proteins regulated including membrane receptors, ion channels and transporters, enzymes and kinases, signaling adapters and chaperones, cell adhesion, and structural proteins. We highlight recent findings correlating disruption of S-acylation to pathophysiology and disease and discuss some of the major challenges and opportunities in this rapidly expanding field.

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2

Shipston, Michael J. "Ion channel regulation by protein S-acylation." Journal of General Physiology 143, no. 6 (May 12, 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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3

Hemsley, Piers A. "S-acylation in plants: an expanding field." Biochemical Society Transactions 48, no. 2 (April 2, 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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4

Locatelli, Carolina, Kimon Lemonidis, Christine Salaun, Nicholas C. O. Tomkinson, and Luke H. Chamberlain. "Identification of key features required for efficient S-acylation and plasma membrane targeting of sprouty-2." Journal of Cell Science 133, no. 21 (October 9, 2020): jcs249664. http://dx.doi.org/10.1242/jcs.249664.

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ABSTRACTSprouty-2 is an important regulator of growth factor signalling and a tumour suppressor protein. The defining feature of this protein is a cysteine-rich domain (CRD) that contains twenty-six cysteine residues and is modified by S-acylation. In this study, we show that the CRD of sprouty-2 is differentially modified by S-acyltransferase enzymes. The high specificity/low activity zDHHC17 enzyme mediated restricted S-acylation of sprouty-2, and cysteine-265 and -268 were identified as key targets of this enzyme. In contrast, the low specificity/high activity zDHHC3 and zDHHC7 enzymes mediated more expansive modification of the sprouty-2 CRD. Nevertheless, S-acylation by all enzymes enhanced sprouty-2 expression, suggesting that S-acylation stabilises this protein. In addition, we identified two charged residues (aspartate-214 and lysine-223), present on opposite faces of a predicted α-helix in the CRD, which are essential for S-acylation of sprouty-2. Interestingly, mutations that perturbed S-acylation also led to a loss of plasma membrane localisation of sprouty-2 in PC12 cells. This study provides insight into the mechanisms and outcomes of sprouty-2 S-acylation, and highlights distinct patterns of S-acylation mediated by different classes of zDHHC enzymes.

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5

BAÑÓ, M. Carmen, S. Caroline JACKSON, and I. Anthony MAGEE. "Pseudo-enzymatic S-acylation of a myristoylated Yes protein tyrosine kinase peptide in vitro may reflect non-enzymatic S-acylation in vivo." Biochemical Journal 330, no. 2 (March 1, 1998): 723–31. http://dx.doi.org/10.1042/bj3300723.

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Covalent attachment of a variety of lipid groups to proteins is now recognized as a major group of post-translational modifications. S-acylation of proteins at cysteine residues is the only modification considered dynamic and thus has the potential for regulating protein function and/or localization. The activities that catalyse reversible S-acylation have not been well characterized and it is not clear whether both the acylation and the deacylation steps are regulated, since in principle it would be sufficient to control only one of them. Both apparently enzymatic and non-enzymatic S-acylation of proteins have previously been reported. Here we show that a synthetic myristoylated c-Yes protein tyrosine kinase undecapeptide undergoes spontaneous S-acylation in vitro when using a long chain acyl-CoA as acyl donor in the absence of any protein. The S-acylation was dependent on myristoylation of the substrate, the length of the incubation period, temperature and substrate concentration. When COS cell fractions were added to the S-acylation reaction no additional peptide:S-acyltransferase activity was detected. These results are consistent with the possibility that membrane-associated proteins may undergo S-acylation in vivo by non-enzymatic transfer of acyl groups from acyl-CoA. In this case, the S-acylation-deacylation process could be controlled by a regulated depalmitoylation mechanism.

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6

Zheng, Lihua, Peng Liu, Qianwen Liu, Tao Wang, and Jiangli Dong. "Dynamic Protein S-Acylation in Plants." International Journal of Molecular Sciences 20, no. 3 (January 29, 2019): 560. http://dx.doi.org/10.3390/ijms20030560.

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Lipid modification is an important post-translational modification. S-acylation is unique among lipid modifications, as it is reversible and has thus attracted much attention. We summarize some proteins that have been shown experimentally to be S-acylated in plants. Two of these S-acylated proteins have been matched to the S-acyl transferase. More importantly, the first protein thioesterase with de-S-acylation activity has been identified in plants. This review shows that S-acylation is important for a variety of different functions in plants and that there are many unexplored aspects of S-acylation in plants.

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7

Hines, P. J. "Location, location, S-acylation." Science 353, no. 6295 (July 7, 2016): 133–34. http://dx.doi.org/10.1126/science.353.6295.133-f.

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8

Lemonidis, Kimon, Oforiwa A. Gorleku, Maria C. Sanchez-Perez, Christopher Grefen, and 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, no. 24 (December 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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9

Zhang, Lian, Karyn Foster, Qiuju Li, and Jeffrey R. Martens. "S-acylation regulates Kv1.5 channel surface expression." American Journal of Physiology-Cell Physiology 293, no. 1 (July 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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10

Schroeder, H., R. Leventis, S. Shahinian, P. A. Walton, and J. R. Silvius. "Lipid-modified, cysteinyl-containing peptides of diverse structures are efficiently S-acylated at the plasma membrane of mammalian cells." Journal of Cell Biology 134, no. 3 (August 1, 1996): 647–60. http://dx.doi.org/10.1083/jcb.134.3.647.

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A variety of cysteine-containing, lipid-modified peptides are found to be S-acylated by cultured mammalian cells. The acylation reaction is highly specific for cysteinyl over serinyl residues and for lipid-modified peptides over hydrophilic peptides. The S-acylation process appears by various criteria to be enzymatic and resembles the S-acylation of plasma membrane-associated proteins in various characteristics, including inhibition by tunicamycin. The substrate range of the S-acylation reaction encompasses, but is not limited to, lipopeptides incorporating the motifs myristoylGC- and -CXC(farnesyl)-OCH3, which are reversibly S-acylated in various intracellular proteins. Mass-spectrometric analysis indicates that palmitoyl residues constitute the predominant but not the only type of S-acyl group coupled to a lipopeptide carrying the myristoylGC- motif, with smaller amounts of S-stearoyl and S-oleoyl substituents also detectable. Fluorescence microscopy using NBD-labeled cysteinyl lipopeptides reveals that the products of lipopeptide S-acylation, which cannot diffuse between membranes, are in almost all cases localized preferentially to the plasma membrane. This preferential localization is found even at reduced temperatures where vesicular transport from the Golgi complex to the plasma membrane is suppressed, strongly suggesting that the plasma membrane itself is the preferred site of S-acylation of these species. Uniquely among the lipopeptides studied, species incorporating an unphysiological N-myristoylcysteinyl- motif also show substantial formation of S-acylated products in a second, intracellular compartment identified as the Golgi complex by its labeling with a fluorescent ceramide. Our results suggest that distinct S-acyltransferases exist in the Golgi complex and plasma membrane compartments and that S-acylation of motifs such as myristoylGC- occurs specifically at the plasma membrane, affording efficient targeting of cellular proteins bearing such motifs to this membrane compartment.

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11

Manhertz-Patterson, Rojae, and 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, no. 02 (April 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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12

Jones, David, Uday Khandavilli, Eileen O’Leary, Simon Lawrence, and Timothy O’Sullivan. "Efficient S-Acylation of Thiourea." SynOpen 02, no. 04 (October 2018): 0263–67. http://dx.doi.org/10.1055/s-0037-1610370.

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Efficient S-acylation of thiourea using a variety of acid chlorides is reported. Structurally diverse aryl and alkyl substrates are compatible with this methodology. Confirmation that acylation occurs exclusively on the sulfur atom of thiourea is provided by single-crystal X-ray crystallographic analysis.

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13

Greaves, Jennifer, and Luke H. Chamberlain. "S-acylation by the DHHC protein family." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 522–24. http://dx.doi.org/10.1042/bst0380522.

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A family of 23 DHHC (Asp-His-His-Cys) proteins that function as mammalian S-acyltransferases has been identified, reinvigorating the study of protein S-acylation. Recent studies have continued to reveal how S-acylation affects target proteins, and have provided glimpses of how DHHC-substrate specificity might be achieved.

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14

Salaun, Christine, Jennifer Greaves, Nicholas C. O. Tomkinson, and Luke H. Chamberlain. "The linker domain of the SNARE protein SNAP25 acts as a flexible molecular spacer that ensures efficient S-acylation." Journal of Biological Chemistry 295, no. 21 (April 21, 2020): 7501–15. http://dx.doi.org/10.1074/jbc.ra120.012726.

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S-Acylation of the SNARE protein SNAP25 (synaptosome-associated protein of 25 kDa) is mediated by a subset of Golgi zinc finger DHHC-type palmitoyltransferase (zDHHC) enzymes, particularly zDHHC17. The ankyrin repeat domain of zDHHC17 interacts with a short linear motif known as the zDHHC ankyrin repeat–binding motif (zDABM) in SNAP25 (112VVASQP117), which is downstream of its S-acylated, cysteine-rich domain (85CGLCVCPC92). Here, we investigated the importance of a flexible linker region (amino acids 93–111, referred to hereafter as the “mini-linker” region) that separates the zDABM and S-acylated cysteines in SNAP25. Shortening the mini-linker did not affect the SNAP25–zDHHC17 interaction but blocked S-acylation. Insertion of additional flexible glycine-serine repeats had no effect on S-acylation, but extended and rigid alanine-proline repeats perturbed it. A SNAP25 mutant in which the mini-linker region was substituted with a flexible glycine-serine linker of the same length underwent efficient S-acylation. Furthermore, this mutant displayed the same intracellular localization as WT SNAP25, indicating that the amino acid composition of the mini-linker is not important for SNAP25 localization. Using the results of previous peptide array experiments, we generated a SNAP25 mutant predicted to have a higher-affinity zDABM. This mutant interacted with zDHHC17 more strongly but was S-acylated with reduced efficiency in HEK293T cells, implying that a lower-affinity interaction of the SNAP25 zDABM with zDHHC17 is optimal for S-acylation efficiency. These results show that amino acids 93–111 in SNAP25 act as a flexible molecular spacer that ensures efficient coupling of the SNAP25–zDHHC17 interaction and S-acylation of SNAP25.

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15

Lemonidis, Kimon, Christine Salaun, Marianna Kouskou, Cinta Diez-Ardanuy, Luke H. Chamberlain, and Jennifer Greaves. "Substrate selectivity in the zDHHC family of S-acyltransferases." Biochemical Society Transactions 45, no. 3 (June 15, 2017): 751–58. http://dx.doi.org/10.1042/bst20160309.

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S-acylation is a reversible lipid modification occurring on cysteine residues mediated by a family of membrane-bound ‘zDHHC’ enzymes. S-acylation predominantly results in anchoring of soluble proteins to membrane compartments or in the trafficking of membrane proteins to different compartments. Recent work has shown that although S-acylation of some proteins may involve very weak interactions with zDHHC enzymes, a pool of zDHHC enzymes exhibit strong and specific interactions with substrates, thereby recruiting them for S-acylation. For example, the ankyrin-repeat domains of zDHHC17 and zDHHC13 interact specifically with unstructured consensus sequences present in some proteins, thus contributing to substrate specificity of these enzymes. In addition to this new information on zDHHC enzyme protein substrate specificity, recent work has also identified marked differences in selectivity of zDHHC enzymes for acyl-CoA substrates and has started to unravel the underlying molecular basis for this lipid selectivity. This review will focus on the protein and acyl-CoA selectivity of zDHHC enzymes.

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16

Percher, Avital, Srinivasan Ramakrishnan, Emmanuelle Thinon, Xiaoqiu Yuan, Jacob S. Yount, and 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, no. 16 (April 4, 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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17

Kordyukova, Larisa V., Marina V. Serebryakova, Vladislav V. Khrustalev, and Michael Veit. "Differential S-acylation of Enveloped Viruses." Protein & Peptide Letters 26, no. 8 (September 11, 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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18

Hemsley, Piers A. "Protein S-acylation in plants (Review)." Molecular Membrane Biology 26, no. 1-2 (January 2009): 114–25. http://dx.doi.org/10.1080/09687680802680090.

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19

Randall, Matthew J., Jennifer L. Ather, Laura R. Hoyt, Anne E. Dixon, and Matthew E. Poynter. "Protein S-Acylation in Pulmonary Disease." Free Radical Biology and Medicine 100 (November 2016): S193. http://dx.doi.org/10.1016/j.freeradbiomed.2016.10.528.

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20

Gu, Si, Xinghua Nie, Amal George, Kyle Tyler, Yu Xing, Ling Qin, and 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, no. 1 (January 4, 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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21

Pedro, Maria P., Aldo A. Vilcaes, Guillermo A. Gomez, and Jose L. Daniotti. "Individual S-acylated cysteines differentially contribute to H-Ras endomembrane trafficking and acylation/deacylation cycles." Molecular Biology of the Cell 28, no. 7 (April 2017): 962–74. http://dx.doi.org/10.1091/mbc.e16-08-0603.

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S-acylation/deacylation cycles and vesicular transport are critical for an adequate subcellular distribution of S-acylated Ras proteins. H-Ras is dually acylated on cysteines 181 and 184, but it is unknown how these residues individually contribute to H-Ras trafficking. In this study, we characterized the acylation and deacylation rates and membrane trafficking of monoacylated H-Ras mutants to analyze their contributions to H-Ras plasma membrane and endomembrane distribution. We demonstrated that dually acylated H-Ras interacts with acyl-protein thioesterases (APTs) 1 and 2 at the plasma membrane. Moreover, single-acylation mutants of H-Ras differed not only in their subcellular distribution, where both proteins localized to different extents at both the Golgi complex and plasma membrane, but also in their deacylation rates, which we showed to be due to different sensitivities to APT1 and APT2. Fluorescence photobleaching and photoactivation experiments also revealed that 1) although S-acylated, single-acylation mutants are incorporated with different efficiencies into Golgi complex to plasma membrane vesicular carriers, and 2) the different deacylation rates of single-acylated H-Ras influence differentially its overall exchange between different compartments by nonvesicular transport. Taken together, our results show that individual S-acylation sites provide singular information about H-Ras subcellular distribution that is required for GTPase signaling.

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22

Rana, Mitra S., Chul-Jin Lee, and Anirban Banerjee. "The molecular mechanism of DHHC protein acyltransferases." Biochemical Society Transactions 47, no. 1 (December 17, 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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23

Ticho, Alexander L., Pooja Malhotra, Christopher R. Manzella, Pradeep K. Dudeja, Seema Saksena, Ravinder K. Gill, and Waddah A. Alrefai. "S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells." Journal of Biological Chemistry 295, no. 14 (February 18, 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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Zmuda, Filip, and Luke H. Chamberlain. "Regulatory effects of post-translational modifications on zDHHC S-acyltransferases." Journal of Biological Chemistry 295, no. 43 (August 17, 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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25

Salaun, Christine, Carolina Locatelli, Filip Zmuda, Juan Cabrera González, and Luke H. Chamberlain. "Accessory proteins of the zDHHC family of S-acylation enzymes." Journal of Cell Science 133, no. 22 (November 15, 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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26

Mahajan, Dinesh, Varun Kumar, Anil Rana, Chhuttan Lal Meena, Nidhi Sharma, and Yashwant Kumar. "Electrophilic Activation of Carboxylic Anhydrides for Nucleophilic Acylation Reactions." Synthesis 50, no. 19 (August 14, 2018): 3902–10. http://dx.doi.org/10.1055/s-0037-1609564.

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Nucleophilic acylation of symmetrical carboxylic anhydrides has inherited limitation of reaction efficiency along with relatively poor reactivity. Traditionally, one equivalent carboxylic acid is generated during nucleophilic acylation of a symmetrical anhydride, which always limits the yield of final product to 50% or less. This is a major drawback, which discourages the use of anhydrides for laboratory or industrial applications. Electrophilic activation of carboxylic anhydride using methanesulfonyl chloride is found to be an efficient method for nucleophilic acylation, which increases product yield by restricting the formation of corresponding acid as a side product. The developed protocol found to be a mild and high yielding methodology for one-pot nucleophilic acylation of carboxylic anhydrides with several type of N- and S-nucleophiles demonstrating appreciable functional group tolerance.

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27

West, Savannah J., Goutham Kodakandla, Qiaochu Wang, Ritika Tewari, Michael X. Zhu, Darren Boehning, and Askar M. Akimzhanov. "S-Acylation regulates store-operated calcium entry." Biophysical Journal 121, no. 3 (February 2022): 387a. http://dx.doi.org/10.1016/j.bpj.2021.11.828.

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28

Birner-Gruenberger, Ruth, and Rolf Breinbauer. "Tracking Protein S-Fatty Acylation with Proteomics." ChemBioChem 17, no. 16 (July 8, 2016): 1488–90. http://dx.doi.org/10.1002/cbic.201600314.

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29

Motion, R. L., P. D. Buckley, A. F. Bennett, and L. F. Blackwell. "Evidence that the cytoplasmic aldehyde dehydrogenase-catalysed oxidation of aldehydes involves a different active-site group from that which catalyses the hydrolysis of 4-nitrophenyl acetate." Biochemical Journal 254, no. 3 (September 15, 1988): 903–6. http://dx.doi.org/10.1042/bj2540903.

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Acylation of the aldehyde dehydrogenase. NADH complex by acetic anhydride leads to the production of acetaldehyde and NAD+. By monitoring changes in nucleotide fluorescence, the rate constant for acylation of the active site of the *enzyme. NADH complex was found to be 11 +/- 3 s-1. The rate of acylation by acetic anhydride at the group that binds aldehydes on the oxidative pathway is clearly rapid enough to maintain significant steady-state concentrations of the required active-site-acylated *enzyme. NADH intermediate despite the rapid hydrolysis of this *enzyme.acyl. NADH intermediate (5-10 s-1) [Blackwell, Motion, MacGibbon, Hardman & Buckley (1987) Biochem. J. 242, 803-808]. Hence reversal of the normal oxidative pathway can occur. However, although acylation of the aldehyde dehydrogenase. NADH complex by 4-nitrophenyl acetate also occurs rapidly with a rate constant of 10.9 +/- 0.6 s-1, even under the most extreme trapping conditions only very small amounts of acetaldehyde are detected [Loomes & Kitson (1986) Biochem. J. 235, 617-619]. Furthermore enzyme-catalysed hydrolysis of 4-nitrophenyl acetate is limited by the rate of deacylation of a group on the enzyme (0.4 s-1), which is an order of magnitude less than deacylation of the group at the active site (5-10 s-1). It is concluded that the enzyme-catalysed 4-nitrophenyl ester hydrolysis involves a group on the enzyme that is different from the active-site group that binds aldehydes on the normal oxidative pathway.

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30

Chumpen Ramirez, Sabrina, Fernando M. Ruggiero, Jose Luis Daniotti, and Javier Valdez Taubas. "Ganglioside glycosyltransferases are S-acylated at conserved cysteine residues involved in homodimerisation." Biochemical Journal 474, no. 16 (August 7, 2017): 2803–16. http://dx.doi.org/10.1042/bcj20170124.

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Ganglioside glycosyltransferases (GGTs) are type II membrane proteins bearing a short N-terminal cytoplasmic tail, a transmembrane domain (TMD), and a lumenal catalytic domain. The expression and activity of these enzymes largely determine the quality of the glycolipids that decorate mammalian cell membranes. Many glycosyltransferases (GTs) are themselves glycosylated, and this is important for their proper localisation, but few if any other post-translational modifications of these proteins have been reported. Here, we show that the GGTs, ST3Gal-V, ST8Sia-I, and β4GalNAcT-I are S-acylated at conserved cysteine residues located close to the cytoplasmic border of their TMDs. ST3Gal-II, a GT that sialylates glycolipids and glycoproteins, is also S-acylated at a conserved cysteine located in the N-terminal cytoplasmic tail. Many other GTs also possess cysteine residues in their cytoplasmic regions, suggesting that this modification occurs also on these GTs. S-acylation, commonly known as palmitoylation, is catalysed by a family of palmitoyltransferases (PATs) that are mostly localised at the Golgi complex but also at the endoplasmic reticulum (ER) and the plasma membrane. Using GT ER retention mutants, we found that S-acylation of β4GalNAcT-I and ST3Gal-II takes place at different compartments, suggesting that these enzymes are not substrates of the same PAT. Finally, we found that cysteines that are the target of S-acylation on β4GalNAcT-I and ST3Gal-II are involved in the formation of homodimers through disulphide bonds. We observed an increase in ST3Gal-II dimers in the presence of the PAT inhibitor 2-bromopalmitate, suggesting that GT homodimerisation may be regulating S-acylation

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31

Qiu, Tian, Saara-Anne Azizi, Shubhashree Pani, and Bryan C. Dickinson. "Abstract 1506: Protein acyl-protein thioesterases affect redox homeostasis and ROS signaling through peroxiredoxin." Cancer Research 85, no. 8_Supplement_1 (April 21, 2025): 1506. https://doi.org/10.1158/1538-7445.am2025-1506.

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Peroxiredoxins (PRDXs) are among the most abundant antioxidants and are widely distributed in cancers. They are associated with tumor cell resistance to cell death, such as apoptosis and ferroptosis. Post-translational modifications of PRDX play a critical role in modulating its activity and tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously discovered that mitochondrial localized PRDX3 and PRDX5 are S-acylated, with dynamic PRDX5 active site cysteine acylation regulating mitochondrial redox homeostasis. In this investigation, we found that all the PRDX family proteins are subject to S-acylation at the nucleophilic cysteine residue in their active site, and that PRDX S-acylation responds dynamically to ROS levels in the cell. The PRDX S-acylation level decreases under acute ROS stress, and increases under physiological, signaling levels of H2O2. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discovered that ROS-stress via exogenous H2O2 activates both the cytosolic and mitochondrial APTs, whereas EGF-stimulated endogenous H2O2 deactivates the cytosolic APTs. These results indicate that APTs help tune H2O2 signal transduction and ROS protection through PRDX S-deacylation. Citation Format: Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C. Dickinson. Protein acyl-protein thioesterases affect redox homeostasis and ROS signaling through peroxiredoxin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1506.

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32

Ghosh, Santanu, Anisha Purkait, and Chandan K. Jana. "Environmentally benign decarboxylative N-, O-, and S-acetylations and acylations." Green Chemistry 22, no. 24 (2020): 8721–27. http://dx.doi.org/10.1039/d0gc03731a.

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33

Daniotti, Jose L., Maria P. Pedro, and Javier Valdez Taubas. "The role of S-acylation in protein trafficking." Traffic 18, no. 11 (September 24, 2017): 699–710. http://dx.doi.org/10.1111/tra.12510.

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34

West, Savannah J., Qiaochu Wang, Michael X. Zhu, Askar M. Akimzhanov, and Darren Boehning. "Regulation of Orai1/STIM1 Function by S-Acylation." Biophysical Journal 118, no. 3 (February 2020): 404a. http://dx.doi.org/10.1016/j.bpj.2019.11.2292.

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35

Azizi, Saara-Anne, Tian Qiu, Noah E. Brookes, and Bryan C. Dickinson. "Regulation of ERK2 activity by dynamic S-acylation." Cell Reports 42, no. 9 (September 2023): 113135. http://dx.doi.org/10.1016/j.celrep.2023.113135.

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36

del Rivero Morfin, Pedro J., and Manu Ben-Johny. "Cutting out the fat: Site-specific deacylation of an ion channel." Journal of Biological Chemistry 295, no. 49 (December 4, 2020): 16497–98. http://dx.doi.org/10.1074/jbc.h120.016490.

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S-Acylation, a reversible post-translational lipid modification of proteins, controls the properties and function of various proteins, including ion channels. Large conductance Ca2+-activated potassium (BK) channels are S-acylated at two sites that impart distinct functional effects. Whereas the enzymes that attach lipid groups are known, the enzymes mediating lipid removal (i.e. deacylation) are largely unknown. Here, McClafferty et al. identify two enzymes, ABHD17a and ABHD17c, that excise BK channel lipid groups with remarkable precision. These findings lend insights into mechanisms that orchestrate the (de)acylation that fine-tunes ion channel function in physiology and disease.

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37

Zlatkine, P., B. Mehul, and A. I. Magee. "Retargeting of cytosolic proteins to the plasma membrane by the Lck protein tyrosine kinase dual acylation motif." Journal of Cell Science 110, no. 5 (March 1, 1997): 673–79. http://dx.doi.org/10.1242/jcs.110.5.673.

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Several members of the Src family of protein tyrosine kinases have a N-terminal dual acylation motif which specifies their myristoylation and S-acylation. These lipid modifications are necessary for correct intracellular localisation to the plasma membrane and to detergent-resistant glycolipid-enriched membrane domains (GEMs). Using chimaeras of the Lck dual acylation motif with two normally cytosolic proteins (chloramphenicol acetyl transferase and galectin-3), we show here that this motif is sufficient to encode correct lipid modification and to target these chimaeras to the plasma membrane, as demonstrated by subcellular fractionation and confocal immunofluorescence microscopy of transiently transfected COS cells. In addition, the chimaeras are resistant to extraction with cold non-ionic detergent, indicating targeting to GEM subdomains in the plasma membrane. The dual acylation motif has potential for targeting proteins to specific plasma membrane subdomains involved in signalling.

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38

Vysyaraju, Ravikanth, Hanumantha Rao B., Subramanyeswara Rao I. V., Venkateswarlu J., Prasada Rao K. V. V., and Siddaiah V.*. "A Novel Process for the Preparation of [(R,S)/(S,R)] and [(S,S)/(R,R)] Chroman epoxides, Key Intermediates in the Synthesis of Nebivolol." International Journal of Bioassays 6, no. 06 (June 2, 2017): 5420. http://dx.doi.org/10.21746/ijbio.2017.06.007.

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A novel, cost effective, scalable process for the preparation of chroman epoxides starting from 4-fluorophenol is described. The highlights of the process are single step O-acylation, fries rearrangement, one pot synthesis of claisen condensation, cyclization, reduction, epoxidation with over all yield of 50.9% [(R,S)/(S,R)]-chroman epoxide-A is 33.9% and [(S,S)/(R,R)]-chroman epoxide-B is 17%.

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39

Li, Yumeng, Shushu Wang, Yanchi Chen, Manjia Li, Xiaoshu Dong, Howard C. Hang, and Tao Peng. "Site-specific chemical fatty-acylation for gain-of-function analysis of protein S-palmitoylation in live cells." Chemical Communications 56, no. 89 (2020): 13880–83. http://dx.doi.org/10.1039/d0cc06073a.

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40

Chen, Baoen, Jixiao Niu, Johannes Kreuzer, Baohui Zheng, Gopala K. Jarugumilli, Wilhelm Haas, and Xu Wu. "Auto-fatty acylation of transcription factor RFX3 regulates ciliogenesis." Proceedings of the National Academy of Sciences 115, no. 36 (August 20, 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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41

BARCLAY, Elaine, Mark O'REILLY та Graeme MILLIGAN. "Activation of an α2A-adrenoceptor–Gαo1 fusion protein dynamically regulates the palmitoylation status of the G protein but not of the receptor". Biochemical Journal 385, № 1 (14 грудня 2004): 197–206. http://dx.doi.org/10.1042/bj20041432.

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Post-translational thio-acylation of a fusion protein between the α2A-adrenoceptor and the α subunit of the G protein Go1 is both dynamic and regulated by agonist binding. Incorporation of [3H]palmitate into the fusion protein was reduced substantially in the presence of the agonist adrenaline. This was dependent on the concentration of adrenaline and correlated with occupancy of the ligand binding site. Both the receptor and G-protein elements of the fusion construct incorporated [3H]palmitate but this occurred more rapidly for the G-protein element and regulation of acylation by the agonist occurred only for the G protein. The kinetics of de-palmitoylation of the α2A-adrenoceptor–Gαo1 fusion were accelerated markedly by agonist. Again, this reflected modulation of the G protein but not of the receptor. Agonist-induced regulation of the kinetics of thio-acylation of the G protein was abolished, however, in a mutant unable to bind guanosine 5′-[γ-[35S]thio]triphosphate ([35S]GTP[S]) in response to adrenaline. Despite the dynamic nature of the post-translational acylation and its regulation by agonist, the ability of adrenaline to activate the G protein, monitored by stimulation of the binding of [35S]GTP[S] to such fusion constructs, was unaffected by the palmitoylation potential of either the receptor or G-protein element.

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42

Stevenson, F. T., S. L. Bursten, R. M. Locksley, and D. H. Lovett. "Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues." Journal of Experimental Medicine 176, no. 4 (October 1, 1992): 1053–62. http://dx.doi.org/10.1084/jem.176.4.1053.

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NH2-terminal glycine myristyl acylation is a cotranslational modification that affects both protein localization and function. However, several proteins that lack NH2-terminal glycine residues, including the interleukin 1 (IL-1) precursors, also contain covalently linked myristate. To date, the site(s) of acylation of these proteins has not been determined. During an evaluation of IL-1 acylation, it was observed that [3H]myristate-labeled human monocyte lysates contained a prominent 26-kD myristylated protein, which was identified as the tumor necrosis factor alpha (TNF) precursor protein on the basis of specific immune precipitation. Radioimmunoprecipitates from the supernates of labeled monocytes indicated that the processed or mature 17-kD form of TNF does not contain myristate, suggesting that the site of acylation occurs within the 76-amino acid propiece of the precursor molecule. As the TNF precursor does not contain an NH2-terminal glycine, we hypothesized that myristyl acylation occurs on the N-epsilon-NH2 groups of lysine, of which two are present in the propiece (K19K20). Synthetic peptides were designed to include all seven lysine residues present within the entire 26-kD TNF precursor, and used in an in vitro myristyl acylation assay containing peptide, myristyl-CoA, and monocyte lysate as a source of enzyme. Analysis of reaction products by reverse phase high performance liquid chromatography and gas phase sequencing demonstrated the exclusive myristyl acylation of K19 and K20, consistent with the presence in monocytes of a specific lysyl N-epsilon-NH2-myristyl transferase activity. The acylated lysine residues are located immediately downstream from a hydrophobic, probable membrane-spanning segment of the propiece. Specific myristyl acylation of the TNF propiece may facilitate membrane insertion or anchoring of this critical inflammatory mediator.

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43

Pal, Mohan, and Stephen L. Bearne. "Synthesis of coenzyme A thioesters using methyl acyl phosphates in an aqueous medium." Org. Biomol. Chem. 12, no. 48 (2014): 9760–63. http://dx.doi.org/10.1039/c4ob02079k.

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44

Lutter, Ferdinand H., Lucie Grokenberger, Maximilian S. Hofmayer, and Paul Knochel. "Cobalt-catalyzed acylation-reactions of (hetero)arylzinc pivalates with thiopyridyl ester derivatives." Chemical Science 10, no. 35 (2019): 8241–45. http://dx.doi.org/10.1039/c9sc01817d.

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45

Kodakandla, Goutham, and Darren F. Boehning. "S-Acylation of STIM1 regulates store-operated calcium entry." Biophysical Journal 121, no. 3 (February 2022): 371a—372a. http://dx.doi.org/10.1016/j.bpj.2021.11.906.

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46

Katritzky, Alan, Mohamed Ibrahim, Siva Panda, Linda Nhon, Ahmed Hamed, and Said El-Feky. "Macrocyclic Peptoids by Selective S-Acylation of Cysteine Esters." Synthesis 45, no. 06 (February 21, 2013): 767–72. http://dx.doi.org/10.1055/s-0032-1318148.

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47

Kodakandla, Goutham, Michael X. Zhu, Askar M. Akimzhanov, and Darren F. Boehning. "S-acylation of SARAF regulates store-operated calcium entry." Biophysical Journal 122, no. 3 (February 2023): 373a—374a. http://dx.doi.org/10.1016/j.bpj.2022.11.2057.

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48

Panina, Irina, Nikolay Krylov, Mohamed Rasheed Gadalla, Elena Aliper, Larisa Kordyukova, Michael Veit, Anton Chugunov, and Roman Efremov. "Molecular Dynamics of DHHC20 Acyltransferase Suggests Principles of Lipid and Protein Substrate Selectivity." International Journal of Molecular Sciences 23, no. 9 (May 3, 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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49

Sakai, Tatsuya, Reiko Ohuchi, and Masanobu Ohuchi. "Fatty Acids on the A/USSR/77 Influenza Virus Hemagglutinin Facilitate the Transition from Hemifusion to Fusion Pore Formation." Journal of Virology 76, no. 9 (May 1, 2002): 4603–11. http://dx.doi.org/10.1128/jvi.76.9.4603-4611.2002.

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ABSTRACT Influenza virus hemagglutinin (HA) has three highly conserved acylation sites close to the carboxyl terminus of the HA2 subunit, one in the transmembrane domain and two in the cytoplasmic domain. Each site is modified by palmitic acid through a thioester linkage to cysteine. To elucidate the biological significance of HA acylation, the acylation sites of HA of influenza virus strain A/USSR/77 (H1N1) were changed by site-directed mutagenesis, and the membrane fusion activity of mutant HAs lacking the acylation site(s) was examined quantitatively using transfer assays of lipid (R18) and aqueous (calcein) dyes. Lipid mixing, so-called hemifusion, activity was not affected by deacylation, whereas transfer of aqueous dye, so-called fusion pore formation, was dramatically restricted. When the fusion reaction was induced by a lower pH than the optimal one, calcein transfer with the mutant HAs was improved, but simultaneously a considerable calcein leakage into the medium was observed. From these results, we conclude that the palmitic acids on the H1 subtype HA facilitate the transition from hemifusion to fusion pore formation.

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50

Sklyarenko, A. V., I. A. Groshkova, I. N. Krestyanova, and S. V. Yarotsky. "Alternative Synthesis of Cefamandole with Biocatalytic Acylation Catalyzed by Immobilized Cephalosporin-Acid Synthetase." Applied Biochemistry and Microbiology 58, no. 3 (June 2022): 251–60. http://dx.doi.org/10.1134/s0003683822030127.

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Abstract The processes of the biocatalytic acylation of 1-methyl-5-mercapto-1,2,3,4-tetrazolil-7-amino-cephalosporanic acid (7-TMCA) and 7-aminocephalosporanic acid (7-ACA) by methyl ester of mandelic acid (MEMA) were optimized with an immobilized cephalosporin-acid synthetase as the biocatalyst. Under optimized conditions in water-organic medium containing 43% (vol/vol) of ethylene glycol at 30°С with a spontaneous pH gradient in the range of 8.0–6.0, the following yields of biocatalytic transformations were reached: (80.8 ± 1.9)% for 7‑TMCA acylation (at a concentration of 100–120 mМ) resulted in cefamandole (CFM) production, and (88.6 ± 2.0)% for 7-ACA acylation of (at concentration of 140–170 mМ) resulted in a semiproduct of CFM (S-p CFM) formation. In the second process, the concentration of the target β-lactam product in the final reaction mixture is one and a half times higher than that with the first one. In light of the undoubted environmental benefits of the chemical transformation of S-p CFM to CFM over the process of the chemical production of 7-TMCA from 7-ACA, we conclude that the second pathway of combined chemical and biocatalytic CFM synthesis is preferable.

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