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Biochemical and Biophysical Research... Apr 2002
Review
Topics: Acyltransferases; Amino Acid Sequence; Biotin; Catalysis; Cloning, Molecular; Fatty Acid Synthase, Type II; Humans; Hydro-Lyases; Membrane Proteins; Molecular Sequence Data; Pigment Epithelium of Eye; Protein Structure, Secondary; Vitamin A
PubMed: 11969222
DOI: 10.1006/bbrc.2001.2021 -
Signal Transduction and Targeted Therapy Dec 2022Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With... (Review)
Review
Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein-protein interactions and protein-DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.
Topics: Acyltransferases; Acylation; Proteins; Protein Processing, Post-Translational
PubMed: 36577755
DOI: 10.1038/s41392-022-01245-y -
Open Biology Jul 2021The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin... (Review)
Review
The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin -acyltransferase (GOAT), a member of the membrane-bound -acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.
Topics: Acylation; Acyltransferases; Animals; Binding Sites; Carrier Proteins; Drug Development; Ghrelin; Humans; Models, Molecular; Neurosecretory Systems; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Signal Transduction; Structure-Activity Relationship; Substrate Specificity
PubMed: 34315274
DOI: 10.1098/rsob.210080 -
Science China. Life Sciences Mar 2016Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate... (Review)
Review
Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.
Topics: Acyltransferases; Animals; Eating; Energy Metabolism; Gene Deletion; Gene Expression Regulation, Enzymologic; Ghrelin; Humans; Obesity; Tissue Distribution
PubMed: 26732975
DOI: 10.1007/s11427-015-4973-6 -
Chemical Reviews Apr 2017The enzymology of 135 assembly lines containing primarily cis-acyltransferase modules is comprehensively analyzed, with greater attention paid to less common phenomena.... (Review)
Review
The enzymology of 135 assembly lines containing primarily cis-acyltransferase modules is comprehensively analyzed, with greater attention paid to less common phenomena. Diverse online transformations, in which the substrate and/or product of the reaction is an acyl chain bound to an acyl carrier protein, are classified so that unusual reactions can be compared and underlying assembly-line logic can emerge. As a complement to the chemistry surrounding the loading, extension, and offloading of assembly lines that construct primarily polyketide products, structural aspects of the assembly-line machinery itself are considered. This review of assembly-line phenomena, covering the literature up to 2017, should thus be informative to the modular polyketide synthase novice and expert alike.
Topics: Acyltransferases; Polyketide Synthases; Polyketides; Substrate Specificity
PubMed: 28394118
DOI: 10.1021/acs.chemrev.6b00683 -
Biochimica Et Biophysica Acta Sep 1997In this article the properties, assay, distribution, subcellular localization, deficiency in congenital peroxisomal disorders, purification and physiological functions... (Review)
Review
In this article the properties, assay, distribution, subcellular localization, deficiency in congenital peroxisomal disorders, purification and physiological functions of dihydroxyacetone phosphate acyltransferase (EC 2.3.1.42) are reviewed.
Topics: Acyltransferases; Animals; Humans; Membrane Proteins; Peroxisomal Disorders; Saccharomyces cerevisiae; Subcellular Fractions
PubMed: 9370313
DOI: 10.1016/s0005-2760(97)00120-3 -
International Journal of Biological... Oct 2018Bacterial lipoproteins have been researched for decades due to their roles in a large number of biological functions. There were no structures of their main three... (Review)
Review
Bacterial lipoproteins have been researched for decades due to their roles in a large number of biological functions. There were no structures of their main three membrane processing enzymes, until 2016 for Lgt and LspA, and then 2017 for Lnt with not one but three simultaneous, independent publications. We have analyzed the recent findings for this apolipoprotein N-acyltransferase Lnt, with comparisons between the novel structures, and with soluble nitrilases, to determine the significance of unique features in terms of substrate's recognition and binding mechanism influenced by exclusive residues, two transmembrane helices, and a flexible loop.
Topics: Acyltransferases; Bacteria; Catalytic Domain; Crystallography, X-Ray; Lipoproteins
PubMed: 29859843
DOI: 10.1016/j.ijbiomac.2018.05.229 -
Current Opinion in Lipidology Jun 2022The turnover of fatty acids (FAs) at the sn-2 position of phospholipids is mediated by the reciprocal actions of phospholipases A2 and lyso-PL acyltransferases (LPLAT).... (Review)
Review
PURPOSE OF REVIEW
The turnover of fatty acids (FAs) at the sn-2 position of phospholipids is mediated by the reciprocal actions of phospholipases A2 and lyso-PL acyltransferases (LPLAT). LPCAT3, a major LPLAT isoform, exhibits a strong specificity for polyunsaturated FAs s (PUFAs). Although the enzyme was originally studied in the context of cardiometabolism, recent investigations have shed light on the role of LPCAT3 in other tissues such as skeletal muscle and in unexpected biological processes such as cell death and oncogenesis.
RECENT FINDINGS
The three-dimensional structure of LPCAT3 has been elucidated allowing further understanding of the mechanism of the acylation reaction as well as the substrate specificity of the enzyme. In skeletal muscle, LPCAT3-mediated phospholipid remodeling modulates membrane domain clustering and insulin signalingLPCAT3 plays an important role in the process of ferroptosis by modulating the PUFA content of phospholipids and possibly of plasmalogens.In tumor-associated macrophages, LPCAT3 can prevent ER stress induced by the tumor microenvironment and may equally modulate antitumor immunity.
SUMMARY
LPCAT3 is an attractive therapeutic target in the cardiometabolic disorders. Nevertheless, the involvement of LPCAT3 in processes such as cell death and oncogenesis demands caution with respect to the potential deleterious effects of enzyme modulation.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Acyltransferases; Carcinogenesis; Humans; Phosphatidylcholine-Sterol O-Acyltransferase; Phosphatidylcholines; Phospholipids; Tumor Microenvironment
PubMed: 35165232
DOI: 10.1097/MOL.0000000000000820 -
Current Opinion in Structural Biology Jun 2023The membrane-bound O-acyltransferase (MBOAT) superfamily catalyses the transfer of acyl chains to substrates implicated in essential cellular functions. Aberrant... (Review)
Review
The membrane-bound O-acyltransferase (MBOAT) superfamily catalyses the transfer of acyl chains to substrates implicated in essential cellular functions. Aberrant function of MBOATs is associated with various diseases and MBOATs are promising drug targets. There has been recent progress in structural characterisation of MBOATs, advancing our understanding of their functional mechanism. Integrating information across the MBOAT family, we characterise a common MBOAT fold and provide a blueprint for substrate and inhibitor engagement. This work provides context for the diverse substrates, mechanisms, and evolutionary relationships of protein and small-molecule MBOATs. Further work should aim to characterise MBOATs, as inherently lipid-associated proteins, within their membrane environment.
Topics: Acyltransferases
PubMed: 37040671
DOI: 10.1016/j.sbi.2023.102589 -
Expert Opinion on Therapeutic Patents Nov 2020DGAT and MGAT enzymes play an important role in triacylglycerol (TGA) biosynthesis. Overexpression of these enzymes may lead to accumulation of TGA in adipose tissues... (Review)
Review
INTRODUCTION
DGAT and MGAT enzymes play an important role in triacylglycerol (TGA) biosynthesis. Overexpression of these enzymes may lead to accumulation of TGA in adipose tissues causing development of diseases such as obesity and diabetes. High triglyceride levels increase risk factors for atherosclerosis, and increase the risk of heart attack, stroke and other heart diseases. DGAT and MGAT inhibitors are used for the treatment of such metabolic diseases. A number of DGAT and MGAT inhibitors entered into clinical and preclinical stages. However, some adverse effects are associated with them. Thus there is need to develop new, potent and safe DGAT and MGAT inhibitors.
AREA COVERED
In this review, the authors carefully searched patent literature and reviewed recent advances since the year 2014. Diverse chemical classes reported in the patents belonging to the category DGAT and MGAT inhibitors have been highlighted.
EXPERT OPINION
DGAT and MGAT inhibitors are now gaining significant importance in the treatment of metabolic diseases. Fused heterocycles with a combination of aromatic and aliphatic hydrophobic substituents could offer more potent DGAT and MGAT inhibitors. Previously reported chemical scaffolds and their DGAT and MGAT inhibitory activity could be employed as an input for some studies to discover novel, potent and safe DGAT and MGAT inhibitors.
Topics: Acyltransferases; Adipose Tissue; Animals; Diacylglycerol O-Acyltransferase; Drug Development; Drug Discovery; Enzyme Inhibitors; Humans; Metabolic Diseases; Patents as Topic; Triglycerides
PubMed: 32878484
DOI: 10.1080/13543776.2020.1815707