Kamat SS

References (15)

Title : Identification of sequence determinants for the ABHD14 enzymes - Vaidya_2023_Proteins__
Author(s) : Vaidya K , Rodrigues G , Gupta S , Devarajan A , Yeolekar M , Madhusudhan MS , Kamat SS
Ref : Proteins , : , 2023
Abstract : Over the course of evolution, enzymes have developed remarkable functional diversity in catalyzing important chemical reactions across various organisms, and understanding how new enzyme functions might have evolved remains an important question in modern enzymology. To systematically annotate functions, based on their protein sequences and available biochemical studies, enzymes with similar catalytic mechanisms have been clustered together into an enzyme superfamily. Typically, enzymes within a superfamily have similar overall three-dimensional structures, conserved catalytic residues, but large variations in substrate recognition sites and residues to accommodate the diverse biochemical reactions that are catalyzed within the superfamily. The serine hydrolases are an excellent example of such an enzyme superfamily. Based on known enzymatic activities and protein sequences, they are split almost equally into the serine proteases and metabolic serine hydrolases. Within the metabolic serine hydrolases, there are two outlying members, ABHD14A and ABHD14B, that have high sequence similarity, but their biological functions remained cryptic till recently. While ABHD14A still lacks any functional annotation to date, we recently showed that ABHD14B functions as a lysine deacetylase in mammals. Given their high sequence similarity, automated databases often wrongly assign ABHD14A and ABHD14B as the same enzyme, and therefore, annotating functions to them in various organisms has been problematic. In this article, we present a bioinformatics study coupled with biochemical experiments, which identifies key sequence determinants for both ABHD14A and ABHD14B, and enable better classification for them. In addition, we map these enzymes on an evolutionary timescale and provide a much-wanted resource for studying these interesting enzymes in different organisms.
ESTHER : Vaidya_2023_Proteins__
PubMedSearch : Vaidya_2023_Proteins__
PubMedID: 37974539
Gene_locus related to this paper: human-ABHD14A , human-CIB

Title : A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals - Rajendran_2022_J.Biol.Chem_298_102128
Author(s) : Rajendran A , Soory A , Khandelwal N , Ratnaparkhi G , Kamat SS
Ref : Journal of Biological Chemistry , 298 :102128 , 2022
Abstract : The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (alpha/beta-hydrolase domain containing protein # 14B) as a novel KDAC, showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A (CoA) to yield acetyl-CoA, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics, and metabolomics analysis. We found from these complementary experiments in vivo, that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice, also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology, and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.
ESTHER : Rajendran_2022_J.Biol.Chem_298_102128
PubMedSearch : Rajendran_2022_J.Biol.Chem_298_102128
PubMedID: 35700823
Gene_locus related to this paper: human-CIB

Title : The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation - Singh_2021_Eur.J.Neurosci__
Author(s) : Singh S , Kamat SS
Ref : European Journal of Neuroscience , : , 2021
Abstract : Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.
ESTHER : Singh_2021_Eur.J.Neurosci__
PubMedSearch : Singh_2021_Eur.J.Neurosci__
PubMedID: 34727579
Gene_locus related to this paper: human-ABHD12 , mouse-abd12

Title : Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs - Khandelwal_2021_Cell.Chem.Biol__
Author(s) : Khandelwal N , Shaikh M , Mhetre A , Singh S , Sajeevan T , Joshi A , Balaji KN , Chakrapani H , Kamat SS
Ref : Cell Chemical Biology , : , 2021
Abstract : In humans, lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.
ESTHER : Khandelwal_2021_Cell.Chem.Biol__
PubMedSearch : Khandelwal_2021_Cell.Chem.Biol__
PubMedID: 33571455
Gene_locus related to this paper: human-ABHD12

Title : A Superfamily-wide Activity Atlas of Serine Hydrolases in Drosophila melanogaster - Kumar_2021_Biochemistry_60_1312
Author(s) : Kumar K , Mhetre A , Ratnaparkhi GS , Kamat SS
Ref : Biochemistry , 60 :1312 , 2021
Abstract : The serine hydrolase (SH) superfamily is, perhaps, one of the largest functional enzyme classes in all forms of life and consists of proteases, peptidases, lipases, and carboxylesterases as representative members. Consistent with the name of this superfamily, all members, without any exception to date, use a nucleophilic serine residue in the enzyme active site to perform hydrolytic-type reactions via a two-step ping-pong mechanism involving a covalent enzyme intermediate. Given the highly conserved catalytic mechanism, this superfamily has served as a classical prototype in the development of several platforms of chemical proteomics techniques, activity-based protein profiling (ABPP), to globally interrogate the functions of its different members in various native, yet complex, biological settings. While ABPP-based proteome-wide activity atlases for SH activities are available in numerous organisms, including humans, to the best of our knowledge, such an analysis for this superfamily is lacking in any insect model. To address this, we initially report a bioinformatics analysis toward the identification and categorization of nonredundant SHs in Drosophila melanogaster. Following up on this in silico analysis, leveraging discovery chemoproteomics, we identify and globally map the full complement of SH activities during various developmental stages and in different adult tissues of Drosophila. Finally, as a proof of concept of the utility of this activity atlas, we highlight sexual dimorphism in SH activities across different tissues in adult D. melanogaster, and we propose new research directions, resources, and tools that this study can provide to the fly community.
ESTHER : Kumar_2021_Biochemistry_60_1312
PubMedSearch : Kumar_2021_Biochemistry_60_1312
PubMedID: 33827210
Gene_locus related to this paper: drome-1vite , drome-2vite , drome-3vite , drome-ACHE , drome-aes01 , drome-aes02 , drome-aes03 , drome-aes04 , drome-aes05 , drome-aes06 , drome-aes08 , drome-aes09 , drome-aes10 , drome-CG1882 , drome-CG2493 , drome-CG3160 , drome-CG3523 , drome-CG3524 , drome-CG4267 , drome-CG4851 , drome-CG4979 , drome-CG5355 , drome-CG5966 , drome-CG6113 , drome-CG6271 , drome-CG6283 , drome-CG6295 , drome-CG6296 , drome-CG8424 , drome-CG8425 , drome-CG9186 , drome-CG9542 , drome-CG9858 , drome-CG11034 , drome-CG11055 , drome-CG12108 , drome-CG15101 , drome-CG15102 , drome-CG15106 , drome-CG17097 , drome-CG17101 , drome-CG17192 , drome-CG17374 , drome-CG18815 , drome-dnlg1 , drome-est6p , drome-EST23aes07 , drome-este4 , drome-este6 , drome-KRAKEN , drome-OME , harsa-e2bfn3

Title : Mapping the neuroanatomy of ABHD16A-ABHD12 & lysophosphatidylserines provides new insights into the pathophysiology of the human neurological disorder PHARC - Singh_2020_Biochemistry_59_2299
Author(s) : Singh S , Joshi A , Kamat SS
Ref : Biochemistry , 59 :2299 , 2020
Abstract : Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology. In vivo, the metabolic serine hydrolases ABHD16A and ABHD12 are major lipases that biosynthesize and degrade lyso-PS respectively. Of biomedical relevance, deleterious mutations to ABHD12 causes accumulation of lyso-PS in the brain, and this deregulated lyso-PS metabolism leads to the human genetic neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). While the roles of ABHD16A and ABHD12 in lyso-PS metabolism in the mammalian brain are well established, the anatomical and (sub)cellular localizations of both lipases, and the functional cross-talk between them towards regulating lyso-PS lipids remain under investigated. Here, using subcellular organelle fractionation, biochemical assays and immunofluorescence based high resolution microscopy, we show that the PS lipase ABHD16A is an endoplasmic reticulum (ER) localized enzyme, an organelle intricately regulating cellular PS levels. Further, leveraging immunohistochemical analysis using genetic ABHD16A and ABHD12 knockout mice as important controls, we map the anatomical distribution of both these lipases in tandem in the murine brain, and show for the first time, the distinct localization of these lipases to different regions and cells of the cerebellum. We complement the aforementioned immunohistochemical studies by quantitatively measuring lyso-PS concentrations in various brain regions using mass spectrometry, and find that the cerebellar lyso-PS levels are most affected by ABHD16A (decreased) or ABHD12 (increased) deletion. Taken together, our studies provide new insights into lyso-PS signaling in the cerebellum, the most atrophic brain region in human PHARC subjects.
ESTHER : Singh_2020_Biochemistry_59_2299
PubMedSearch : Singh_2020_Biochemistry_59_2299
PubMedID: 32462874
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A

Title : The Lysophosphatidylserines-An Emerging Class of Signalling Lysophospholipids - Shanbhag_2020_J.Membr.Biol_253_381
Author(s) : Shanbhag K , Mhetre A , Khandelwal N , Kamat SS
Ref : J Membr Biol , 253 :381 , 2020
Abstract : Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid.
ESTHER : Shanbhag_2020_J.Membr.Biol_253_381
PubMedSearch : Shanbhag_2020_J.Membr.Biol_253_381
PubMedID: 32767057

Title : Functional Annotation of ABHD14B, an Orphan Serine Hydrolase Enzyme - Rajendran_2020_Biochemistry_59_183
Author(s) : Rajendran A , Vaidya K , Mendoza J , Bridwell-Rabb J , Kamat SS
Ref : Biochemistry , 59 :183 , 2020
Abstract : The metabolic serine hydrolase family is, arguably, one of the largest functional enzyme classes in mammals, including humans, comprising 1-2% of the total proteome. This enzyme family uses a conserved nucleophilic serine residue in the active site to perform diverse hydrolytic reactions and consists of proteases, lipases, esterases, amidases, and transacylases, which are prototypical members of this family. In humans, this enzyme family consists of >250, of which approximately 40% members remain unannotated, in terms of both their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAFII250-interacting factor B, as it was found to be associated with transcription initiation factor TFIID. The crystal structure of human ABHD14B was determined more than a decade ago; however, its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme's ability to transfer an acetyl group from a post-translationally acetylated lysine to coenzyme A (CoA), to yield acetyl-CoA, while regenerating the free amine of protein lysine residues. We validate these findings by in vitro biochemical assays using recombinantly purified human ABHD14B in conjunction with cellular studies in a mammalian cell line by knocking down ABHD14B and by identification of a putative substrate binding site. Finally, we report the development and characterization of a much-needed, exquisitely selective ABHD14B antibody, and using it, we map the cellular and tissue distribution of ABHD14B and prospective metabolic pathways that this enzyme might biologically regulate.
ESTHER : Rajendran_2020_Biochemistry_59_183
PubMedSearch : Rajendran_2020_Biochemistry_59_183
PubMedID: 31478652
Gene_locus related to this paper: human-CIB

Title : A chemical-genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase - Kelkar_2019_Nat.Chem.Biol_15_169
Author(s) : Kelkar DS , Ravikumar G , Mehendale N , Singh S , Joshi A , Sharma AK , Mhetre A , Rajendran A , Chakrapani H , Kamat SS
Ref : Nat Chemical Biology , 15 :169 , 2019
Abstract : Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, oxidative stress results, in which excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a proapoptotic 'eat me' signal, is produced in response to elevated ROS, yet little is known regarding its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells. We used this molecule to detect, characterize and study oxidized PS in mammalian cells. We developed a chemical-genetic screen to identify enzymes that regulate oxidized PS in mammalian cells and found that the lipase ABHD12 hydrolyzes oxidized PS. We validated these findings in different physiological settings including primary peritoneal macrophages and brains from Abhd12(-/-) mice under inflammatory stress, and in the process, we functionally annotated an enzyme regulating oxidized PS in vivo.
ESTHER : Kelkar_2019_Nat.Chem.Biol_15_169
PubMedSearch : Kelkar_2019_Nat.Chem.Biol_15_169
PubMedID: 30643283
Gene_locus related to this paper: human-ABHD12

Title : Biochemical characterization of the PHARC-associated serine hydrolase ABHD12 reveals its preference for very-long-chain lipids - Joshi_2018_J.Biol.Chem_293_16953
Author(s) : Joshi A , Shaikh M , Singh S , Rajendran A , Mhetre A , Kamat SS
Ref : Journal of Biological Chemistry , 293 :16953 , 2018
Abstract : Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare genetic human neurological disorder caused by null mutations to the Abhd12 gene, which encodes the integral membrane serine hydrolase enzyme ABHD12. Although the role that ABHD12 plays in PHARC is understood, the thorough biochemical characterization of ABHD12 is lacking. Here, we report the facile synthesis of mono-1-(fatty)acyl-glycerol lipids of varying chain lengths and unsaturation and use this lipid substrate library to biochemically characterize recombinant mammalian ABHD12. The substrate profiling study for ABHD12 suggested that this enzyme requires glycosylation for optimal activity and that it has a strong preference for very-long-chain lipid substrates. We further validated this substrate profile against brain membrane lysates generated from WT and ABHD12 knockout mice. Finally, using cellular organelle fractionation and immunofluorescence assays, we show that mammalian ABHD12 is enriched on the endoplasmic reticulum membrane, where most of the very-long-chain fatty acids are biosynthesized in cells. Taken together, our findings provide a biochemical explanation for why very-long-chain lipids (such as lysophosphatidylserine lipids) accumulate in the brains of ABHD12 knockout mice, which is a murine model of PHARC.
ESTHER : Joshi_2018_J.Biol.Chem_293_16953
PubMedSearch : Joshi_2018_J.Biol.Chem_293_16953
PubMedID: 30237167
Gene_locus related to this paper: human-ABHD12

Title : Mice lacking lipid droplet-associated hydrolase, a gene linked to human prostate cancer, have normal cholesterol ester metabolism - Kory_2017_J.Lipid.Res_58_226
Author(s) : Kory N , Grond S , Kamat SS , Li Z , Krahmer N , Chitraju C , Zhou P , Frohlich F , Semova I , Ejsing C , Zechner R , Cravatt BF , Farese RV, Jr. , Walther TC
Ref : J Lipid Res , 58 :226 , 2017
Abstract : Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer. Homologs of LDAH have been identified as proteins of lipid droplets (LDs). LDs are cellular organelles that store neutral lipids, such as triacylglycerols and sterol esters, as precursors for membrane components and as reservoirs of metabolic energy. LDAH is reported to hydrolyze cholesterol esters and to be important in macrophage cholesterol ester metabolism. Here, we confirm that LDAH is localized to LDs in several model systems. We generated a murine model in which Ldah is disrupted but found no evidence for a major function of LDAH in cholesterol ester or triacylglycerol metabolism in vivo, nor a role in energy or glucose metabolism. Our data suggest that LDAH is not a major cholesterol ester hydrolase, and an alternative metabolic function may be responsible for its possible effect on development of prostate cancer.
ESTHER : Kory_2017_J.Lipid.Res_58_226
PubMedSearch : Kory_2017_J.Lipid.Res_58_226
PubMedID: 27836991
Gene_locus related to this paper: human-LDAH , mouse-Ldah

Title : Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase - Kolar_2016_Biochemistry_55_4636
Author(s) : Kolar MJ , Kamat SS , Parsons WH , Homan EA , Maher T , Peroni OD , Syed I , Fjeld K , Molven A , Kahn BB , Cravatt BF , Saghatelian A
Ref : Biochemistry , 55 :4636 , 2016
Abstract : A recently discovered class of endogenous mammalian lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), possesses anti-diabetic and anti-inflammatory activities. Here, we identified and validated carboxyl ester lipase (CEL), a pancreatic enzyme hydrolyzing cholesteryl esters and other dietary lipids, as a FAHFA hydrolase. Variants of CEL have been linked to maturity-onset diabetes of the young, type 8 (MODY8), and to chronic pancreatitis. We tested the FAHFA hydrolysis activity of the CEL MODY8 variant and found a modest increase in activity as compared with that of the normal enzyme. Together, the data suggest that CEL might break down dietary FAHFAs.
ESTHER : Kolar_2016_Biochemistry_55_4636
PubMedSearch : Kolar_2016_Biochemistry_55_4636
PubMedID: 27509211
Gene_locus related to this paper: human-CEL

Title : AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs - Parsons_2016_Nat.Chem.Biol_12_367
Author(s) : Parsons WH , Kolar MJ , Kamat SS , Cognetta AB, 3rd , Hulce JJ , Saez E , Kahn BB , Saghatelian A , Cravatt BF
Ref : Nat Chemical Biology , 12 :367 , 2016
Abstract : Enzyme classes may contain outlier members that share mechanistic, but not sequence or structural, relatedness with more common representatives. The functional annotation of such exceptional proteins can be challenging. Here, we use activity-based profiling to discover that the poorly characterized multipass transmembrane proteins AIG1 and ADTRP are atypical hydrolytic enzymes that depend on conserved threonine and histidine residues for catalysis. Both AIG1 and ADTRP hydrolyze bioactive fatty acid esters of hydroxy fatty acids (FAHFAs) but not other major classes of lipids. We identify multiple cell-active, covalent inhibitors of AIG1 and show that these agents block FAHFA hydrolysis in mammalian cells. These results indicate that AIG1 and ADTRP are founding members of an evolutionarily conserved class of transmembrane threonine hydrolases involved in bioactive lipid metabolism. More generally, our findings demonstrate how chemical proteomics can excavate potential cases of convergent or parallel protein evolution that defy conventional sequence- and structure-based predictions.
ESTHER : Parsons_2016_Nat.Chem.Biol_12_367
PubMedSearch : Parsons_2016_Nat.Chem.Biol_12_367
PubMedID: 27018888

Title : Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay - Kamat_2015_Nat.Chem.Biol_11_164
Author(s) : Kamat SS , Camara K , Parsons WH , Chen DH , Dix MM , Bird TD , Howell AR , Cravatt BF
Ref : Nat Chemical Biology , 11 :164 , 2015
Abstract : Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo. Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a(-/-) mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12(-/-) mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo, designating these enzymes as potential targets for treating neuroimmunological disorders.
ESTHER : Kamat_2015_Nat.Chem.Biol_11_164
PubMedSearch : Kamat_2015_Nat.Chem.Biol_11_164
PubMedID: 25580854
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A , mouse-abd12 , mouse-Abhd16a

Title : Combining cross-metathesis and activity-based protein profiling: New beta-lactone motifs for targeting serine hydrolases - Camara_2015_Bioorg.Med.Chem.Lett_25_317
Author(s) : Camara K , Kamat SS , Lasota CC , Cravatt BF , Howell AR
Ref : Bioorganic & Medicinal Chemistry Lett , 25 :317 , 2015
Abstract : beta-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of alpha-methylene-beta-lactones offers rapid access to structurally diverse, previously unexplored beta-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead beta-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the alpha-methylene-beta-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.
ESTHER : Camara_2015_Bioorg.Med.Chem.Lett_25_317
PubMedSearch : Camara_2015_Bioorg.Med.Chem.Lett_25_317
PubMedID: 25541002