Rajendran A

References (5)

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 : 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 : Optimization of medium composition for lipase production by Candida rugosa NCIM 3462 using response surface methodology - Rajendran_2007_Can.J.Microbiol_53_643
Author(s) : Rajendran A , Thangavelu V
Ref : Can J Microbiol , 53 :643 , 2007
Abstract : A sequential optimization approach using statistical design of experiments was employed to enhance the lipase production by Candida rugosa in submerged batch fermentation. Twelve medium components were evaluated initially using the Plackett-Burman 2-level factorial design. The significant variables affecting lipase production were found to be glucose, olive oil, peptone, (NH4)2SO4, and FeCl3.6H2O. Various vegetable oils were tested in the second step, and among them, groundnut oil was found to be the best inducer for lipase production by C. rugosa. The third step was to identify the optimal values of the significant medium components with groundnut oil as the inducer using response surface methodology. The regression equation obtained from the experimental data designed using a central composite design was solved, and analyzing the response surface contour plots, the optimal concentrations of the significant variables were determined. A maximum lipase activity of 5.95 U.mL-1, which is 1.64 times the maximum activity obtained in the Plackett-Burman experimental trials, was observed. The optimum combination of medium constituents contained 19.604 g.L-1 glucose, 13.065 mL.L-1 groundnut oil, 7.473 g.L-1 peptone, 0.962 g.L-1 (NH4)2SO4, 0.0019 g.L-1 FeCl3.6H2O, and other insignificant components at the fixed level. A predictive model of the combined effects of the independent variables using response surface methodology and an artificial neural network was proposed. The unstructured kinetic models, logistic model, and Luedeking-Piret model were used to describe cell mass and lipase production. The parameters of the models were evaluated and the lipase production by C. rugosa was found to be growth associated.
ESTHER : Rajendran_2007_Can.J.Microbiol_53_643
PubMedSearch : Rajendran_2007_Can.J.Microbiol_53_643
PubMedID: 17668023