A chemical–genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase

Kelkar, Dhanashree S.; Ravikumar, Govindan; Mehendale, Neelay; Singh, Simran Jeet; Joshi, Amitabh; Sharma, Ajay; Mhetre, Amol; Rajendran, Abinaya; Chakrapani, Harinath; Kamat, Siddhesh S.

doi:10.1038/s41589-018-0195-0

Cited by 58 publications

(129 citation statements)

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“…Indeed, the higher the number of bis‐allylic hydrogen atoms in a given acyl chain, the more likely it is to be oxidizable, and the rate of lipid peroxidation scales with the degree of unsaturation in membrane phospholipids (Figure A). While less energetically favorable, monounsaturated fatty acyl chains can also be oxidized in response to small molecule ROS inducers and physiological stimuli (e.g., see ref …”

Section: Lipid Peroxide Formation and Propagationmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.

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Section: Lipid Peroxide Formation and Propagationmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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“…Similarly, pharmacological inhibition of ABHD12 resulted in a significant accumulation of LysoPS in human macrophages and a significant enhancement of the immune responses of the cells in vivo [17]. Importantly, Kelkar et al later showed that ABHD12 also catalyzed the hydrolysis of an oxidized-PS to LysoPS which was further hydrolyzed and degraded by ABHD12 [32]. More recently, LysoPS with a very-long-chain fatty acid (~C24:0), which is a preferential substrate for ABHD12, was shown to efficiently induce pro-inflammatory responses of macrophages via Toll-like receptor 2 (TLR2) [15].…”

Section: Abhd16a and Abhd12mentioning

confidence: 99%

Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid

Omi

Kano

Aoki

2021

Cell Biochem Biophys

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Lysophosphatidylserine (LysoPS) is an emerging lysophospholipid (LPL) mediator, which acts through G protein-coupled receptors, like lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). LysoPS is detected in various tissues and cells and thought to be produced mainly by the deacylation of phosphatidylserine. LysoPS has been known to stimulate degranulation of mast cells. Recently, four LysoPS-specific G protein-coupled receptors (GPCRs) were identified. These GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs and are predominantly expressed in immune cells such as lymphocytes and macrophages. Studies on knockout mice of these GPCRs have revealed that LysoPS has immune-modulatory functions. Up-regulation of a LysoPS-producing enzyme, PS-specific phospholipase A1, was frequently observed in situations where the immune system is activated including autoimmune diseases and organ transplantations. Therefore, modulation of LysoPS signaling appears to be a promising method for providing therapies for the treatment of immune diseases. In this review, we summarize the biology of LysoPS-producing enzymes and receptors, recent developments in LysoPS signal modulators, and prospects for future therapeutic applications.

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“…All mammalian cell lines (HEK293T, HeLa, A549, THP1 and MCF7) described in this paper were purchased from ATCC, and cultured in complete medium [RPMI1640 supplemented with 10% (v/v) FBS, and 1% (v/v) penicillin-streptomycin (Pen-Strep) (MP Biomedicals)] at 37 °C with 5 % (v/v) CO 2 unless otherwise mentioned. The cell cultures were stained routinely with 4',6-diamidino-2-phenylindole (DAPI) and assessed by microscopy to ensure that they were devoid of any mycoplasma contamination using established protocols 33 . All cell lines were cultured in 15 cm tissue culture dishes (Eppendorf), and upon 80% confluence were harvested by scrapping, washed with Dulbecco's phosphate buffer saline (DPBS) (3x times), centrifuged at 200g for 5 mins to remove excess DPBS, and stored at -80 °C till further use.…”

Section: Mammalian Cell Culturementioning

confidence: 99%

Functional Annotation of ABHD14B, an Orphan Serine Hydrolase Enzyme

et al. 2019

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The metabolic serine hydrolase family, is arguably, one of the largest functional enzyme class in mammals, including humans, comprising of 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 as prototypical members of this family. In humans, this enzyme family consists of >250 members, of which, approximately 40% members remain unannotated, both in terms of their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAF II 250-interacting factor B, as it was found associated with the transcription initiation factor TFIID. The crystal structure of human ABHD14B has been solved for over a decade, however its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme's ability in transferring an acetyl group from a post-translationally acetylated-lysine to coenzyme A (CoA), to yield acetyl-CoA, while re-generating 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 modeling substrates into the enzyme active site. Finally, we report, the development and characterization of a much needed, exquisitely selective ABHD14B antibody, using which, we

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A chemical–genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase

Cited by 58 publications

References 59 publications

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid

Functional Annotation of ABHD14B, an Orphan Serine Hydrolase Enzyme

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