Parsons WH

References (5)

Title : AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice - Erikci_2020_J.Biol.Chem_295_5891
Author(s) : Erikci Ertunc M , Kok BP , Parsons WH , Wang JG , Tan D , Donaldson CJ , Pinto AFM , Vaughan JM , Ngo N , Lum KM , Henry CL , Coppola AR , Niphakis MJ , Cravatt BF , Saez E , Saghatelian A
Ref : Journal of Biological Chemistry , 295 :5891 , 2020
Abstract : Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9(th) carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.
ESTHER : Erikci_2020_J.Biol.Chem_295_5891
PubMedSearch : Erikci_2020_J.Biol.Chem_295_5891
PubMedID: 32152231

Title : Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan - Chen_2019_Nat.Chem.Biol_15_453
Author(s) : Chen AL , Lum KM , Lara-Gonzalez P , Ogasawara D , Cognetta AB, 3rd , To A , Parsons WH , Simon GM , Desai A , Petrascheck M , Bar-Peled L , Cravatt BF
Ref : Nat Chemical Biology , 15 :453 , 2019
Abstract : Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184-an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL)-as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog. We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.
ESTHER : Chen_2019_Nat.Chem.Biol_15_453
PubMedSearch : Chen_2019_Nat.Chem.Biol_15_453
PubMedID: 30911178

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