Srinivasan P

References (2)

Title : Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2) - Nagano_2013_Bioorg.Med.Chem.Lett_23_839
Author(s) : Nagano JM , Hsu KL , Whitby LR , Niphakis MJ , Speers AE , Brown SJ , Spicer T , Fernandez-Vega V , Ferguson J , Hodder P , Srinivasan P , Gonzalez TD , Rosen H , Bahnson BJ , Cravatt BF
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :839 , 2013
Abstract : Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems.
ESTHER : Nagano_2013_Bioorg.Med.Chem.Lett_23_839
PubMedSearch : Nagano_2013_Bioorg.Med.Chem.Lett_23_839
PubMedID: 23260346

Title : Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes - Samanta_2009_Biochem.Pharmacol_78_420
Author(s) : Samanta U , Kirby SD , Srinivasan P , Cerasoli DM , Bahnson BJ
Ref : Biochemical Pharmacology , 78 :420 , 2009
Abstract : The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.
ESTHER : Samanta_2009_Biochem.Pharmacol_78_420
PubMedSearch : Samanta_2009_Biochem.Pharmacol_78_420
PubMedID: 19394314
Gene_locus related to this paper: human-PLA2G7