Structure-activity studies of L-canaline-mediated inhibition of porcine alanine aminotransferase

Chemical Research in Toxicology
D R WorthenP A Crooks

Abstract

L-Canaline [L-2-amino-4-(aminooxy)butanoic acid] (L-CAN) and a family of eleven structurally related analogs were synthesized and evaluated for their inhibitory effect on PLP-dependent alanine aminotransferase (AlaAT) (EC 2.6.1.2) obtained from porcine heart. These congeners were selected to determine the stereochemical, aliphatic chain length, and aminooxy substitutional effects on L-CAN-mediated inhibition of AlaAT activity. L-CAN was the most effective inhibitor of the tested compounds; 10(-7) M L-CAN elicited a 55% reduction in AlaAT activity after a 5 min exposure. This deleterious effect results from the ability of L-CAN to react avidly with PLP moiety of the enzyme to form a stable, L-CAN-PLP oxime. In contrast, the methyl and ethyl esters of L-CAN reduced AlaAT activity by only 8% and 6%, respectively. While all of the L-enantiomeric forms of the tested compound were more potent AlaAT inhibitors than their corresponding D-stereoisomers, the D-enantiomers, particularly D-canaline, were active. Chain shortening or lengthening dramatically curtailed L-CAN-mediated loss in AlaAT activity, but the replacement of the alpha-amino group with a hydrogen was of little consequence in this regard. AlaAT was treated with L-CAN in th...Continue Reading

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Citations

Feb 21, 2008·Organic Letters·Joanna GajewiakGlenn D Prestwich
May 2, 2002·Anti-cancer Drugs·Aimee K BencePeter A Crooks
Aug 22, 2000·Antimicrobial Agents and Chemotherapy·B J Berger
Aug 26, 2014·Medicinal Research Reviews·Hyunbeom LeeRichard B Silverman
Nov 2, 2016·Organic & Biomolecular Chemistry·N Chen, J Xie
Dec 25, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Aimee K Bence, Peter A Crooks

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