- Structure-activity studies of L-canaline-mediated inhibition of porcine alanine aminotransferase
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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 the 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 α-amino group with a hydrogen was of little consequence in this regard. AlaAT was treated with L-CAN in the presence of free PLP to assess PLP capacity to protect AlaAT against 10-7 M L-CAN- dependent inactivation. L-CAN retained approximately two-thirds of its inhibitory ability in the presence of equimolar PLP, but AlaAT inhibition was reduced 90% by a 10-fold excess of PLP over L-CAN.
- Worthen, David R.,Ratliff, Darian K.,Rosenthal, Gerald A.,Trifonov,Crooks, Peter A.
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- COMPOUNDS FOR MODULATING THE GLYCOLYSIS ENZYME COMPLEX AND/OR THE TRANSAMINASE COMPLEX
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The invention relates to compounds for modulating the glycolysis enzyme complex and the transaminase complex, pharmaceutical compositions containing said compounds, and to the uses of said compounds for the production of pharmaceutical compositions for the treatment of different illnesses.
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(2008/06/13)
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