Derivatives of cinnamic acid interact with the nucleotide binding site of mitochondrial aldehyde dehydrogenase. Effects on the dehydrogenase reaction and stimulation of esterase activity by nucleotides.
A wide variety of cinnamic acid derivatives are inhibitors of the low Km mitochondrial aldehyde dehydrogenase. Two of the most potent inhibitors are alpha-cyano-3,4-dihydroxythiocinnamamide (Ki0.6 microM) and alpha-cyano-3,4,5-trihydroxycinnamonitrile (Ki2.6 microM). With propionaldehyde as substrate the inhibition by these compounds was competitive with respect to NAD+. alpha-Fluorocinnamate was a much less effective inhibitor of the enzyme, with mixed behaviour towards NAD+, but with a major competitive component. These cinnamic acid derivatives were ineffective as inhibitors of the aldehyde dehydrogenase-catalysed hydrolysis of p-nitrophenyl acetate, but inhibited the ability of NAD+ and NADH to activate this activity. Inhibition of the stimulation of esterase activity was competitive with respect to NAD+ and NADH, and the derived Ki values were the same as for inhibition of dehydrogenase activity. NAD+, but not acetaldehyde, could elute the low Km aldehyde dehydrogenase from alpha-cyanocinnamate-Sepharose, to which the enzyme binds specifically (Poole RC and Halestrap AP, Biochem J 259: 105-110, 1989). The cinnamic acid derivatives have little effect on lactate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase or a high Km aldehyde dehydrogenase present in rat liver mitochondria. It is concluded that some cinnamic acid derivatives are potent inhibitors of the low Km aldehyde dehydrogenase, by competing with NAD+/NADH for binding to the enzyme. They are much less effective as inhibitors of other NAD(+)-dependent dehydrogenases.
Poole
R C
RC
Department of Biochemistry, School of Medical Sciences, University of Bristol, U.K.
Bowden
N J
NJ
Halestrap
A P
AP
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D001665:Binding Sites; D002934:Cinnamates / Q000494:pharmacology*; D004950:Esterases / Q000378:metabolism; D005985:Glyceraldehyde / Q000378:metabolism; D007700:Kinetics; D008930:Mitochondria, Liver / Q000201:enzymology*; D027501:Monocarboxylic Acid Transporters; D009243:NAD / Q000378:metabolism / Q000494:pharmacology; D009711:Nucleotides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D002934:Cinnamates; D027501:Monocarboxylic Acid Transporters; D009711:Nucleotides; D009243:NAD; C018253:alpha-cyanocinnamate; C029010:cinnamic acid; C042045:2-fluorocinnamic acid; D005985:Glyceraldehyde; D000444:Aldehyde Dehydrogenase; D004950:Esterases