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
Rc. Poole et al., 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, Biochemical pharmacology, 45(8), 1993, pp. 1621-1630
A wide variety of cinnamic acid derivatives are inhibitors of the low
K(m) mitochondrial aldehyde dehydrogenase. Two of the most potent inhi
bitors are alpha-cyano-3,4-dihydroxythiocinnamamide (K(i) 0.6 muM) and
alpha-cyano-3,4,5-trihydroxycinnamonitrile (K(i) 2.6 muM). With propi
onaldehyde as substrate the inhibition by these compounds was competit
ive with respect to NAD+. Alpha-fluorocinnamate was a much less effect
ive inhibitor of the enzyme, with mixed behaviour towards NAD+, but wi
th a major competitive component. These cinnamic acid derivatives were
ineffective as inhibitors of the aldehyde dehydrogenase-catalysed hyd
rolysis of p-nitrophenyl acetate, but inhibited the ability of NAD+ an
d NADH to activate this activity. Inhibition of the stimulation of est
erase activity was competitive with respect to NAD+ and NADH, and the
derived K(i) values were the same as for inhibition of dehydrogenase a
ctivity. NAD+, but not acetaldehyde, could elute the low K(m) aldehyde
dehydrogenase from alpha-cyanocinnamate-Sepharose, to which the enzym
e binds specifically (Poole RC and Halestrap AP, Biochem J 259: 105-11
0, 1989). The cinnamic acid derivatives have little effect on lactate
dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase or a high K(m)
aldehyde dehydrogenase present in rat liver mitochondria. It is concl
uded that some cinnamic acid derivatives are potent inhibitors of the
low K(m) aldehyde dehydrogenase, by competing with NAD+/NADH for bindi
ng to the enzyme. They are much less effective as inhibitors of other
NAD+-dependent dehydrogenases.