Effects of structural analogues of the substrate and allosteric regulator of the human mitochondrial NAD(P)+-dependent malic enzyme.
Fumarate, a four-carbon trans dicarboxylic acid, is the allosteric activator of the human mitochondrial NAD(P)(+)-dependent malic enzyme (m-NAD(P)-ME). In this paper, we discuss the effects of the structural analogues of fumarate on human m-NAD(P)-ME. Succinate, a dicarboxylic acid with a carbon-carbon single bond, can also activate the enzyme, but the activating effect of succinate is less than that of fumarate. Succinamide, a diamide of succinate, cannot activate the enzyme and is a poor active-site inhibitor. The cis isomer of fumarate, maleic acid, significantly inhibits the ME activity, suggesting that the trans configuration of fumarate is crucial for operating the allosteric regulation of the enzyme. Other dicarboxylic acids, including glutaconic acid, malonic acid and alpha-ketoglutarate, cannot activate the enzyme and inversely inhibit enzyme activity. Our data suggest that these structural analogues are mainly active-site inhibitors, although they may enter the allosteric site to inhibit the enzyme. Furthermore, these data also suggest that the dicarboxylic acid must be in a trans conformation for allosteric activation of the enzyme.
Su
Kuo-Liang
KL
Department of Life Sciences, National Chung-Hsing University, 250, Kuo-Kuang Road, Taichung 40227, Taiwan.
Chang
Kuan-Yu
KY
Hung
Hui-Chih
HC
D000494:Allosteric Regulation / Q000187:drug effects*; D000495:Allosteric Site / Q000187:drug effects; D018360:Crystallography, X-Ray; D003998:Dicarboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D005650:Fumarates / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008293:Malates / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D019802:Succinic Acid / Q000737:chemistry / Q000378:metabolism
D003998:Dicarboxylic Acids; D005650:Fumarates; D008293:Malates; C030298:malic acid; C032005:fumaric acid; D019802:Succinic Acid; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating)