Effects of structural analogues of the substrate and allosteric regulator of the human mitochondrial NAD(P)+-dependent malic enzyme.

Full Abstract

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.

Author information

Author/s: Su, Kuo-Liang (KL); Chang, Kuan-Yu (KY); Hung, Hui-Chih (HC);

Affiliation: Department of Life Sciences, National Chung-Hsing University, 250, Kuo-Kuang Road, Taichung 40227, Taiwan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem), published in England. (Language: eng)

Reference: 2009-Aug; vol 17 (issue 15) : pp 5414-9

Dates: Created 2009/07/21; Completed 2009/10/13;

PMID: 19595601, status: MEDLINE (last retrieved date: 10/13/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Allosteric Regulation - drug effects
Allosteric Site - drug effects
Crystallography, X-Ray
Dicarboxylic Acids - chemistry; pharmacology
Fumarates - chemistry; metabolism
Humans
Malate Dehydrogenase - antagonists & inhibitors; genetics; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Dicarboxylic Acids (0) ; Fumarates (0) ; Malates (0) ; Succinic Acid (110-15-6) ; fumaric acid (110-17-8) ; malic acid (6915-15-7) ; Malate Dehydrogenase (EC 1.1.1.37) ; malate dehydrogenase (decarboxylating) (EC 1.1.1.39)

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