Stereo-electronic control of reaction selectivity in short-chain dehydrogenases: Decarboxylation, epimerization, and dehydration

Sugar nucleotide?modifying enzymes of the short-chain dehydrogenase/reductase type use transient oxidation?reduction by a tightly bound nicotinamide cofactor as a common strategy of catalysis to promote a diverse set of reactions, including decarboxylation, single- or double-site epimerization, and dehydration. Although the basic mechanistic principles have been worked out decades ago, the finely tuned control of reactivity and selectivity in several of these enzymes remains enigmatic. Recent evidence on uridine 5'-diphosphate (UDP)glucuronic acid decarboxylases (UDP-xylose synthase, UDPapiose/UDP-xylose synthase) and UDP-glucuronic acid-4epimerase suggests that stereo-electronic constraints established at the enzyme?s active site control the selectivity, and the timing of the catalytic reaction steps, in the conversion of the common substrate toward different products. The mechanistic idea of stereo-electronic control is extended to epimerases and dehydratases that deprotonate the Ca of the transient ketohexose intermediate. The human guanosine 5'-diphosphate (GDP)-mannose 4,6-dehydratase was recently shown to use a minimal catalytic machinery, exactly as predicted earlier from theoretical considerations, for the 0-elimination of water from the keto-hexose species.

Automated summary

Sugar nucleotide-modifying enzymes of the short-chain dehydrogenase/reductase type utilize transient oxidation-reduction by tightly bound nicotinamide cofactor for catalysis. Recent evidence suggests stereo-electronic constraints at the enzyme's active site control selectivity and timing of catalytic reaction steps. The mechanistic idea of stereo-electronic control is extended to epimerases and dehydratases.