guanosine 5'-diphosphate-D-mannose oxidoreductase
guanosine diphosphomannose oxidoreductase
guanosine diphosphomannose 4,6-dehydratase
Structural and kinetic analysis of Escherichia coli GDP-mannose 4,6 dehydratase provides insights into the enzyme's catalytic mechanism and regulation by GDP-fucose.
Identification and characterization of GDP-d-mannose 4,6-dehydratase and GDP-l-fucose snthetase in a GDP-l-fucose biosynthetic gene cluster from Helicobacter pylori.
Identification of two GDP-6-deoxy-D-lyxo-4-hexulose reductases synthesizing GDP-D-rhamnose in Aneurinibacillus thermoaerophilus L420-91T.
Structure of the MUR1 GDP-mannose 4,6-dehydratase from Arabidopsis thaliana: implications for ligand binding and specificity.
Crystal structure of a tetrameric GDP-D-mannose 4,6-dehydratase from a bacterial GDP-D-rhamnose biosynthetic pathway.
Chemical insights from structural studies of enzymes.
This enzyme belongs to the Short-chain dehydrogenases/reductases (SDR). Although a catalytic residue is different, this enzyme is homologous to the counterpart enzyme from bacteria and human (D00543 in EzCatDB). This enzyme catalyzes reactions similar to those by its homologous enzyme, dTDP-D-glucose-4,6-dehydratase (EC 4.2.1.46, D00262 in EzCatDB) (see [5] and [6]). The difference from the homologous enzyme is that this enzyme has only one acidic residue as a general acid/base, whearas the homologue uses two acidic residues. According to the literature [4], [5] and [6], this enzyme catalyzes at least three reactions: oxidation of GDP-mannose (hydride transfer from GDP-mannose to nicotinamide), dehydration (elimination of a hydroxyl group from C6), and rereduction of C5-C6 double bond to methyl group (hydride transfer from nicotinamide to the intermediate). Taken together, this enzyme catalyzes the following reactions: (A) Hydride transfer from C4 atom of substrate to NADP, forming a 4-keto intermediate (I00088): (A0) Lys189 (of 1n7g) modulates the activity (or pKa) of Tyr185 via 2'-hydroxyl group of NADP, along with the N1 atom of the nicotinamide group in NADP, whereas Ser162 modulates the pKa of 4-hydroxyl oxygen of the substrate. (A1) Tyr185 acts as a general base to deprotonate the 4-hydroxyl oxygen of the substrate. Meanwhile, the hydride transfer occurs from the C4-carbon of the substrate to the C4 atom of the nicotinamide, forming 4-keto intermediate. (B) Isomerization from the 4-keto intermediato to form an enol/enolate intermediate (I00089): (B0) Arg253 might modulate the pKa of Glu164 as a general base. Moreover, the 4-keto carbonyl group may increase the acidity of the C5 atom. (B1) Glu164 acts as a general base to deprotonate the C5 atom, leading to formation of enol/enolate intermediate. (C) Elimination of hydroxyl group from C6 of the enol/enolate intermediate, forming 4-keto-5,6-mannosen intermediate (I00090): (C0) GDP-phosphoryl groups in the intermediate might modulate the pKa of Glu164 as a general acid. (C1) Glu164 acts as a general acid to protonate O6 hydroxyl group, to release a water molecule, and to form the 4-keto-5,6-ene intermediate from the enol/enolate intermediate. (D) Hydride transfer from NAD(P)H to C6 atom of the intermediate: (D0) A slight rotation of the hexose ring of intermediate might be necessary for the reaction. Lys189 modulates the activity (or pKa) of Tyr185 via 2'-hydroxyl group of NADP, along with the N1 atom of the nicotinamide group in NADP. (D1) Hydride transfer from NAD(P)H to C6 atom of the hexose ring in the intermediate. Meanwhile, a general acid must protonate the C5 atom of the hexose. According to the literature [5], Ser162, which is corresponding to Thr126 (of 1rpn in D00543), seems to be positioned to play a role as a general acid. Since this residue is close enough to Tyr185, Tyr185 might act as a general acid via Thr126 to protonate the C5 atom.