Structural highlights
Function[GMDS_HUMAN] Conversion of GDP-D-mannose to GDP-4-keto-6-D-deoxymannose. Publication Abstract from PubMedBiosynthesis of 6-deoxy sugars, including l-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hexose nucleotide precursors as the first committed step. Here, we determined pre- and postcatalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5 and C6, coupled to NADP-mediated hydride transfer from C4 to C6. We show that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate. We also show that the overall multistep catalytic reaction involves the fewest position changes of enzyme and substrate groups and that it proceeds under conserved exploitation of the basic (minimal) catalytic machinery of short-chain dehydrogenase/reductases. A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.,Pfeiffer M, Johansson C, Krojer T, Kavanagh KL, Oppermann U, Nidetzky B ACS Catal. 2019 Apr 5;9(4):2962-2968. doi: 10.1021/acscatal.9b00064. Epub 2019, Mar 1. PMID:30984471[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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