6GPL

Crystal structure of human GDP-D-mannose 4,6-dehydratase in complex with GDP-4k6d-Man

Summary for 6GPL

• Entry DOI: 10.2210/pdb6gpl/pdb
• Descriptor: GDP-mannose 4,6 dehydratase, BICINE, [[(2~{R},3~{S},4~{R},5~{R})-5-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},6~{R})-6-methyl-3,4-bis(oxidanyl)-5-oxidanylidene-oxan-2-yl] hydrogen phosphate, ... (6 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 166270.57

Authors

Pfeiffer, M.,Krojer, T.,Johansson, C.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Nidetzky, B.,Oppermann, U.,Structural Genomics Consortium (SGC) (deposition date: 2018-06-06, release date: 2018-07-18, Last modification date: 2024-05-15)

Primary citation

Pfeiffer, M.,Johansson, C.,Krojer, T.,Kavanagh, K.L.,Oppermann, U.,Nidetzky, B.
A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase.
Acs Catalysis, 9:2962-2968, 2019

PubMed Abstract: Biosynthesis 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, Tyr and Glu, promotes a 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.

PubMed: 30984471
DOI: 10.1021/acscatal.9b00064

Experimental method

X-RAY DIFFRACTION (1.76 Å)