The structure of the 1L-myo-inositol-1-phosphate synthase-NAD+-2-deoxy-D-glucitol 6-(E)-vinylhomophosphonate complex demands a revision of the enzyme mechanism.
1l-myo-inositol 1-phosphate (MIP) synthase catalyzes the conversion of d-glucose 6-phosphate to 1l-myo-inositol 1-phosphate, the first and rate-limiting step in the biosynthesis of all inositol-containing compounds. It involves an oxidation, enolization, intramolecular aldol cyclization, and reduction. Here we present the structure of MIP synthase in complex with NAD(+) and a high-affinity inhibitor, 2-deoxy-d-glucitol 6-(E)-vinylhomophosphonate. This structure reveals interactions between the enzyme active site residues and the inhibitor that are significantly different from that proposed for 2-deoxy-d-glucitol 6-phosphate in the previously published structure of MIP synthase-NAD(+)-2-deoxy-d-glucitol 6-phosphate. There are several other conformational changes in NAD(+) and the enzyme active site as well. Based on the new structural data, we propose a new and completely different mechanism for MIP synthase.
Jin
Xiangshu
X
Michigan State University, Chemistry Department, East Lansing, Michigan 48824, USA.
Foley
Kathleen M
KM
Geiger
James H
JH
D001665:Binding Sites; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D007296:Myo-Inositol-1-Phosphate Synthase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D013403:Sugar Phosphates / Q000737:chemistry* / Q000378:metabolism*
C403168:2-deoxyglucitol 6-phosphate; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D013403:Sugar Phosphates; D009243:NAD; D013012:Sorbitol; D007296:Myo-Inositol-1-Phosphate Synthase