Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 23, Pages 12896-12901Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.181466998
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- NIGMS NIH HHS [R29 GM5462, R29 GM054762, P50 GM062529, P50 GM62529] Funding Source: Medline
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X-ray structures of two enzymes in the sterol/isoprenoid blosynthesis pathway have been determined in a structural genomics pilot study. Mevalonate-5-diphosphate clecarboxylase (MDD) is a single-domain alpha/beta protein that catalyzes the last of three sequential ATP-depenclent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) is an alpha/beta metalloenzyme that catalyzes interconversion of isopentenyl diphosphate and dimethylallyl diphosphate, which condense in the next step toward synthesis of sterols and a host of natural products. Homology modeling of related proteins and comparisons of the MIDD and IDI structures with two other experimentally determined structures have shown that MDD is a member of the GHMP superfamily of small-molecule kinases and IDI is similar to the nudix hydrolases, which act on nucleotide diphosphate-containing substrates. Structural models were produced for 379 proteins, encompassing a substantial fraction of both protein superfamilies. All three enzymes responsible for synthesis of isopentenyl diphosphate from mevalonate (mevalonate kinase, phosphomevalonate kinase, and MDD) share the same fold, catalyze phosphorylation of chemically similar substrates (MDD decarboxylation involves phosphorylation of mevalonate diphosphate), and seem to have evolved from a common ancestor. These structures and the structural models derived from them provide a framework for interpreting biochemical function and evolutionary relationships.
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