Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis

Jeffrey B. Bonanno, Carme Edo, Narayanan Eswar, Ursula Pieper, Michael J. Romanowski, Valentin Ilyin, Sue Ellen Gerchman, Helen Kycia, F. William Studier, Andrej Sali, Stephen K. Burley

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Abstract

X-ray structures of two enzymes in the sterol/isoprenoid biosynthesis pathway have been determined in a structural genomics pilot study. Mevalonate-5-diphosphate decarboxylase (MDD) is a single-domain α/β protein that catalyzes the last of three sequential ATP-dependent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) is an α/β 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 MDD 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.

Original languageEnglish (US)
Pages (from-to)12896-12901
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number23
DOIs
StatePublished - Nov 6 2001

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Bonanno, J. B., Edo, C., Eswar, N., Pieper, U., Romanowski, M. J., Ilyin, V., Gerchman, S. E., Kycia, H., Studier, F. W., Sali, A., & Burley, S. K. (2001). Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 98(23), 12896-12901. https://doi.org/10.1073/pnas.181466998