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

Research output: Contribution to journalArticle

101 Citations (Scopus)

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
Externally publishedYes

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pyrophosphomevalonate decarboxylase
Terpenes
Sterols
Genomics
Isomerases
Mevalonic Acid
Enzymes
Diphosphates
Structural Models
mevalonate kinase
Phosphorylation
Proteins
Decarboxylation
Biological Products
Phosphotransferases
Nucleotides
Adenosine Triphosphate
X-Rays
5-diphosphomevalonic acid

ASJC Scopus subject areas

  • Genetics
  • General

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Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. / Bonanno, Jeffrey B.; Edo, Carme; Eswar, Narayanan; Pieper, Ursula; Romanowski, Michael J.; Ilyin, Valentin; Gerchman, Sue Ellen; Kycia, Helen; Studier, F. William; Sali, Andrej; Burley, Stephen K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 23, 06.11.2001, p. 12896-12901.

Research output: Contribution to journalArticle

Bonanno, JB, Edo, C, Eswar, N, Pieper, U, Romanowski, MJ, Ilyin, V, Gerchman, SE, Kycia, H, Studier, FW, Sali, A & Burley, SK 2001, 'Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 23, pp. 12896-12901. https://doi.org/10.1073/pnas.181466998
Bonanno, Jeffrey B. ; Edo, Carme ; Eswar, Narayanan ; Pieper, Ursula ; Romanowski, Michael J. ; Ilyin, Valentin ; Gerchman, Sue Ellen ; Kycia, Helen ; Studier, F. William ; Sali, Andrej ; Burley, Stephen K. / Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 23. pp. 12896-12901.
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AU - Ilyin, Valentin

AU - Gerchman, Sue Ellen

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AU - Sali, Andrej

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