Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis

Samantha E. Greasley, Patricia Horton, Joseph Ramcharan, G. Peter Beardsley, Stephen J. Benkovic, Ian A. Wilson

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

ATIC, the product of the purH gene, is a 64 kDa bifunctional enzyme that possesses the final two activities in de novo purine biosynthesis, AICAR transformylase and IMP cyclohydrolase. The crystal structure of avian ATIC has been determined to 1.75 Å resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of ∼5,000 Å2 per monomer. Each monomer is composed of two novel, separate functional domains. The N-terminal domain (up to residue 199) is responsible for the IMPCH activity, whereas the AICAR Tfase activity resides in the C-terminal domain (200-593). The active sites of the IMPCH and AICAR Tfase domains are ∼50 Å apart, with no structural evidence of a tunnel connecting the two active sites. The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation.

Original languageEnglish (US)
Pages (from-to)402-406
Number of pages5
JournalNature Structural Biology
Volume8
Issue number5
DOIs
StatePublished - 2001

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Genetics

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