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Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates

Academic Article
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Overview

related to degree

  • Wolan, Dennis, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 1999 - 2004

authors

  • Cheong, C. G.
  • Wolan, Dennis
  • Greasley, S. E.
  • Horton, P. A.
  • Beardsley, G. P.
  • Wilson, Ian

publication date

  • April 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.

subject areas

  • Amino Acid Sequence
  • Anions
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Electrons
  • Enzyme Inhibitors
  • Humans
  • Hydrogen Bonding
  • Hydroxymethyl and Formyl Transferases
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Multienzyme Complexes
  • Nucleotide Deaminases
  • Protein Binding
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Sulfonamides
  • Tetrahydrofolates
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M313691200

PubMed ID

  • 14966129
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Additional Document Info

start page

  • 18034

end page

  • 18045

volume

  • 279

issue

  • 17

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