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

J Biol Chem. 2004 Apr 23;279(17):18034-45. doi: 10.1074/jbc.M313691200. Epub 2004 Feb 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Anions
  • BW 1540
  • BW 2315
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Sulfonamides
  • Tetrahydrofolates
  • inosine monophosphate synthase
  • Hydroxymethyl and Formyl Transferases
  • Nucleotide Deaminases

Associated data

  • PDB/1P4R
  • PDB/1PL0