Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis.
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 A resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of approximately 5,000 A(2) 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 approximately 50 A 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.
Greasley
S E
SE
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Horton
P
P
Ramcharan
J
J
Beardsley
G P
GP
Benkovic
S J
SJ
Wilson
I A
IA
D000818:Animals; D001665:Binding Sites; D001717:Birds; D018360:Crystallography, X-Ray; D019281:Dimerization; D019877:Hydroxymethyl and Formyl Transferases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism; D009709:Nucleotide Deaminases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011687:Purines / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D009097:Multienzyme Complexes; D011687:Purines; D011993:Recombinant Fusion Proteins; C113120:inosine monophosphate synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase