Linked Life Data

12501179

Source:http://linkedlifedata.com/resource/pubmed/id/12501179

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
52
pubmed:dateCreated
2002-12-26
pubmed:databankReference
pubmed:abstractText
ATIC encompasses both AICAR transformylase and IMP cyclohydrolase activities that are responsible for the catalysis of the penultimate and final steps of the purine de novo synthesis pathway. The formyl transfer reaction catalyzed by the AICAR Tfase domain is substantially more demanding than that catalyzed by the other folate-dependent enzyme of the purine biosynthesis pathway, GAR transformylase. Identification of the AICAR Tfase active site and key catalytic residues is essential to elucidate how the non-nucleophilic AICAR amino group is activated for formyl transfer. Hence, the crystal structure of dimeric avian ATIC was determined as a complex with the AICAR Tfase substrate AICAR, as well as with an IMP cyclohydrolase inhibitor, XMP, to 1.93 A resolution. AICAR is bound at the dimer interface of the transformylase domains and forms an extensive hydrogen bonding network with a multitude of active site residues. The crystal structure suggests that the conformation of the 4-carboxamide of AICAR is poised to increase the nucleophilicity of the C5 amine, while proton abstraction occurs via His(268) concomitant with formyl transfer. Lys(267) is likely to be involved in the stabilization of the anionic formyl transfer transition state and in subsequent protonation of the THF leaving group.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
31
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
15505-13
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12501179-Animals, pubmed-meshheading:12501179-Binding Sites, pubmed-meshheading:12501179-Birds, pubmed-meshheading:12501179-Computer Simulation, pubmed-meshheading:12501179-Crystallography, X-Ray, pubmed-meshheading:12501179-Dimerization, pubmed-meshheading:12501179-Enzyme Activation, pubmed-meshheading:12501179-Hydroxymethyl and Formyl Transferases, pubmed-meshheading:12501179-Models, Molecular, pubmed-meshheading:12501179-Multienzyme Complexes, pubmed-meshheading:12501179-Nucleotide Deaminases, pubmed-meshheading:12501179-Phosphoribosylaminoimidazolecarboxamide Formyltransferase, pubmed-meshheading:12501179-Protein Structure, Secondary, pubmed-meshheading:12501179-Protein Structure, Tertiary, pubmed-meshheading:12501179-Structure-Activity Relationship, pubmed-meshheading:12501179-Substrate Specificity
pubmed:year
2002
pubmed:articleTitle
Structural insights into the avian AICAR transformylase mechanism.
pubmed:affiliation
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't