Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.

Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Research Abstract Details 

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Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Abstract Text:

Lan Xu,Youhoon Chong,Inkyu Hwang,Anthony D'Onofrio,Kristen Amore,G Peter Beardsley,Chenglong Li,Arthur J Olson,Dale L Boger,Ian A Wilson,

The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.

Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Publishing Authors By Initials

L Xu,Y Chong,I Hwang,A D'Onofrio,K Amore,GP Beardsley,C Li,AJ Olson,DL Boger,IA Wilson,

For similar heterocyclic compounds: heterocyclic compounds, 2-ring: purines research abstracts see: heterocyclic compounds: heterocyclic compounds, 2-ring: purines research

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Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 13033-46

Journal Abbreviation:

ISSN: 0021-9258

DAY: 26

MONTH: 02

YEAR: 2007

Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Keywords Mesh Terms:

KEYWORDS: Purines

MESH TERMS: biosynthesis

Chemical & Substance for Abstract: Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. Information

Substance Name: Phosphoribosylaminoimidazolecarboxamide

Registry Number: EC 2.1.2.3

Grant and Affiliation Information for Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase.

AFFILIATION: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Country: United States

AGENCY: United States NCI

GRANT: R24 CA95830

ACRONYM: CA

MEDLINETA: J Biol Chem

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