2Y89

CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS PHOSPHORIBOSYL ISOMERASE A (VARIANT D11N)

2Y89 の概要

• エントリーDOI: 10.2210/pdb2y89/pdb
• 関連するPDBエントリー: 2Y85 2Y88
• 分子名称: PHOSPHORIBOSYL ISOMERASE A, SULFATE ION (3 entities in total)
• 機能のキーワード: isomerase, aromatic amino acid biosynthesis, tryptophan biosynthesis, tim barrel, histidine biosynthesis
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26330.22

構造登録者

Due, A.V.,Kuper, J.,Geerlof, A.,Wilmanns, M. (登録日: 2011-02-03, 公開日: 2011-03-02, 最終更新日: 2024-05-08)

主引用文献

Due, A.V.,Kuper, J.,Geerlof, A.,Kries, J.P.,Wilmanns, M.
Bisubstrate Specificity in Histidine/Tryptophan Biosynthesis Isomerase from Mycobacterium Tuberculosis by Active Site Metamorphosis.
Proc.Natl.Acad.Sci.USA, 108:3554-, 2011

PubMed Abstract: In histidine and tryptophan biosynthesis, two related isomerization reactions are generally catalyzed by two specific single-substrate enzymes (HisA and TrpF), sharing a similar (β/α)(8)-barrel scaffold. However, in some actinobacteria, one of the two encoding genes (trpF) is missing and the two reactions are instead catalyzed by one bisubstrate enzyme (PriA). To unravel the unknown mechanism of bisubstrate specificity, we used the Mycobacterium tuberculosis PriA enzyme as a model. Comparative structural analysis of the active site of the enzyme showed that PriA undergoes a reaction-specific and substrate-induced metamorphosis of the active site architecture, demonstrating its unique ability to essentially form two different substrate-specific actives sites. Furthermore, we found that one of the two catalytic residues in PriA, which are identical in both isomerization reactions, is recruited by a substrate-dependent mechanism into the active site to allow its involvement in catalysis. Comparison of the structural data from PriA with one of the two single-substrate enzymes (TrpF) revealed substantial differences in the active site architecture, suggesting independent evolution. To support these observations, we identified six small molecule compounds that inhibited both PriA-catalyzed isomerization reactions but had no effect on TrpF activity. Our data demonstrate an opportunity for organism-specific inhibition of enzymatic catalysis by taking advantage of the distinct ability for bisubstrate catalysis in the M. tuberculosis enzyme.

PubMed: 21321225
DOI: 10.1073/PNAS.1015996108

実験手法

X-RAY DIFFRACTION (2.5 Å)