2Y85

CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS PHOSPHORIBOSYL ISOMERASE WITH BOUND RCDRP

Summary for 2Y85

• Entry DOI: 10.2210/pdb2y85/pdb
• Related: 2Y88 2Y89
• Descriptor: PHOSPHORIBOSYL ISOMERASE A, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: isomerase, bifunctional enzyme, tryptophan biosynthesis, histidine biosynthesis, tim-barrel, aromatic amino acid biosynthesis
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Cellular location: Cytoplasm (By similarity): P60578
• Total number of polymer chains: 4
• Total formula weight: 104434.75

Authors

Kuper, J.,Geerlof, A.,Wilmanns, M. (deposition date: 2011-02-03, release date: 2011-03-02, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)