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Title: Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis

Authors:
; ; ; ; ORCiD logo; ORCiD logo; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYNIHOTHER
OSTI Identifier:
1390888
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; Journal Volume: 114; Journal Issue: 29
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Pham, Truc V., Murkin, Andrew S., Moynihan, Margaret M., Harris, Lawrence, Tyler, Peter C., Shetty, Nishant, Sacchettini, James C., Huang, Hsiao-ling, and Meek, Thomas D. Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis. United States: N. p., 2017. Web. doi:10.1073/pnas.1706134114.
Pham, Truc V., Murkin, Andrew S., Moynihan, Margaret M., Harris, Lawrence, Tyler, Peter C., Shetty, Nishant, Sacchettini, James C., Huang, Hsiao-ling, & Meek, Thomas D. Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis. United States. doi:10.1073/pnas.1706134114.
Pham, Truc V., Murkin, Andrew S., Moynihan, Margaret M., Harris, Lawrence, Tyler, Peter C., Shetty, Nishant, Sacchettini, James C., Huang, Hsiao-ling, and Meek, Thomas D. 2017. "Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis". United States. doi:10.1073/pnas.1706134114.
@article{osti_1390888,
title = {Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis},
author = {Pham, Truc V. and Murkin, Andrew S. and Moynihan, Margaret M. and Harris, Lawrence and Tyler, Peter C. and Shetty, Nishant and Sacchettini, James C. and Huang, Hsiao-ling and Meek, Thomas D.},
abstractNote = {},
doi = {10.1073/pnas.1706134114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 29,
volume = 114,
place = {United States},
year = 2017,
month = 7
}
  • MbtI (rv2386c) from Mycobacterium tuberculosis catalyzes the initial transformation in mycobactin biosynthesis by converting chorismate to salicylate. We report here the structure of MbtI at 2.5 {angstrom} resolution and demonstrate that isochorismate is a kinetically competent intermediate in the synthesis of salicylate from chorismate. At pH values below 7.5 isochorismate is the dominant product while above this pH value the enzyme converts chorismate to salicylate without the accumulation of isochorismate in solution. The salicylate and isochorismate synthase activities of MbtI are Mg{sup 2+}-dependent, and in the absence of Mg{sup 2+} MbtI has a promiscuous chorismate mutase activity similar to thatmore » of the isochorismate pyruvate lyase, PchB, from Pseudomonas aeruginosa. MbtI is part of a larger family of chorismate-binding enzymes descended from a common ancestor (the MST family), that includes the isochorismate synthases and anthranilate synthases. The lack of active site residues unique to pyruvate eliminating members of this family, combined with the observed chorismate mutase activity, suggests that MbtI may exploit a sigmatropic pyruvate elimination mechanism similar to that proposed for PchB. Using a combination of structural, kinetic, and sequence based studies we propose a mechanism for MbtI applicable to all members of the MST enzyme family.« less
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