Mycobacterium tuberculosis chorismate mutase: A potential target for TB.

Manjulatha Khanapur, Mallika Alvala, Maddela Prabhakar, K Shiva Kumar, R K Edwin, P S V K Sri Saranya, Raj Kumar Patel, Gopalakrishnan Bulusu, P Misra, Manojit Pal

Journal: Bioorganic & medicinal chemistry 2017;25(6):1725-1736

PMID: 28202315

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Abstract

Mycobacterium tuberculosis chorismate mutase (MtbCM) catalyzes the rearrangement of chorismate to prephenate in the shikimate biosynthetic pathway to form the essential amino acids, phenylalanine and tyrosine. Two genes encoding chorismate mutase have been identified in Mtb. The secretory form,∗MtbCM (encoded by Rv1885c) is assumed to play a key role in pathogenesis of tuberculosis. Also, the inhibition of MtbCM may hinder the supply of nutrients to the organism. Indeed, the existence of chorismate mutase (CM) in bacteria, fungi and higher plants but not in human and low sequence homology among known CM makes it an interesting target for the discovery of anti-tubercular agents. The present article mainly focuses on the recent developments in the structure, function and inhibition of MtbCM. The understanding of various aspects of MtbCM as presented in the current article may facilitate the design and subsequent chemical synthesis of new inhibitors against ∗MtbCM, that could lead to the discovery and development of novel and potent anti-tubercular agents in future.

Address: Department of Medicinal Chemistry, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.; Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.; Department of Chemistry, Osmania University, Hyderabad 500 007, India.; Department of Molecular Modeling, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.; Department of Molecular Modeling, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India; TCS Innovation Labs-Hyderabad (Life Sciences Division), Tata Consultancy Services Limited, Madhapur, Hyderabad 500 081, India.; Department of Medicinal Chemistry, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India. Electronic address: [email protected].

DOI: 10.1016/j.bmc.2017.02.001

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MeSH Terms: Amino Acid Sequence, Antitubercular Agents, Chorismate Mutase, Enzyme Inhibitors, Models, Molecular, Mycobacterium tuberculosis, Protein Conformation, Sequence Homology, Amino Acid