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Mol Cell. 2015 Nov 19;60(4):637-50. doi: 10.1016/j.molcel.2015.10.016. Epub 2015 Nov 12.

Polyketide Quinones Are Alternate Intermediate Electron Carriers during Mycobacterial Respiration in Oxygen-Deficient Niches.

Author information

1
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India.
2
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
3
CSIR-North East Institute of Science and Technology, Jorhat 785006, India.
4
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India.
5
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
6
Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
7
Department of Microbiology and Cell Biology, Centre for Infectious Disease and Research, Indian Institute of Science, Bangalore 560012, India.
8
Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India; CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
9
Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA.
10
International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
11
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
12
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110020, India; Academy of Scientific and Innovative Research, Rafi Marg, New Delhi 110001, India; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: rsg@igib.res.in.

Abstract

Mycobacterium tuberculosis (Mtb) adaptation to hypoxia is considered crucial to its prolonged latent persistence in humans. Mtb lesions are known to contain physiologically heterogeneous microenvironments that bring about differential responses from bacteria. Here we exploit metabolic variability within biofilm cells to identify alternate respiratory polyketide quinones (PkQs) from both Mycobacterium smegmatis (Msmeg) and Mtb. PkQs are specifically expressed in biofilms and other oxygen-deficient niches to maintain cellular bioenergetics. Under such conditions, these metabolites function as mobile electron carriers in the respiratory electron transport chain. In the absence of PkQs, mycobacteria escape from the hypoxic core of biofilms and prefer oxygen-rich conditions. Unlike the ubiquitous isoprenoid pathway for the biosynthesis of respiratory quinones, PkQs are produced by type III polyketide synthases using fatty acyl-CoA precursors. The biosynthetic pathway is conserved in several other bacterial genomes, and our study reveals a redox-balancing chemicocellular process in microbial physiology.

PMID:
26585386
PMCID:
PMC6051517
DOI:
10.1016/j.molcel.2015.10.016
[Indexed for MEDLINE]
Free PMC Article

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