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

posted Dec 24, 2015, 3:38 AM by SRamachandran Igib
Tuberculosis (TB) is one of the leading causes of infectious disease mortality. India is the highest TB burden country in the world with about 25% of the global TB burden (TB India 2014, Revised National TB Control Programme Annual Status Report). It is generally believed that one third of the world population is latently infected with Mycobacterium tuberculosis (Mtb), the causative organism of TB. This latent bacterium gets reactivated upon immune system weakening that can happen during several other disease conditions. The asymptomatic latent population is extremely difficult to diagnose and there is no effective drug for this growth form of Mtb. In the latent state the bacteria undergo substantial metabolic remodeling whose mechanistic understanding is vague. Although the metabolic pathways are slowed down, the bacteria have to sustain a threshold supply of ATP. Mtb has the genomic repertoire to modulate the respiratory pathways but the mechanism of this modulation is poorly understood. Oxygen level changes are known to affect the respiratory electron transport chain and bacteria are known to utilize alternate electron carriers and acceptors at different oxygen partial pressure.
Several Gram-negative bacteria are known to switch between ubiquinone (CoQ) to menaquinone (MK) with decreasing oxygen concentrations, this mode of exchange between isoprenoid quinones is absent in Gram-positive species. Surprisingly, the only known respiratory electron carrier quinone from mycobacteria, MK, is markedly downregulated in hypoxic condition. We recently identified a novel electron shuttling molecule, polyketide quinone (PkQ), in mycobacteria that support bacterial survival in oxygen-depleted habitats. Unlike canonical respiratory quinones that are derived from isoprenoid pathway, these molecules are produced by a polyketide synthase based pathway. PkQs function as electron carriers in the respiratory electron transport chain. This biosynthetic system is conserved in all mycobacteria as well as several Actinobacteria and a few Proteobacteria, suggesting a key role of these quinones in bacterial adaptability.

Amitesh Anand, Priyanka Verma, Anil Kumar Singh, Sandeep Kaushik, Rajesh Pandey, Ce Shi, Harneet Kaur, Manbeena Chawla, Chandra Kumar Elechalawar, Dhirendra Kumar, Yong Yang, Neel S. Bhavesh, Rajkumar Banerjee, Debasis Dash, Amit Singh, Vivek T. Natarajan, Anil K. Ojha, Courtney C. Aldrich & Rajesh S. Gokhale
Polyketide Quinones Are Alternate Intermediate Electron Carriers during Mycobacterial Respiration in Oxygen-Deficient Niches

Molecular Cell, November, 2015
DOI: http://dx.doi.org/10.1016/j.molcel.2015.10.016