Journal article

Cellular and Structural Basis of Synthesis of the Unique Intermediate Dehydro-F-420-0 in Mycobacteria

Rhys Grinter, Blair Ney, Rajini Brammananth, Christopher K Barlow, Paul RF Cordero, David L Gillett, Thierry Izore, Max J Cryle, Liam K Harold, Gregory M Cook, George Taiaroa, Deborah A Williamson, Andrew C Warden, John G Oakeshott, Matthew C Taylor, Paul K Crellin, Colin J Jackson, Ralf B Schittenhelm, Ross L Coppel, Chris Greening

MSYSTEMS | AMER SOC MICROBIOLOGY | Published : 2020

Abstract

F420 is a low-potential redox cofactor used by diverse bacteria and archaea. In mycobacteria, this cofactor has multiple roles, including adaptation to redox stress, cell wall biosynthesis, and activation of the clinical antitubercular prodrugs pretomanid and delamanid. A recent biochemical study proposed a revised biosynthesis pathway for F420 in mycobacteria; it was suggested that phosphoenolpyruvate served as a metabolic precursor for this pathway, rather than 2-phospholactate as long proposed, but these findings were subsequently challenged. In this work, we combined metabolomic, genetic, and structural analyses to resolve these discrepancies and determine the basis of F420 biosynthesis ..

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Grants

Awarded by ARC DECRA Fellowship


Awarded by NHMRC EL2 Fellowship


Awarded by NHMRC New Investigator Grant


Awarded by NHMRC


Awarded by ARC Discovery Grant


Funding Acknowledgements

This work was supported by an ARC DECRA Fellowship (DE170100310; awarded to C.G.), an NHMRC EL2 Fellowship (APP1178715; awarded to C.G.), an NHMRC New Investigator Grant (APP1142699; awarded to C.G.), an NHMRC grant (APP1139832; awarded to C.J.J., C.G., and G.M.C.), a Monash University Science-Medicine Seed Grant (awarded to C.G. and M.J.C.), Monash University Doctoral Scholarships (awarded to P.R.F.C. and D.L.G.), and an ARC Discovery Grant (DP180102463; awarded to R.L.C.).