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| Autori principali: | , , , , , , , , , , , , |
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| Natura: | Artículo Open Access |
| Pubblicazione: |
Wiley
2026
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| Accesso online: | https://onlinelibrary.wiley.com/doi/10.1002/prot.70139 |
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Sommario:
- The Mycobacterium tuberculosis Rv0132c Gene Product Mtb‐ FGD2 Can Act as an F 420 ‐Dependent Glucose Dehydrogenase Adewale V. Aderemi Matthew Snee Richard B. Tunnicliffe Linus O. Johanissen Matthew J. Cliff Colin W. Levy Derren J. Heyes Marina Golovanova Thomas A. Jowitt Sam Hay Andrew W. Munro Jonathan P. Waltho David Leys Proteins: Structure, Function, and Bioinformatics ABSTRACT The role of the cell envelope‐associated Rv0132c/FGD2 from Mycobacterium tuberculosis has long been a subject of debate. Importantly, FGD2 is found only in pathogenic mycobacteria, making it a potential drug target. While some suggest it functions as a glucose‐6‐phosphate dehydrogenase, others propose it acts instead as an F 420 ‐dependent hydroxy‐mycolic acid dehydrogenase—an activity linked to cell‐wall remodeling and inhibition by the anti‐tubercular drug pretomanid. Yet, direct evidence for either activity has been lacking. Here, we heterologously express and purify active Mtb‐FGD2, and demonstrate that the enzyme binds the F 420 cofactor with nanomolar affinity. Crystal structures for both the apo‐ form and the F 420 complex reveal that the Mtb‐FGD2 active site architecture is consistent with sugar substrates but notably lacks a phosphate‐binding pocket. Biochemical assays confirm that Mtb‐FGD2 functions efficiently as an F 420 ‐dependent glucose dehydrogenase in vitro. Computational docking combined with molecular dynamics simulations further supports the formation of a catalytically plausible β‐D‐glucose:F 420 ternary complex. When coupled to other F 420 ‐dependent enzymes, Mtb‐FGD2 readily supports glucose‐driven F 420 .H 2 ‐dependent oxidoreductase activity. Our data thus suggest that the Mtb‐FGD2 provides reduced F 420 .H 2 in a glucose‐dependent manner to support mycobacterial F 420 .H 2 ‐dependent oxidoreductases in the cell envelope. 10.1002/prot.70139 http://creativecommons.org/licenses/by/4.0/