Biosynthetic versatility and coordinated action of 5'-deoxyadenosyl radicals in deazaflavin biosynthesis

Journal of the American Chemical Society
Benjamin PhilmusTadhg P Begley

Abstract

Coenzyme F420 is a redox cofactor found in methanogens and in various actinobacteria. Despite the major biological importance of this cofactor, the biosynthesis of its deazaflavin core (8-hydroxy-5-deazaflavin, F(o)) is still poorly understood. F(o) synthase, the enzyme involved, is an unusual multidomain radical SAM enzyme that uses two separate 5'-deoxyadenosyl radicals to catalyze F(o) formation. In this paper, we report a detailed mechanistic study on this complex enzyme that led us to identify (1) the hydrogen atoms abstracted from the substrate by the two radical SAM domains, (2) the second tyrosine-derived product, (3) the reaction product of the CofH-catalyzed reaction, (4) the demonstration that this product is a substrate for CofG, and (5) a stereochemical study that is consistent with the formation of a p-hydroxybenzyl radical at the CofH active site. These results enable us to propose a mechanism for F(o) synthase and uncover a new catalytic motif in radical SAM enzymology involving the use of two 5'-deoxyadenosyl radicals to mediate the formation of a complex heterocycle.

References

Oct 31, 1978·Biochemistry·L D EirichR S Wolfe
Mar 5, 2011·Chemical Reviews·Jessica L Vey, Catherine L Drennan
Jul 19, 2013·The Journal of Physical Chemistry. B·Ulrich WeiningerMikael Akke
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Citations

Jul 24, 2015·Biochemistry·Dhananjay M BhandariTadhg P Begley
Jul 26, 2016·Frontiers in Chemistry·Wei DingQi Zhang
Dec 9, 2016·Chemical Communications : Chem Comm·Haocheng QianzhuQi Zhang
Apr 19, 2016·Chemical Communications : Chem Comm·Alhosna BenjdiaOlivier Berteau
Aug 6, 2016·Chemical Communications : Chem Comm·Xinjian JiQi Zhang
Apr 29, 2016·Microbiology and Molecular Biology Reviews : MMBR·Chris GreeningColin J Jackson
Dec 7, 2018·Organic & Biomolecular Chemistry·Yujie WuQi Zhang
Feb 11, 2016·Biochemical Society Transactions·Alhosna Benjdia, Olivier Berteau
Feb 23, 2020·Current Opinion in Chemical Biology·Wei DingQi Zhang
Apr 15, 2021·FEMS Microbiology Reviews·Rhys Grinter, Chris Greening
Mar 7, 2021·Journal of Industrial Microbiology & Biotechnology·Yuxuan YeTodd K Hyster

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR

Software Mentioned

Clustal Omega

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