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Review
. 2018 Jan 30;57(4):390-402.
doi: 10.1021/acs.biochem.7b00878. Epub 2017 Nov 9.

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

Kenichi Yokoyama  1
Affiliations
Review

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

Kenichi Yokoyama. Biochemistry. .

Abstract

The radical SAM (S-adenosyl-l-methionine) superfamily is one of the largest group of enzymes with >113000 annotated sequences [Landgraf, B. J., et al. (2016) Annu. Rev. Biochem. 85, 485-514]. Members of this superfamily catalyze the reductive cleavage of SAM using an oxygen sensitive 4Fe-4S cluster to transiently generate 5'-deoxyadenosyl radical that is subsequently used to initiate diverse free radical-mediated reactions. Because of the unique reactivity of free radicals, radical SAM enzymes frequently catalyze chemically challenging reactions critical for the biosynthesis of unique structures of cofactors and natural products. In this Perspective, I will discuss the impact of characterizing novel functions in radical SAM enzymes on our understanding of biosynthetic pathways and use two recent examples from my own group with a particular emphasis on two radical SAM enzymes that are responsible for carbon skeleton formation during the biosynthesis of a cofactor and natural products.

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Figures

Figure 1
Figure 1
Reductive cleavage of SAM reaction common to all radical SAM enzymes.
Figure 2
Figure 2
Moco pathway and proposed functions of MoaA and MoaC. (A) Overview of the Moco biosynthetic pathway. The symbols on GTP and cPMP indicate the source of the carbon and nitrogen atoms in cPMP as determined by isotope labeling studies–. (B and C) Previously proposed functions of MoaA and MoaC with a single step mechanism (B) and stepwise mechanism– (C). (D) Our proposal using 3′,8-cH2GTP as the product of MoaA and substrate for MoaC.
Figure 3
Figure 3
MoaC-catalyzed conversion of 3′,8-cH2GTP to cPMP. (A and B) X-ray crystal structures of K51A-MoaC in complex with the substrate, 3′,8-cH2GTP (A), and wt-MoaC in complex with the product, cPMP (B). (C) The proposed motion of loop 3 and the N-terminal loop during MoaC catalysis. (D) Proposed conformationally guided mechanism of MoaC catalysis. Figures were adapted with permission from Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 6347-52.
Figure 4
Figure 4
MoaA-catalyzed conversion of GTP to 3′,8-cH2GTP. (A) The proposed mechanism of MoaA catalysis. The transfer of the H atom at the 3′ position to the 5′ position of 5′-dA was demonstrated using deuterium-labeled GTP–. (B) The active site structure of MoaA. SAM was modeled based on the comparison of the crystal structures of MoaA in complex with SAM (PDB ID, 1TV8) and that in complex with GTP (PDB ID, 2FB3). Reprinted with permission from J. Am. Chem. Soc. 2013, 135, 7019-32. Copyright 2013 American Chemical Society.
Figure 5
Figure 5
Possible mechanisms for SAM cleavage by radical SAM enzymes.
Figure 6
Figure 6
(A) Fungal cell wall structure. (B) Putative biosynthetic pathways for OA-related antifungal nucleosides. (C) Previously proposed mechanism for OA biosynthesis.
Figure 7
Figure 7
(A) Proposed mechanism for PolH catalysis. (B) Putative antifungal nucleoside biosynthetic gene clusters.
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References

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