Radical S-Adenosylmethionine (SAM) Enzymes in Cofactor Biosynthesis: A Treasure Trove of Complex Organic Radical Rearrangement Reactions

Angad P Mehta,Sameh H Abdelwahed,Nilkamal Mahanta,Dmytro Fedoseyenko,Benjamin Philmus,Lisa E Cooper,Yiquan Liu,Isita Jhulki,Steven E Ealick,Tadhg P Begley

doi:10.1074/jbc.r114.623793

Angad P Mehta, Sameh H Abdelwahed + Show 8 more

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https://doi.org/10.1074/jbc.r114.623793

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Abstract

In this minireview, we describe the radical S-adenosylmethionine enzymes involved in the biosynthesis of thiamin, menaquinone, molybdopterin, coenzyme F420, and heme. Our focus is on the remarkably complex organic rearrangements involved, many of which have no precedent in organic or biological chemistry.

Highlights

This minireview focuses on the organic chemistry of the radical SAM enzymes involved in cofactor biosynthesis: thiamin [1], F0 [2], menaquinone [3], molybdopterin [4], and heme [5] (Fig. 1). (Biotin and lipoic biosynthesis uses radical SAM enzymology and is covered separately in another minireview in this series [42].) In contrast to iron(IV)-oxo-derived radicals, where the dominant chemistry involves radical recombination with the iron-bound oxygen (P450 rebound rate of Ͼ1010 sϪ1) [3], radicals formed by hydrogen atom transfer to the 5Ј-deoxyadenosyl (5Ј-dA) radical are more persistent because the reverse reaction is relatively slow
Thiamin pyrophosphate [1] is an important cofactor in carbohydrate metabolism and branched chain amino acid biosynthesis, where it plays a key role in stabilization of the acyl carbanion biosynthon
This mechanism is supported by labeling studies [5,6,7,8], by the identification of CO and formate as reaction products [4, 5], and by a structure of the enzyme with desamino-aminoimidazole ribotide (AIR) bound at the active site [4]

Summary

Introduction

This minireview focuses on the organic chemistry of the radical SAM enzymes involved in cofactor biosynthesis: thiamin [1], F0 [2], menaquinone [3], molybdopterin [4], and heme [5] (Fig. 1). (Biotin and lipoic biosynthesis uses radical SAM enzymology and is covered separately in another minireview in this series [42].) In contrast to iron(IV)-oxo-derived radicals, where the dominant chemistry involves radical recombination with the iron-bound oxygen (P450 rebound rate of Ͼ1010 sϪ1) [3], radicals formed by hydrogen atom transfer to the 5Ј-deoxyadenosyl (5Ј-dA) radical are more persistent because the reverse reaction is relatively slow. Radical 7 abstracts a hydrogen atom from 6 to form 10. Electrophilic addition to the aminoimidazole followed by hydrogen atom transfer gives 14. The regenerated 5Ј-dA radical [7] abstracts a hydrogen atom from 14 to form 15.

Results

Conclusion