Adenosyl Radical: Reagent and Catalyst in Enzyme Reactions

Abstract

Lead in Adenosine is undoubtedly an ancient biological molecule that is a component of many enzyme cofactors; ATP, FADH, NAD(P)H, and coenzyme A, to name but a few, and, of course, of RNA. Here we present an overview of the role of adenosine in its most reactive form: as an organic radical formed either by homolytic cleavage of adenosylcobalamin (coenzyme B12, AdoCbl) or by single-electron reduction of S-adenosylmethionine (AdoMet) complexed to an iron-sulfur cluster. Although many of the enzymes we discuss are newly discovered, adenosine’s role as a radical cofactor most likely arose very early in evolution, before the advent of photosynthesis and the production of molecular oxygen which rapidly inactivates many radical enzymes. AdoCbl-dependent enzymes appear to be confined to a rather narrow repertoire of rearrangement reactions involving 1,2-hydrogen atom migrations. In contrast, there has been a recent explosion in the number radical AdoMet enzymes discovered that catalyze a remarkably wide range of chemically challenging reactions. Although all the radical AdoMet enzymes so far characterized come from anaerobically growing microbes and are very oxygen sensitive, there is tantalizing evidence that some of these enzymes may be active in aerobic organisms including humans.

Molecular hijacking of siroheme for the synthesis of heme and d 1 heme

“…S5A). This process is analogous to the proposed fragmentation of glutamate in the reaction catalyzed by coenzyme B 12 -dependent glutamate mutase, where an acrylate molecule and glycyl radical are formed prior to the rearrangement into 3-methylaspartate (25,26). However, in the case of the reaction catalyzed by AhbC the enzyme presumably converts the acetate radical to acetate by providing a further electron (and proton), which could come from a second predicted Fe-S center on the protein.…”

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

“…Central to the mechanism of all radical SAM enzymes is the generation of a highly reactive 5Ј-deoxyadenosyl radical (Ado ⅐ ) (1,4,17). This is accomplished through one-electron reduction of SAM by the [Fe 4 S 4 ] cluster ( Fig.…”

“…Sequence analyses indicate that there are potentially thousands of members of the radical SAM superfamily, but to date, relatively few of these enzymes have been isolated and characterized (15, 16). Radical SAM enzymes were until recently thought to be confined to the microbial realm but intriguingly have now been identified in higher aerobic organisms, including plants and animals (3).Central to the mechanism of all radical SAM enzymes is the generation of a highly reactive 5Ј-deoxyadenosyl radical (Ado ⅐ ) (1,4,17). This is accomplished through one-electron reduction of SAM by the [Fe 4 S 4 ] cluster (Fig.…”

Complex Biotransformations Catalyzed by Radical S-Adenosylmethionine Enzymes

“…As the C␣ of the glycyl radical carries the largest spin density, it should be more reactive compared with the carboxyl group. Why the reaction does not proceed with the attack of the C␣ of the glycyl radical on the system, as found in glutamate mutase (10,18), is unclear. It is possibly because the glycyl radical is tightly sequestered in the enzyme's active site, leaving the C␣ too far to react with the indole ring.…”

“…The Ado radical chemistry is also found in adenosylcobalamin (AdoCbl)-dependent family enzymes. In this case, the Ado radical is produced via the homolytic cleavage of the cobalt-carbon bond of the corrin cofactor (10,18,19). However, the number and diversity of the AdoCbl-dependent enzymes are in no way comparable with those of the radical AdoMet enzymes.…”