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Radical SAM enzymes: surprises along the path to understanding mechanism.

ABSTRACT: As the field of radical SAM enzymology has grown from a few examples in the 1990s to hundreds of thousands today, a fundamental question has remained: how does Nature use S-adenosyl-L-methionine to initiate radical reactions? This was a driving question when we first began studying pyruvate formate-lyase activating enzyme in 1993, and our journey for answers has brought us to many surprising discoveries, from the direct coordination of SAM to a unique iron in a [4Fe-4S] cluster, to our recent discovery of an organometallic intermediate and our ability to quantitatively produce and characterize the long-sought 5'-deoxyadenosyl radical intermediate. These adventures and what we have learned along the way about this fundamentally novel chemistry is described in this review.

SUBMITTER: Broderick WE

PROVIDER: S-EPMC8837180 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Radical SAM enzymes: surprises along the path to understanding mechanism.

Broderick William E WE Broderick Joan B JB

Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 20190907 6

As the field of radical SAM enzymology has grown from a few examples in the 1990s to hundreds of thousands today, a fundamental question has remained: how does Nature use S-adenosyl-L-methionine to initiate radical reactions? This was a driving question when we first began studying pyruvate formate-lyase activating enzyme in 1993, and our journey for answers has brought us to many surprising discoveries, from the direct coordination of SAM to a unique iron in a [4Fe-4S] cluster, to our recent di ...[more]

PMID: 31494759

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Project description:A [4Fe-4S](+) cluster reduces a bound S-adenosylmethionine (SAM) molecule, cleaving it into methionine and a 5'-deoxyadenosyl radical (5'-dA(•)). This step initiates the varied chemistry catalyzed by each of the so-called radical SAM enzymes. The strongly oxidizing 5'-dA(•) is quenched by abstracting a H-atom from a target species. In some cases, this species is an exogenous molecule of substrate, for example, L-tyrosine in the [FeFe] hydrogenase maturase, HydG. In other cases, the target is a proteinaceous residue as in all the glycyl radical forming enzymes. The generation of this initial radical species and the subsequent chemistry involving downstream radical intermediates is meticulously controlled by the enzyme so as to prevent unwanted reactions. But the manner in which this control is exerted is unknown. Electron paramagnetic resonance (EPR) spectroscopy has proven to be a valuable tool used to gain insight into these mechanisms. In this Account, we summarize efforts to trap such radical intermediates in radical SAM enzymes and highlight four examples in which EPR spectroscopic results have shed significant light on the corresponding mechanism. For lysine 2,3-aminomutase, nearly each possible intermediate, from an analogue of the initial 5'-dA(•) to the product radical L-β-lysine, has been explored. A paramagnetic intermediate observed in biotin synthase is shown to involve an auxiliary [FeS] cluster whose bridging sulfide is a co-substrate for the final step in the biosynthesis of vitamin B7. In HydG, the L-tyrosine substrate is converted in unprecedented fashion to a 4-oxidobenzyl radical on the way to generating CO and CN(-) ligands for the [FeFe] cluster of hydrogenase. And finally, EPR has confirmed a mechanistic proposal for the antibiotic resistance protein Cfr, which methylates the unactivated sp(2)-hybridized C8-carbon of an adenosine base of 23S ribosomal RNA. These four systems provide just a brief survey of the ever-growing set of radical SAM enzymes. The diverse chemistries catalyzed by these enzymes make them an intriguing target for continuing study, and EPR spectroscopy, in particular, seems ideally placed to contribute to our understanding.

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Radical SAM enzymes: surprises along the path to understanding mechanism.

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Radical SAM enzymes: surprises along the path to understanding mechanism.

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