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Radical SAM Enzymes and Metallocofactor Assembly: A Structural Point of View.

ABSTRACT: This Review focuses on the structure-function relationship of radical S-adenosyl-l-methionine (SAM) enzymes involved in the assembly of metallocofactors corresponding to the active sites of [FeFe]-hydrogenase and nitrogenase [MoFe]-protein. It does not claim to correspond to an extensive review on the assembly machineries of these enzyme active sites, for which many good reviews are already available, but instead deals with the contribution of structural data to the understanding of their chemical mechanism (Buren et al. Chem. Rev.2020, 142 ( (25), ) 11006-11012; Britt et al. Chem. Sci.2020, 11 ( (38), ), 10313-10323). Hence, we will present the history and current knowledge about the radical SAM maturases HydE, HydG, and NifB as well as what, in our opinion, should be done in the near future to overcome the existing barriers in our understanding of this fascinating chemistry that intertwine organic radicals and organometallic complexes.

SUBMITTER: Nicolet Y

PROVIDER: S-EPMC10114646 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Radical SAM Enzymes and Metallocofactor Assembly: A Structural Point of View.

Nicolet Yvain Y Cherrier Mickael V MV Amara Patricia P

ACS bio & med chem Au 20211120 1

This Review focuses on the structure-function relationship of radical <i>S</i>-adenosyl-l-methionine (SAM) enzymes involved in the assembly of metallocofactors corresponding to the active sites of [FeFe]-hydrogenase and nitrogenase [MoFe]-protein. It does not claim to correspond to an extensive review on the assembly machineries of these enzyme active sites, for which many good reviews are already available, but instead deals with the contribution of structural data to the understanding of their ...[more]

PMID: 37102176

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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 and Metallocofactor Assembly: A Structural Point of View.

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Radical SAM Enzymes and Metallocofactor Assembly: A Structural Point of View.

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