Emerging Diversity of the Cobalamin‐Dependent Methyltransferases Involving Radical‐Based Mechanisms

Abstract

Cobalamins comprise a group of cobalt-containing organometallic cofactors that play important roles in cellular metabolism. Although many cobalamin-dependent methyltransferases (e.g., methionine synthase MetH) have been extensively studied, a new group of methyltransferases that are cobalamin-dependent and utilize radical chemistry in catalysis is just beginning to be appreciated. In this Concept article, we summarize recent advances in the understanding of the radical-based and cobalamin-dependent methyltransferases and discuss the functional and mechanistic diversity of this emerging class of enzymes.

The Catalytic Mechanism of the Class C Radical S‐Adenosylmethionine Methyltransferase NosN

“…[1] Methylation can also occur at non-nucleophilic centers such as inert carbon or phosphorous atoms through radical-based mechanisms. [2] Currently,a ll of the known radical-based methyltransferases belong to the radical SAM superfamily, al arge enzyme superfamily consisting of more than 16,500 members found in all three domains of life. [3] Radical SAM enzymes utilize a[ 4Fe-4S] cluster to bind SAM and reductively cleave its carbon-sulfur bond to produce ah ighly reactive 5'-deoxyadenosyl (dAdo) radical, which initiates ahighly diverse array of reactions,including the methylation of various non-nucleophilic substrates.…”

“…[3] Radical SAM enzymes utilize a[ 4Fe-4S] cluster to bind SAM and reductively cleave its carbon-sulfur bond to produce ah ighly reactive 5'-deoxyadenosyl (dAdo) radical, which initiates ahighly diverse array of reactions,including the methylation of various non-nucleophilic substrates. [2] While most radical SAM methyltransferases (RSMTs) share asimilar strategy in using SAM both as amethyl donor and aradical initiator,the catalytic mechanisms of RSMTs are diverse. [2] NosN is ar adical SAM enzyme that is involved in the biosynthesis of nosiheptide (1), [4] ac linically interesting thiopeptide antibiotic produced by Streptomyces actuosus ( Figure 1A).…”

“…[2] While most radical SAM methyltransferases (RSMTs) share asimilar strategy in using SAM both as amethyl donor and aradical initiator,the catalytic mechanisms of RSMTs are diverse. [2] NosN is ar adical SAM enzyme that is involved in the biosynthesis of nosiheptide (1), [4] ac linically interesting thiopeptide antibiotic produced by Streptomyces actuosus ( Figure 1A). [5] Nosiheptide belongs to the large class of ribosomally synthesized and posttranslationally modified peptides (RiPPs).…”

Ribosomal Natural Products, Tailored To Fit

“…42,43 β-Methylation of amino acids is observed in several RiPP classes. For instance, during bottromycin A2 biosynthesis, four β- C -methylations are accomplished by three enzymes (Figure 5B).…”

Parallel pathways in the biosynthesis of aminoglycoside antibiotics

“…GenD2 and GenS are responsible for the amination of the C3'' position of gentamicin A2, and the resulting amino group is methylated by GenN to afford a C3'' methylamino group 28 . GenD1 belongs to the class B radical SAM methyltransferases 29, 30 , which utilizes a cobalamin cofactor and installs a methyl group on the C4'' position 31, 32 . Gentamicin X2 is then methylated at the C6' position by GenK, which, like GenD1, also belongs to the class B radical SAM methyltransferase, leading to the production of gentamicin G418 33 .…”