Nucleoside-linked shunt products in the reaction catalyzed by the class C radical S-adenosylmethionine methyltransferase NosN

Ding, Wei; Yu, Yi; Ji, Xinjian; Qianzhu, Haocheng; Chen, Fen‐Er; Deng, Zixin; Zhang, Qi

doi:10.1039/c7cc02162c

Cited by 21 publications

(16 citation statements)

References 41 publications

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“…S -guanosylmethionine and S -cytidinylmethionine) have provided indirect support for this mechanistic proposal. 32 The work on NosN presents a new paradigm for cobalamin-independent rSAM MTs. Whether this proposed mechanism holds for other class C rSAM MTs remains an area of active investigation.…”

Section: Ripp Biosynthetic Reactions Catalyzed By Rsam Enzymesmentioning

confidence: 99%

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

2017

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, such as broad and narrow spectrum growth suppressors, antidiabetics, as well as antinociception and anticancer agents. Owing to these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied. RiPP biosynthesis often involves enzymes that perform unique chemistry with intriguing reaction mechanisms, which attract chemists and biochemists alike to study and re-engineer these pathways. One particular type of RiPP biosynthetic enzyme is the so-called radical S-adenosylmethionine (rSAM) enzyme, which utilize radical-based chemistry to install several distinct PTMs. Here, we describe the rSAM enzymes characterized over the past decade that catalyze six reactions types from several RiPP biosynthetic pathways. We present the current state of mechanistic understanding and conclude with possible directions for future characterization of this enzyme family.

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Section: Ripp Biosynthetic Reactions Catalyzed By Rsam Enzymesmentioning

confidence: 99%

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

2017

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“…The methyltransferase activity of the class C radical SAM enzyme NosN has been recently reconstituted in vitro in our lab, which was shown to install a methyl group on the indole C4 of the MIA moiety 32 , 33 . Neither MIA ( 3 ) nor 2 is the NosN substrate, while this enzyme was shown to methylate 9 , an N -acetylcysteamine (SNAC) thioester derivative of MIA, to produce 10 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that the radical SAM methyltransferase NosN is responsible for attaching a methyl group on the C4 of MIA moiety and this methylation reaction involves a key methylene radical derived from 5′-methylthioadenosine, a SAM cleavage product 32 , 33 . The nosN -knockout mutant of S. actuosus produced a nosiheptide analogue ( 2 ), which contains an indolyl- S -cysteine moiety, whereas the side ring is not formed 14 , 32 .…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of the nosiheptide indole side ring centers on a cryptic carrier protein NosJ

Ding

et al. 2017

Nat Commun

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Nosiheptide is a prototypal thiopeptide antibiotic, containing an indole side ring in addition to its thiopeptide-characteristic macrocylic scaffold. This indole ring is derived from 3-methyl-2-indolic acid (MIA), a product of the radical S-adenosylmethionine enzyme NosL, but how MIA is incorporated into nosiheptide biosynthesis remains to be investigated. Here we report functional dissection of a series of enzymes involved in nosiheptide biosynthesis. We show NosI activates MIA and transfers it to the phosphopantetheinyl arm of a carrier protein NosJ. NosN then acts on the NosJ-bound MIA and installs a methyl group on the indole C4, and the resulting dimethylindolyl moiety is released from NosJ by a hydrolase-like enzyme NosK. Surface plasmon resonance analysis show that the molecular complex of NosJ with NosN is much more stable than those with other enzymes, revealing an elegant biosynthetic strategy in which the reaction flux is controlled by protein–protein interactions with different binding affinities.

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“…These enzymes, which are characterized by sequence homologies with HemN (Layer et al, 2002 ) are referred as class C radical SAM methyl-transferases in contrast to B 12 -dependent radical SAM enzymes which belong to class B methyl-transferases (Zhang et al, 2011b ). Two enzymes, TbtI and NosN, involved in, respectively, the biosynthesis of the thiopeptide thiomuracin (Mahanta et al, 2017 ) and nosiheptide (Ding et al, 2017a , b ), have been recently characterized. In an unexpected manner, it has been proposed that NosN uses the SAM cofactor to generate not only 5′-dA but also 5′-methylthioadenosine (MTA) (Ding et al, 2017a ).…”

Section: Radical Sam Enzymes Involved In Ripp Methyl Transfer Reactiomentioning

confidence: 99%

Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)

2017

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Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large and diverse family of natural products. They possess interesting biological properties such as antibiotic or anticancer activities, making them attractive for therapeutic applications. In contrast to polyketides and non-ribosomal peptides, RiPPs derive from ribosomal peptides and are post-translationally modified by diverse enzyme families. Among them, the emerging superfamily of radical SAM enzymes has been shown to play a major role. These enzymes catalyze the formation of a wide range of post-translational modifications some of them having no counterparts in living systems or synthetic chemistry. The investigation of radical SAM enzymes has not only illuminated unprecedented strategies used by living systems to tailor peptides into complex natural products but has also allowed to uncover novel RiPP families. In this review, we summarize the current knowledge on radical SAM enzymes catalyzing RiPP post-translational modifications and discuss their mechanisms and growing importance notably in the context of the human microbiota.

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Nucleoside-linked shunt products in the reaction catalyzed by the class C radical S-adenosylmethionine methyltransferase NosN

Cited by 21 publications

References 41 publications

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Biosynthesis of the nosiheptide indole side ring centers on a cryptic carrier protein NosJ

Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)

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