Fine-tuning of a radical-based reaction by radical
            <i>S</i>
            -adenosyl-L-methionine tryptophan lyase

Sicoli, Giuseppe; Mouesca, Jean‐Marie; Zeppieri, Laura; Amara, Patricia; Martin, Lydie; Barra, Anne‐Laure; Fontecilla‐Camps, Juan C.; Gambarelli, Serge; Nicolet, Yvain

doi:10.1126/science.aad8995

Cited by 55 publications

(71 citation statements)

References 28 publications

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“…According to the proposed mechanism, radical 74 could undergo a second β scission forming intermediate 69 which can then tautomerize to form the product ( 62) while radical 70 can form 63 and 64 , as previously proposed. 86 In this regard, NosL differs from other tyrosine lyases (e.g. ThiH), 9 although all start with amino hydrogen abstraction to form 65 .…”

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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“…(1) These enzymes utilize a [4Fe-4S] + cluster and S -adenosylmethionine (SAM) to catalyze a remarkably diverse array of finely-tuned (2) radical reactions that are central to key pathways, such as heme and chlorophyll biosynthesis, vitamin biosynthesis, DNA repair, and metal cluster assembly. (1) Spectroscopic studies of the radical SAM enzymes pyruvate formate-lyase activating enzyme (PFL-AE) and lysine 2,3-aminomutase (LAM), as confirmed by X-ray structure determinations, demonstrated that these enzymes bind SAM as a classical coordination complex in which the amino and carboxyl moieties of SAM chelate the unique iron of a [4Fe-4S] cluster.…”

mentioning

confidence: 99%

Radical SAM catalysis via an organometallic intermediate with an Fe–[5′-C]-deoxyadenosyl bond

Horitani

Shisler

Broderick

et al. 2016

Science

118

182

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Radical SAM enzymes use a [4Fe-4S] cluster to cleave S-adenosylmethionine (SAM) to initiate diverse radical reactions. These are thought to involve the 5′-deoxyadenosyl radical intermediate, which has not yet been detected. Here we rapid freeze-quench trap a catalytically competent intermediate in the reaction catalyzed by the radical SAM enzyme pyruvate formate-lyase activating enzyme. Characterization of the intermediate by electron paramagnetic resonance and 13C, 57Fe electron-nuclear double resonance spectroscopies reveals that it contains an organometallic center in which 5′-carbon of a SAM-derived deoxyadenosyl moiety forms a bond to the unique iron of the [4Fe-4S] cluster. Discovery of this intermediate extends the list of enzymatic bio-organometallic centers to the radical SAM enzymes, the largest enzyme superfamily known, and reveals intriguing parallels to B12 radical enzymes.

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“…Richardson et al study the water hexamer (H 2 O) 6 , which is the smallest cluster with a three-dimensional geometry and has been dubbed the smallest water droplet (3). Advanced spectroscopic methods have yielded experimental information on its structure and properties (4).…”

Section: Pathway 1 Cα-c Cleavagementioning

confidence: 99%

“…There are more than 113,000 radical SAM enzymes, but only a small number are both biochemically and structurally characterized, and many of the reaction mechanisms remain enigmatic. On page 1320 of this issue, Sicoli et al provide evidence for unexpected radical intermediates in the mechanism of the radical SAM enzyme NosL (6).…”

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confidence: 95%

A radically unexpected mechanism

Bridwell‐Rabb

Drennan

2016

Science

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From amino acid to bacterial warfare agent. The radical SAM enzyme NosL catalyzes the transformation of L-tryptophan into MIA, a component of the antibiotic nosiheptide. NosL uses a [4Fe-4S] cluster and SAM to generate a 59-dAdo• species. 59-dAdo• abstracts a hydrogen atom from the amino moiety of L-tryptophan to initiate catalysis.Unexpected mechanism. Literature precedence favored a Cα-Cβ cleavage pathway for the biosynthesis of MIA from L-tryptophan, but the work of Sicoli et al. instead provides support for the unprecedented Cα-C cleavage pathway.

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Fine-tuning of a radical-based reaction by radical S -adenosyl-L-methionine tryptophan lyase

Cited by 55 publications

References 28 publications

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Radical SAM catalysis via an organometallic intermediate with an Fe–[5′-C]-deoxyadenosyl bond

A radically unexpected mechanism

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