Following the electrons: peculiarities in the catalytic cycles of radical SAM enzymes

Ruszczycky, Mark W.; Zhong, Aoshu; Liu, Hung‐wen

doi:10.1039/c7np00058h

Cited by 36 publications

(32 citation statements)

References 77 publications

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“…The notion that MftC catalyzes two distinct chemistries in the same active, an oxidative decarboxylation of the C-terminus and a subsequent redox neutral C-C bond formation (Scheme 1), is intriguing. Whereas most reactions within the RS protein family can be classified as either oxidative or redox neutral (for a review see 33 ), MftC seems to be an outlier in that it can “redox-flip.” The ability of MftC to redox-flip, or accommodate both oxidative to redox neutral reactions, is certainly unique to the RS-SPASM subfamily, in which all proteins characterized to date have been shown to catalyze net oxidative reactions on the peptide substrate. In order for MftC to catalyze both reactions, we propose that two independent or combinatorial scenarios must play out: 1) the active site undergoes stepwise rearrangement, setting up MftC for both types of redox reactions and/or 2) the potentials of the [Fe-S] clusters within MftC are modulated to accommodate both types of redox reactions.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism

et al. 2019

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Mycofactocin is a putative redox cofactor and is classified as a ribosomally synthesized and post-translationally modified peptide (RiPP). Some RiPP natural products, including mycofactocin, rely on a radical S-adenosylmethionine (RS, SAM) protein to modify the precursor peptide. Mycofactocin maturase, MftC, is a unique RS protein that catalyzes the oxidative decarboxylation and C-C bond formation on the precursor peptide MftA. However, the number, chemical nature, and catalytic roles for the MftC [Fe-S] clusters remain unknown. Here, we report that MftC binds a RS [4Fe-4S] cluster and two auxiliary [4Fe-4S] clusters that are required for MftA modification. Furthermore, electron paramagnetic resonance spectra of MftC suggest that SAM and MftA affect the environments of the RS and Aux I cluster whereas the Aux II cluster is unaffected by the substrates. Lastly, reduction potential assignments of individual [4Fe-4S] clusters by protein film voltammetry show that their potentials are within 100 mV of each other.

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Section: Introductionmentioning

confidence: 99%

Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism

et al. 2019

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“…[11b,c] It can be expected that such a type of redox-neutrality may apply to many other radical SAM enzymes. [20] Finally, we attempt to reveal the distribution of DDMAA synthases and their associated arsenic metabolic pathways in nature. To this end, we performed a BLAST search and retrieved 5000 sequences from the UniProt database, which were then incorporated into a sequence similarity network (SSN) (Figure 6 A).…”

Section: Angewandte Chemiementioning

confidence: 99%

Characterization and Mechanistic Study of the Radical SAM Enzyme ArsS Involved in Arsenosugar Biosynthesis

Cheng

et al. 2021

Angew Chem Int Ed

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Arsenosugars are a group of arsenic‐containing ribosides that are found predominantly in marine algae but also in terrestrial organisms. It has been proposed that arsenosugar biosynthesis involves a key intermediate 5′‐deoxy‐5′‐dimethylarsinoyl‐adenosine (DDMAA), but how DDMAA is produced remains elusive. Now, we report characterization of ArsS as a DDMAA synthase, which catalyzes a radical S‐adenosylmethionine (SAM)‐mediated alkylation (adenosylation) of dimethylarsenite (DMAsIII) to produce DDMAA. This radical‐mediated reaction is redox neutral, and multiple turnover can be achieved without external reductant. Phylogenomic and biochemical analyses revealed that DDMAA synthases are widespread in distinct bacterial phyla with similar catalytic efficiencies; these enzymes likely originated from cyanobacteria. This study reveals a key step in arsenosugar biosynthesis and also a new paradigm in radical SAM chemistry, highlighting the catalytic diversity of this superfamily of enzymes.

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“…The fate of the carbon‐centered radicals in these two distinct enzyme classes depends on the substrate framework's functional groups and alternative modes and timing of radical quenching. In accord with the multiple turnover roles of catalysts, both classes of enzymes, the iron‐oxygenases and the radical SAM enzymes, must be returned to starting oxidation states at the end of each catalytic cycle …”

Section: Radical‐based Cascadesmentioning

confidence: 99%

Enzymatic Cascade Reactions in Biosynthesis

2019

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Cascade reactions in organic synthesis, especially in natural product campaigns with biomimetic strategies, have previously been reviewed. Here we take up the complementary topic of enzyme-mediated cascade reactions and note their widespread occurrence. To facilitate comparison with the mechanistic categorizations of cascade reactions by synthetic chemists and delineate the common underlying chemistry, we discuss four types of enzymatic cascade reactions: those mediated by nucleophilic, electrophilic, pericyclic, and radical-based chemistries. Two subtypes of enzyme generating radical cascades exist at opposite ends of the oxygen abundance spectrum. Iron-based enzymes use O2 to generate high valent iron-oxo species to homolyze unactivated C-H bonds in substrates that set off skeletal rearrangements. At the anaerobic end, enzymes reversibly cleave S-adenosylmethionine (SAM) to generate the 5'-deoxyadenosyl radical as a powerful oxidant to initiate C-H bond homolysis in bound substrates. The latter enzymes are termed radical SAM enzymes. We categorize the former as "thwarted oxygenases".

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Following the electrons: peculiarities in the catalytic cycles of radical SAM enzymes

Cited by 36 publications

References 77 publications

Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism

Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism

Characterization and Mechanistic Study of the Radical SAM Enzyme ArsS Involved in Arsenosugar Biosynthesis

Enzymatic Cascade Reactions in Biosynthesis

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