The Radical <i>S</i>-Adenosyl-<scp>l</scp>-methionine Enzyme MftC Catalyzes an Oxidative Decarboxylation of the C-Terminus of the MftA Peptide

Bruender, Nathan A.; Bandarian, Vahe

doi:10.1021/acs.biochem.6b00355

Cited by 58 publications

(85 citation statements)

References 27 publications

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“…Members of TIGR03971 appear in gene clusters near mycofactocin system protein genes mftA, mftB, and mftC567. For example, in M. paratuberculosis a putative carveol dehydrogenase (MAP_RS21280, UniProt ID Q73SC8, SSGCID target ID MypaA.01326.b) is encoded near genes for the mycofactocin precursor MftA (MAP_RS21310), the mycofactocin modification chaperone MftB (MAP_RS21315), the mycofactocin radical SAM maturase MftC (MAP_RS21320), the mycofactocin system heme/Flavin oxidoreductase MftD (MAP_RS21325), and the mycofactocin system creatininase family protein (MAP_RS21330).…”

Section: Resultsmentioning

confidence: 99%

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Mycofactocin-associated mycobacterial dehydrogenases with non-exchangeable NAD cofactors

Haft

Pierce

Mayclin

et al. 2017

Sci Rep

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During human infection, Mycobacterium tuberculosis (Mtb) survives the normally bacteriocidal phagosome of macrophages. Mtb and related species may be able to combat this harsh acidic environment which contains reactive oxygen species due to the mycobacterial genomes encoding a large number of dehydrogenases. Typically, dehydrogenase cofactor binding sites are open to solvent, which allows NAD/NADH exchange to support multiple turnover. Interestingly, mycobacterial short chain dehydrogenases/reductases (SDRs) within family TIGR03971 contain an insertion at the NAD binding site. Here we present crystal structures of 9 mycobacterial SDRs in which the insertion buries the NAD cofactor except for a small portion of the nicotinamide ring. Line broadening and STD-NMR experiments did not show NAD or NADH exchange on the NMR timescale. STD-NMR demonstrated binding of the potential substrate carveol, the potential product carvone, the inhibitor tricyclazol, and an external redox partner 2,6-dichloroindophenol (DCIP). Therefore, these SDRs appear to contain a non-exchangeable NAD cofactor and may rely on an external redox partner, rather than cofactor exchange, for multiple turnover. Incidentally, these genes always appear in conjunction with the mftA gene, which encodes the short peptide MftA, and with other genes proposed to convert MftA into the external redox partner mycofactocin.

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Section: Resultsmentioning

confidence: 99%

“…Recently, the recombinant expression and characterization of MftA, MftB, and MftC have been reported67. The chaperone MftB was reported to bind the mycofactocin precursor MftA with an affinity of approximately 120 nM and the rSAM MftC with an affinity of approximately 2 μM.…”

mentioning

confidence: 99%

Mycofactocin-associated mycobacterial dehydrogenases with non-exchangeable NAD cofactors

Haft

Pierce

Mayclin

et al. 2017

Sci Rep

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“…In the mycofactocin biosynthetic pathway, the peptide chaperone is a stand-alone protein (MftB), and in the thurincin H biosynthetic pathway, the peptide chaperone is fused to the N terminus of the RS protein (ThnB). Although morphologically different, it was shown in both systems that the peptide chaperone protein/domain is required for catalytic turnover by the RS protein (28,29,35). These findings led us to the hypothesis that the PqqD domain is ubiquitous among the remaining characterized RS-SPASM proteins (excluding AnSME).…”

Section: Minireview: Free Radical Enzymology Of Peptidesmentioning

confidence: 99%

“…Mycofactocin is predicted to be a redox cofactor used by a niche set of dehydrogenases found largely in the Mycobacterium genera (26,27). Initially, it was thought that MftC catalyzed the oxidative decarboxylation of the C-terminal tyrosine found on the peptide MftA, resulting in an ␣␤-unsaturated bond (28,29). However, a more detailed mechanistic study demonstrated that the decarboxylated peptide is only an intermediate of a two-step reaction (30).…”

Section: Carbon-carbon Bond Creation: Pqqe Strb and Mftcmentioning

confidence: 99%

At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology

Latham

Barr

Klinman

2017

Journal of Biological Chemistry

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Radical S-adenosylmethionine (RS) enzymology has emerged as a major biochemical strategy for the homolytic cleavage of unactivated C-H bonds. At the same time, the post-translational modification of ribosomally synthesized peptides is a rapidly expanding area of investigation. We discuss the functional cross-section of these two disciplines, highlighting the recently uncovered importance of protein-protein interactions, especially between the peptide substrate and its chaperone, which functions either as a stand-alone protein or as an N-terminal fusion to the respective RS enzyme. The need for further work on this class of enzymes is emphasized, given the poorly understood roles performed by multiple, auxiliary iron-sulfur clusters and the paucity of protein X-ray structural data.Modern biochemistry has seen the exponential growth of two exciting areas of research that focus individually on the post-translational modification of ribosomally synthesized and post-translationally modified peptides (RiPPs) 2 (1) and on the structure and mechanism of free radical conversions catalyzed by radical S-adenosylmethionine (RS) enzymes (2, 3). These separate fields have recently converged within a growing family of enzymes that bring about free radical-based, post-translational modifications on ribosomally produced peptide substrates. RS enzymes function by cleavage of a [4Fe-4S] clusterbound S-adenosylmethionine to form methionine and a deoxyadenosyl radical. This radical then initiates the reaction by abstracting a hydrogen atom from the substrate. The [4Fe-4S] cluster that accomplishes this reaction has a characteristic CX 3 CXC motif, with each of the cysteines coordinated to a single iron, leaving an open coordination sphere where SAM binds and is cleaved. A subset of RS enzymes belongs to a family that contains an additional conserved structural motif annotated as a SPASM domain and referred to as RS-SPASM proteins. Although the exact function of the SPASM domain is unknown, it has been shown that it houses generally two additional iron-sulfur clusters that are critical in RS-SPASM chemistry. Using the perspective of the pathway for production of the bacterial cofactor pyrroloquinoline quinone (PQQ), we compare and highlight some of the unique properties among these RS-SPASM-dependent RiPP systems. Bioinformatics analyses suggest that the family members will extend far beyond the examples presented herein.

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“…How are the precursor peptides processed to generate methanobactins (24)? New knowledge about the enzymes involved in other peptide post-translational modifications is becoming available (31,32 (15)? Have all of the accessory proteins for cytochrome oxidase assembly been identified (16)?…”

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confidence: 99%

Introduction to Metals in Biology 2018: Copper homeostasis and utilization in redox enzymes

Guengerich

2018

Journal of Biological Chemistry

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The Radical S-Adenosyl-l-methionine Enzyme MftC Catalyzes an Oxidative Decarboxylation of the C-Terminus of the MftA Peptide

Cited by 58 publications

References 27 publications

Mycofactocin-associated mycobacterial dehydrogenases with non-exchangeable NAD cofactors

Mycofactocin-associated mycobacterial dehydrogenases with non-exchangeable NAD cofactors

At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology

Introduction to Metals in Biology 2018: Copper homeostasis and utilization in redox enzymes

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