Discovery, production, and biological assay of an unusual flavenoid cofactor involved in lincomycin biosynthesis.

Coats, J. H.; Li, Grace P.; Kuo, Ming-S. T.; Yurek, David A.

doi:10.7164/antibiotics.42.472

Cited by 38 publications

(29 citation statements)

References 7 publications

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“…1D) is involved in hydride transfer during reductive transformation of carbon dioxide and acetate into methane in methanogenic archaea (103,151,258,299,514). Coenzyme F 420 has also been found in certain streptomycetes, in which it serves as a cofactor in the biosynthesis of tetracycline and lincomycin (74,189,347,369). Mycobacterium and Nocardia spp.…”

Section: Other Natural Flavinsmentioning

confidence: 99%

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Abbas

Sibirny

2011

Microbiol Mol Biol Rev

325

272

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SUMMARY Riboflavin [7,8-dimethyl-10-(1′- d -ribityl)isoalloxazine, vitamin B 2 ] is an obligatory component of human and animal diets, as it serves as the precursor of flavin coenzymes, flavin mononucleotide, and flavin adenine dinucleotide, which are involved in oxidative metabolism and other processes. Commercially produced riboflavin is used in agriculture, medicine, and the food industry. Riboflavin synthesis starts from GTP and ribulose-5-phosphate and proceeds through pyrimidine and pteridine intermediates. Flavin nucleotides are synthesized in two consecutive reactions from riboflavin. Some microorganisms and all animal cells are capable of riboflavin uptake, whereas many microorganisms have distinct systems for riboflavin excretion to the medium. Regulation of riboflavin synthesis in bacteria occurs by repression at the transcriptional level by flavin mononucleotide, which binds to nascent noncoding mRNA and blocks further transcription (named the riboswitch). In flavinogenic molds, riboflavin overproduction starts at the stationary phase and is accompanied by derepression of enzymes involved in riboflavin synthesis, sporulation, and mycelial lysis. In flavinogenic yeasts, transcriptional repression of riboflavin synthesis is exerted by iron ions and not by flavins. The putative transcription factor encoded by SEF1 is somehow involved in this regulation. Most commercial riboflavin is currently produced or was produced earlier by microbial synthesis using special selected strains of Bacillus subtilis , Ashbya gossypii , and Candida famata . Whereas earlier RF overproducers were isolated by classical selection, current producers of riboflavin and flavin nucleotides have been developed using modern approaches of metabolic engineering that involve overexpression of structural and regulatory genes of the RF biosynthetic pathway as well as genes involved in the overproduction of the purine precursor of riboflavin, GTP.

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Section: Other Natural Flavinsmentioning

confidence: 99%

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Abbas

Sibirny

2011

Microbiol Mol Biol Rev

325

272

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“…Encoded by the oxytetracycline (oxy), chlorotetracycline (ctc), and dactylocyclinone (dac) gene clusters (29), these enzymes are members of the flavin/deazaflavin oxidoreductase (FDOR) superfamily (30) and utilize F 420 H 2 reduced through the action of Fno (387). F 420 is also required for the synthesis of lincosamide antibiotics by Streptomyces lincolnensis strains (146,388,389), including lincomycin, the precursor of the clinical semisynthetic antibiotic clindamycin (390). On the basis of the accumulation of 4-propylidene-3,4-dihydropyrrole-2-carboxylic acid by strains unable to biosynthesize F 420 , it is proposed that an F 420 H 2 -dependent reductase catalyzes the reduction of the imine moiety of the dihydropyrrole to tetrapyrrole (Fig.…”

Section: Streptomycetesmentioning

confidence: 99%

“…F 420 -dependent processes already provide essential steps in some industrial processes, for example in the synthesis of some of the oldest-known antibiotic classes (29,381), and there is considerable potential to expand the role of F 420 -dependent enzymes as catalysts for synthetic chemistry. F 420 H 2 -dependent reductases of the FDOR and LLHT superfamilies can catalyze the stereospecific reduction of enones (28,55,291,409) and imines (50,388,393) in diverse heterocycles. The broad substrate range of these enzymes may be particularly useful for catalyzing hydride addition to nonnatural compounds in a potentially stereospecific manner (479,480).…”

Section: Industrial Biocatalysismentioning

confidence: 99%

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Greening

Ahmed

Mohamed

et al. 2016

Microbiol Mol Biol Rev

160

208

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SUMMARY5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5-deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate-reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420in methanogenic archaea in processes such as substrate oxidation, C1pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid byMycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Foand F420are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.

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“…First, since Streptomyces mutants lacking F 420 biosynthetic capabilities can grow without F 420 supplementation (8,31,39), we expected that F 420 would not be required for in vitro growth of the closely related mycobacteria, whereas in several archaea F 420 is essential for growth. Thus, with mycobacteria, no supplementation with F 420 should be required in the screening medium (F 420 is not commercially available and is expensive to produce, e.g., compared to the purchase of NADP.).…”

mentioning

confidence: 99%

“…In archaea, F 420 is essential for methylenetetrahydromethanopterin reductase, some hydrogenases, formate and methylenetetrahydromethanopterin dehydrogenases, some alcohol dehydrogenases, and quinone oxidoreductase activities (18,21,23,26,27,47). F 420 is used by Streptomyces for tetracycline and lincomycin biosynthesis (8,31,39) and perhaps in mitomycin C biosynthesis (29). In Mycobacterium and Nocardia, F 420 is used by F 420 -dependent glucose-6-phosphate dehydrogenase (35,36) and is required for activation of the experimental antituberculosis drug PA-824 by Mycobacterium tuberculosis and Mycobacterium bovis strain BCG (45).…”

mentioning

confidence: 99%

Use of Transposon Tn 5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F ₄₂₀ Biosynthesis by Mycobacterium bovis BCG

et al. 2001

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Three transposon Tn5367 mutagenesis vectors (phAE94, pPR28, and pPR29) were used to create a collection of insertion mutants of Mycobacterium bovis strain BCG. A strategy to select for transposon-generated mutants that cannot make coenzyme F 420 was developed using the nitroimidazopyran-based antituberculosis drug PA-824. One-third of 134 PA-824-resistant mutants were defective in F 420 accumulation. Two mutants that could not make F 420 -5,6 but which made the biosynthesis intermediate FO were examined more closely. These mutants contained transposons inserted in two adjacent homologues of Mycobacterium tuberculosis genes, which we have named fbiA and fbiB for F 420 biosynthesis. Homologues of fbiA were found in all seven microorganisms that have been fully sequenced and annotated and that are known to make F 420 . fbiB homologues were found in all but one such organism. Complementation of the fbiA mutant with fbiAB and complementation of the fbiB mutant with fbiB both restored the F 420 -5,6 phenotype. Complementation of the fbiA mutant with fbiA or fbiB alone did not restore the F 420 -5,6 phenotype, but the fbiA mutant complemented with fbiA produced F 420 -2,3,4 at levels similar to F 420 -5,6 made by the wild-type strain, but produced much less F 420 -5. These data demonstrate that both genes are essential for normal F 420 -5,6 production and suggest that the fbiA mutation has a partial polar effect on fbiB. Reverse transcription-PCR data demonstrated that fbiA and fbiB constitute an operon. However, very low levels of fbiB mRNA are produced by the fbiA mutant, suggesting that a low-level alternative start site is located upstream of fbiB. The specific reactions catalyzed by FbiA and FbiB are unknown, but both function between FO and F 420 -5,6, since FO is made by both mutants.

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Discovery, production, and biological assay of an unusual flavenoid cofactor involved in lincomycin biosynthesis.

Cited by 38 publications

References 7 publications

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Use of Transposon Tn 5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F ₄₂₀ Biosynthesis by Mycobacterium bovis BCG

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Discovery, production, and biological assay of an unusual flavenoid cofactor involved in lincomycin biosynthesis.

Cited by 38 publications

References 7 publications

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions

Use of Transposon Tn 5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F 420 Biosynthesis by Mycobacterium bovis BCG

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Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Use of Transposon Tn 5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F ₄₂₀ Biosynthesis by Mycobacterium bovis BCG