Structure of Coenzyme F420 Dependent Methylenetetrahydromethanopterin Reductase from Two Methanogenic Archaea

Shima, Seigo; Warkentin, Eberhard; Grabarse, Wolfgang; Sordel, Melanie; Wicke, Michaela; Thauer, Rudolf K.; Ermler, Ulrich

doi:10.1006/jmbi.2000.3909

Cited by 75 publications

(63 citation statements)

References 65 publications

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“…For identification of the conserved Mer-type secondary structure features and F 420 -binding residues and for prediction of the DIM B-interacting elements in the Rv2951c protein, the amino acid sequences of this protein and selected Mer homologs for which X-ray crystallographic three-dimensional structures of the F 420 -bound forms are available (17,(35)(36)(37) were aligned by PROMALS3D at http://prodata.swmed.edu /promals3d/promals3d.php and by manual adjustments (38).…”

Section: Methodsmentioning

confidence: 99%

“…For this purpose, we performed a structure-based sequence alignment (Fig. 2) by utilizing the X-ray crystallographic structures of Mer from two methanogenic archaea, Methanopyrus kandleri and Methanosarcina barkeri (MkMer and MbMer, respectively) (36,37), and two Mer homologs, an F 420 -dependent secondary alcohol dehydrogenase (Adf) from another methanogen (35) and Fgd of M. tuberculosis (17) (Fig. 2).…”

Section: Analysis Of the Structural Characteristics Of The Rv2951c Prmentioning

confidence: 99%

“…Mer, Adf, and Fgd induce a butterfly conformation at the si face of bound F 420 by holding the coenzyme with conserved structural elements (marked with asterisks in Fig. 2) (17,(35)(36)(37) (Fig. 2).…”

Section: Analysis Of the Structural Characteristics Of The Rv2951c Prmentioning

confidence: 99%

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F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Purwantini

Daniels²,

Mukhopadhyay

2016

J Bacteriol

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Phthiocerol dimycocerosates (PDIM) are a group of cell surface-associated apolar lipids of Mycobacterium tuberculosis and closely related mycobacteria, such as Mycobacterium bovis and Mycobacterium leprae. A characteristic methoxy group of these lipids is generated from the methylation of a hydroxyl group of the direct precursors, the phthiotriols. The precursors arise from the reduction of phthiodiolones, the keto intermediates, by a ketoreductase. The putative phthiodiolone ketoreductase (PKR) is encoded by Rv2951c in M. tuberculosis and BCG_2972c in M. bovis BCG, and these open reading frames (ORFs) encode identical amino acid sequences. We investigated the cofactor requirement of the BCG_2972c protein. A comparative analysis based on the crystallographic structures of similar enzymes identified structural elements for binding of coenzyme F 420 and hydrophobic phthiodiolones in PKR. Coenzyme F 420 is a deazaflavin coenzyme that serves several key functions in pathogenic and nonpathogenic mycobacteria. We found that an M. bovis BCG mutant lacking F 420 -dependent glucose-6-phosphate dehydrogenase (Fgd), which generates F 420 H 2 (glucose-6-phosphate ؉ F 420 ¡ 6-phosphogluconate ؉ F 420 H 2 ), was devoid of phthiocerols and accumulated phthiodiolones. When the mutant was provided with F 420 H 2 , a broken-cell slurry of the mutant converted accumulated phthiodiolones to phthiocerols; F 420 H 2 was generated in situ from F 420 and glucose-6-phosphate by the action of Fgd. Thus, the reaction mixture was competent in reducing phthiodiolones to phthiotriols (phthiodiolones ؉ F 420 H 2 ¡ phthiotriols ؉ F 420 ), which were then methylated to phthiocerols. These results established the mycobacterial phthiodiolone ketoreductase as an F 420 H 2 -dependent enzyme (fPKR). A phylogenetic analysis of close homologs of fPKR revealed potential F 420 -dependent lipidmodifying enzymes in a broad range of mycobacteria. IMPORTANCEMycobacterium tuberculosis is the causative agent of tuberculosis, and phthiocerol dimycocerosates (PDIM) protect this pathogen from the early innate immune response of an infected host. Thus, the PDIM synthesis system is a potential target for the development of effective treatments for tuberculosis. The current study shows that a PDIM synthesis enzyme is dependent on the coenzyme F 420 . F 420 is universally present in mycobacteria and absent in humans. This finding expands the number of experimentally validated F 420 -dependent enzymes in M. tuberculosis to six, each of which helps the pathogen to evade killing by the host immune system, and one of which activates an antituberculosis drug, PA-824. This work also has relevance to leprosy, since similar waxy lipids are found in Mycobacterium leprae.

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Section: Methodsmentioning

confidence: 99%

Section: Analysis Of the Structural Characteristics Of The Rv2951c Prmentioning

confidence: 99%

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F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Purwantini

Daniels²,

Mukhopadhyay

2016

J Bacteriol

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“…Among them are the one-carbon reactions of methanogenesis (Thauer, 1998;Shima et al, 2000;Hagemeier et al, 2003), the biosynthesis pathways of tetracycline antibiotics (Wang et al, 2013) and the biodegradation of picrate and aflatoxins (Ebert et al, 2001;Taylor et al, 2010;Lapalikar et al, 2012). The cofactor appears to have been selected for these roles because of its unique electrochemical properties compared with the ubiquitous flavin and nicotinamide cofactors FMN (flavin mononucleotide), FAD (flavin adenine dinucleotide) and NAD(P) (nicotinamide adenine dinucleotide (phosphate)) (Walsh, 1986;Greening et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

“…This enables reduced F 420 (F 420 H 2 ) to reduce a wide range of organic compounds otherwise recalcitrant to activation (Jacobson and Walsh, 1984;Greening et al, 2016a). As an obligate two-electron carrier, the cofactor can transform alkene, alkyne, alcohol and imine groups through hydride transfer reactions (Shima et al, 2000;Hagemeier et al, 2003;Aufhammer et al, 2004;Shen et al, 2009;Wang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria

et al. 2016

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F 420 is a low-potential redox cofactor that mediates the transformations of a wide range of complex organic compounds. Considered one of the rarest cofactors in biology, F 420 is best known for its role in methanogenesis and has only been chemically identified in two phyla to date, the Euryarchaeota and Actinobacteria. In this work, we show that this cofactor is more widely distributed than previously reported. We detected the genes encoding all five known F 420 biosynthesis enzymes (cofC, cofD, cofE, cofG and cofH) in at least 653 bacterial and 173 archaeal species, including members of the dominant soil phyla Proteobacteria, Chloroflexi and Firmicutes. Metagenome datamining validated that these genes were disproportionately abundant in aerated soils compared with other ecosystems. We confirmed through high-performance liquid chromatography analysis that aerobically grown stationary-phase cultures of three bacterial species, Paracoccus denitrificans, Oligotropha carboxidovorans and Thermomicrobium roseum, synthesized F 420 , with oligoglutamate sidechains of different lengths. To understand the evolution of F 420 biosynthesis, we also analyzed the distribution, phylogeny and genetic organization of the cof genes. Our data suggest that although the F o precursor to F 420 originated in methanogens, F 420 itself was first synthesized in an ancestral actinobacterium. F 420 biosynthesis genes were then disseminated horizontally to archaea and other bacteria. Together, our findings suggest that the cofactor is more significant in aerobic bacterial metabolism and soil ecosystem composition than previously thought. The cofactor may confer several competitive advantages for aerobic soil bacteria by mediating their central metabolic processes and broadening the range of organic compounds they can synthesize, detoxify and mineralize.

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N⁵,N¹⁰‐methylenetetrahydromethanopterin reductase from Methanocaldococcus jannaschii also serves as a methylglyoxal reductase

et al. 2017

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In Methanocaldococcus jannaschii, methylglyoxal (MG) is required for aromatic amino acid biosynthesis. Previously, the reduction of MG to lactaldehyde in Methanocaldococcus jannaschii cell extracts using either NADPH or F H was demonstrated; however, the enzyme responsible was not identified. Using NADPH as the reductant, the unknown enzyme was purified from cell extracts of Methanocaldococcus jannaschii and determined to be the F -dependent N ,N -methylenetetrahydromethanopterin reductase (Mer). Here, we report that the recombinantly overexpressed Mer is able to use NADPH and MG (K of 1.6 and 1.0 mm, respectively) to produce lactaldehyde. Additionally, Mer does not catalyze the reduction of MG to lactaldehyde in the presence of reduced Fo, the precursor of F .

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Structure of Coenzyme F420 Dependent Methylenetetrahydromethanopterin Reductase from Two Methanogenic Archaea

Cited by 75 publications

References 65 publications

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria

N⁵,N¹⁰‐methylenetetrahydromethanopterin reductase from Methanocaldococcus jannaschii also serves as a methylglyoxal reductase

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Structure of Coenzyme F420 Dependent Methylenetetrahydromethanopterin Reductase from Two Methanogenic Archaea

Cited by 75 publications

References 65 publications

F 420 H 2 Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F 420 H 2 Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria

N5,N10‐methylenetetrahydromethanopterin reductase from Methanocaldococcus jannaschii also serves as a methylglyoxal reductase

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F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

N⁵,N¹⁰‐methylenetetrahydromethanopterin reductase from Methanocaldococcus jannaschii also serves as a methylglyoxal reductase