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Robin Teufel

Bio: Robin Teufel is an academic researcher from University of Freiburg. The author has contributed to research in topics: Flavin group & Cofactor. The author has an hindex of 14, co-authored 26 publications receiving 965 citations. Previous affiliations of Robin Teufel include University of California, San Diego & Scripps Research Institute.

Papers
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Journal ArticleDOI
TL;DR: This work elucidates the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida, and provides insight into the natural remediation of man-made environmental contaminants such as styrene.
Abstract: Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or styrene) is metabolized by bacteria via phenylacetate. Surprisingly, the bacterial catabolism of phenylalanine and phenylacetate remained an unsolved problem. Although a phenylacetate metabolic gene cluster had been identified, the underlying biochemistry remained largely unknown. Here we elucidate the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida. This strategy is exceptional in several aspects. Intermediates are processed as CoA thioesters, and the aromatic ring of phenylacetyl-CoA becomes activated to a ring 1,2-epoxide by a distinct multicomponent oxygenase. The reactive nonaromatic epoxide is isomerized to a seven-member O-heterocyclic enol ether, an oxepin. This isomerization is followed by hydrolytic ring cleavage and β-oxidation steps, leading to acetyl-CoA and succinyl-CoA. This widespread paradigm differs significantly from the established chemistry of aerobic aromatic catabolism, thus widening our view of how organisms exploit such inert substrates. It provides insight into the natural remediation of man-made environmental contaminants such as styrene. Furthermore, this pathway occurs in various pathogens, where its reactive early intermediates may contribute to virulence.

304 citations

Journal ArticleDOI
28 Nov 2013-Nature
TL;DR: The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry, and provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.
Abstract: Structural and functional studies reveal how the bacterial flavoenzyme EncM catalyses the oxygenation–dehydrogenation dual oxidation of a highly reactive substrate, and show that EncM maintains a stable flavin oxygenating species that promotes substrate oxidation and triggers a rarely seen Favorskii-type rearrangement. Flavoproteins, which contain either a flavin adenine dinucleotide or a flavin mononucleotide cofactor, are redox-active proteins involved in a broad range of biological processes including bioluminescence, photosynthesis and DNA repair. Here the authors undertook structural and functional studies to examine how the bacterial flavoenzyme EncM catalyses the oxygenation–dehydrogenation oxidation of a highly reactive substrate. They observed previously unknown flavin redox biochemistry: EncM maintains a stable flavin-oxygenating species that promotes substrate oxidation and triggers a rarely seen, Favorskii-type rearrangement that is central to the biosynthesis of the marine antibiotic enterocin. Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families1,2. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate1,3,4. Here we report that the bacterial flavoenzyme EncM5,6 catalyses the peroxyflavin-independent oxygenation–dehydrogenation dual oxidation of a highly reactive poly(β-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.

126 citations

Journal ArticleDOI
TL;DR: The findings indicate that the autotrophic carbon fixation cycles in Chloroflexus and in the Sulfolobales evolved independently and that different genes/enzymes have been recruited in the two lineages that catalyze the same kinds of reactions.
Abstract: A 3-hydroxypropionate/4-hydroxybutyrate cycle operates in autotrophic CO2 fixation in various Crenarchaea, as studied in some detail in Metallosphaera sedula This cycle and the autotrophic 3-hydroxypropionate cycle in Chloroflexus aurantiacus have in common the conversion of acetyl-coenzyme A (CoA) and two bicarbonates via 3-hydroxypropionate to succinyl-CoA Both cycles require the reductive conversion of 3-hydroxypropionate to propionyl-CoA In M sedula the reaction sequence is catalyzed by three enzymes The first enzyme, 3-hydroxypropionyl-CoA synthetase, catalyzes the CoA- and MgATP-dependent formation of 3-hydroxypropionyl-CoA The next two enzymes were purified from M sedula or Sulfolobus tokodaii and studied 3-Hydroxypropionyl-CoA dehydratase, a member of the enoyl-CoA hydratase family, eliminates water from 3-hydroxypropionyl-CoA to form acryloyl-CoA Acryloyl-CoA reductase, a member of the zinc-containing alcohol dehydrogenase family, reduces acryloyl-CoA with NADPH to propionyl-CoA Genes highly similar to the Metallosphaera CoA synthetase, dehydratase, and reductase genes were found in autotrophic members of the Sulfolobales The encoded enzymes are only distantly related to the respective three enzyme domains of propionyl-CoA synthase from C aurantiacus, where this trifunctional enzyme catalyzes all three reactions This indicates that the autotrophic carbon fixation cycles in Chloroflexus and in the Sulfolobales evolved independently and that different genes/enzymes have been recruited in the two lineages that catalyze the same kinds of reactions

96 citations

Journal ArticleDOI
TL;DR: A highly unusual aromatic polyketide-terpene hybrid intermediate is formed which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate.
Abstract: The polycyclic merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities that are produced by the marine bacterium Streptomyces sp. strain CNH-189. Here we employ heterologously produced enzymes and chemical synthesis to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide-terpene hybrid intermediate that features an unprecedented branched sesquiterpene moiety. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium-dependent haloperoxidase, thus completing the remarkably efficient pathway.

75 citations

Journal ArticleDOI
TL;DR: It is proposed that formation of this flavin-N5-oxides species occurs by hydrogen-transfer from Fl(red) to molecular oxygen, allowing radical coupling of the formed protonated superoxide and anionic flavin semiquinone at N5, before elimination of water affords the Fl(N5[O]) cofactor.
Abstract: The ubiquitous flavin-dependent monooxygenases commonly catalyze oxygenation reactions by means of a transient C4a–peroxyflavin. A recent study, however, suggested an unprecedented flavin-oxygenating species, proposed as the flavin-N5-oxide (FlN5[O]), as key to an oxidative Favorskii-type rearrangement in the biosynthesis of the bacterial polyketide antibiotic enterocin. This stable superoxidized flavin is covalently tethered to the enzyme EncM and converted into FADH2 (Flred) during substrate turnover. Subsequent reaction of Flred with molecular oxygen restores the postulated FlN5[O] via an unknown pathway. Here, we provide direct evidence for the FlN5[O] species via isotope labeling, proteolytic digestion, and high-resolution tandem mass spectrometry of EncM. We propose that formation of this species occurs by hydrogen-transfer from Flred to molecular oxygen, allowing radical coupling of the formed protonated superoxide and anionic flavin semiquinone at N5, before elimination of water affords the FlN5[O...

70 citations


Cited by
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Journal ArticleDOI
TL;DR: These strategies are based on different ring activation mechanisms that consist of either formation of a non-aromatic ring-epoxide under oxic conditions, or reduction of the aromatic ring under anoxic conditions using one of two completely different systems.
Abstract: Aromatic compounds are both common growth substrates for microorganisms and prominent environmental pollutants. The crucial step in their degradation is overcoming the resonance energy that stabilizes the ring structure. The classical strategy for degradation comprises an attack by oxygenases that hydroxylate and finally cleave the ring with the help of activated molecular oxygen. Here, we describe three alternative strategies used by microorganisms to degrade aromatic compounds. All three of these methods involve the use of CoA thioesters and ring cleavage by hydrolysis. However, these strategies are based on different ring activation mechanisms that consist of either formation of a non-aromatic ring-epoxide under oxic conditions, or reduction of the aromatic ring under anoxic conditions using one of two completely different systems.

889 citations

Journal ArticleDOI
TL;DR: Large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.
Abstract: In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance. Colorectal cancer stages are associated with distinct microbial and metabolomic profiles that could shed light on cancer progression.

599 citations

Journal ArticleDOI
TL;DR: The diverse carbon fixation mechanisms that are found in archaea differ fundamentally from those of the well-known Calvin cycle, and their distribution mirrors the phylogenetic positions of the archaeal lineages and the needs of the ecological niches that they occupy.
Abstract: The acquisition of cellular carbon from inorganic carbon is a prerequisite for life and marked the transition from the inorganic to the organic world. Recent theories of the origins of life assume that chemo-evolution took place in a hot volcanic flow setting through a transition metal-catalysed, autocatalytic carbon fixation cycle. Many archaea live in volcanic habitats under such constraints, in high temperatures with only inorganic substances and often under anoxic conditions. In this Review, we describe the diverse carbon fixation mechanisms that are found in archaea. These reactions differ fundamentally from those of the well-known Calvin cycle, and their distribution mirrors the phylogenetic positions of the archaeal lineages and the needs of the ecological niches that they occupy.

558 citations

Journal ArticleDOI
TL;DR: An update of the classification of flavin-dependent monooxygenases is presented and the latest advances in the understanding of their catalytic and structural properties are summarized.

395 citations

Journal ArticleDOI
TL;DR: This Review will give the first systematic overview on enzymes catalyzing the formation of organosulfur natural products by investigating a broad range of enzymes, sulfur shuttles, and chemical mechanisms for generating carbon-sulfur bonds.
Abstract: Sulfur plays a critical role for the development and maintenance of life on earth, which is reflected by the wealth of primary metabolites, macromolecules, and cofactors bearing this element. Whereas a large body of knowledge has existed for sulfur trafficking in primary metabolism, the secondary metabolism involving sulfur has long been neglected. Yet, diverse sulfur functionalities have a major impact on the biological activities of natural products. Recent research at the genetic, biochemical, and chemical levels has unearthed a broad range of enzymes, sulfur shuttles, and chemical mechanisms for generating carbon–sulfur bonds. This Review will give the first systematic overview on enzymes catalyzing the formation of organosulfur natural products.

336 citations