Ene reductases from the Old Yellow Enzyme (OYE) family reduce C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited biocatalysis. Going beyond its canonical function, we show that members of this enzyme can also catalyze formation C-C bonds. α,β-Unsaturated aldehydes and ketones containing additional electrophilic group undergo reductive cyclization. Mechanistically, two-electron-reduced...

Bacterial tropone natural products such as tropolone, tropodithietic acid, or the roseobacticides play crucial roles in various terrestrial and marine symbiotic interactions virulence factors, antibiotics, algaecides, quorum sensing signals. We now show that their poorly understood biosynthesis depends on a shunt product from aerobic CoA-dependent phenylacetic acid catabolism is salvaged by dedicated acyl-CoA dehydrogenase-like flavoenzyme TdaE. Further characterization of TdaE revealed an...

Paracoccidioidomycosis (PCM), caused by Paracoccidioides , is a systemic mycosis with granulomatous character and restricted therapeutic arsenal. The aim of this work was to search for new alternatives treat largely neglected tropical mycosis, such as PCM.

The structural diversification of natural products is instrumental to their versatile bioactivities. In this context, redox tailoring enzymes are commonly involved in the modification and functionalization advanced pathway intermediates en route mature products. recent years, flavoprotein monooxygenases have been shown mediate numerous reactions that include not only (aromatic) hydroxylation, Baeyer–Villiger oxidation, or epoxidation but also oxygenations coupled extensive remodeling carbon...

The biosynthesis of the bacterial antibiotic dihydroxytropolone was reconstituted in vitro starting from a catabolic shunt product. involved key flavoprotein monooxygenase TrlE further structurally and mechanistically characterized.

The berberine bridge enzyme from the California poppy Eschscholzia californica ( Ec BBE ) catalyzes oxidative cyclization of S )‐reticuline to )‐scoulerine, that is, formation in biosynthesis benzylisoquinoline alkaloids. Interestingly, a large number ‐ like genes have been identified plants lack alkaloid biosynthesis. This finding raised question primordial role plant kingdom, which prompted us investigate closest relative Physcomitrella patens Pp 1), most basal harboring gene. Here, we...

D-2-hydroxyglutaric aciduria is a neurometabolic disorder, characterized by the accumulation of D-2-hydroxyglutarate (D-2HG) in human mitochondria. Increased levels D-2HG are detected humans exhibiting point mutations genes encoding isocitrate dehydrogenase, citrate carrier, electron transferring flavoprotein (ETF) and its downstream acceptor ETF-ubiquinone oxidoreductase or dehydrogenase (hD2HGDH). However, while pathogenicity several amino acid replacements former four proteins has been...

The medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by bisbenzannulated [5,6]-spiroketal pharmacophore that was recently shown to be assembled flavin-dependent enzymes. In particular, flavoprotein monooxygenase proved critical drastic oxidative rearrangement of pentangular precursor and installment an intermediate [6,6]-spiroketal moiety. Here we...

Abstract En‐Reduktasen der “Old Yellow Enzyme”(OYE)‐Familie reduzieren die C=C‐Doppelbindung in α,β‐ungesättigten Verbindungen, eine elektronenziehende Gruppe (z. B. Carbonyl‐Gruppe) tragen. Diese asymmetrische Reduktion hat Biokatalyse Anwendung gefunden. Es konnte gezeigt werden, dass Mitglieder dieser Enzymfamilie außerdem noch Bildung von C‐C‐Bindungen katalysieren können. Mit Aldehyden und Ketonen, zusätzliche elektrophile enthalten, kann reduktive Cyclisierung erfolgen. Dabei überträgt...

Abstract Antimicrobial resistance represents a major threat to human health and knowledge of the underlying mechanisms is therefore vital. Here, we report discovery characterization oxidoreductases that inactivate broad‐spectrum antibiotic chloramphenicol via dual oxidation C3‐hydroxyl group. Accordingly, either depends on standalone glucose‐methanol‐choline (GMC)‐type flavoenzymes, or additional aldehyde dehydrogenases boost overall turnover. These enzymes also enable inactivation analogues...

Aim: A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations. Methods: Docking, molecular dynamics, cell growth inhibition and protein binding assays were search validation. Results: Two molecules termed CS8 CaCS02 identified. Further studies minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a 512 32 μg·ml-1 CaCS02, respectively. In addition, showed strong...

Electron-transferring flavoproteins (ETFs) have been found in all kingdoms of life, mostly assisting shuttling electrons to the respiratory chain for ATP production. While human (h) ETF has studied great detail, very little is known about biochemical properties homologous protein model organism Saccharomyces cerevisiae (yETF). In view absence client dehydrogenases, example, acyl-CoA dehydrogenases involved β-oxidation fatty acids, d-lactate dehydrogenase 2 (Dld2) appeared be only relevant...

The often complex control of bacterial natural product biosynthesis typically involves global and pathway-specific transcriptional regulators gene expression, which limits the yield bioactive compounds under laboratory conditions. However, little is known about regulation mechanisms on enzymatic level. Here, we report a novel regulatory principle for products involving dedicated acetyltransferase, modifies redox-tailoring enzyme thereby enables pathway furcation alternating pharmacophore...

The efficient inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by the broad-spectrum herbicide glyphosate validates shikimate pathway as a promising target for developing antimicrobial, fungicidal and herbicidal agents. last enzyme this pathway, chorismate (CS), catalyses an unusual reaction, making it attractive novel inhibitors. Therefore, we tested series azo-dyes their inhibitory potential against CS from pathogenic fungus Paracoccidioides brasiliensis (PbCS) identified...

Abstract The medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by bisbenzannulated [5,6]‐spiroketal pharmacophore that was recently shown to be assembled flavin‐dependent enzymes. In particular, flavoprotein monooxygenase proved critical drastic oxidative rearrangement of pentangular precursor and installment an intermediate [6,6]‐spiroketal moiety....