Abstract:Terpenoid natural products comprise a wide range of molecular architectures that typically result from C–C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated f… Show more
“…Group D flavoprotein monooxygenases ( Table 1 ) catalyze hydroxylation of aromatic compounds but also N -hydroxylation reactions are described. Members of group D can be divided into FAD- and FMN-dependent enzymes, while some are also promiscuous towards the flavin co-substrate [ 7 , 48 , 49 ]. This clustering is also reflected by phylogenetic analysis of group D ( Figure 2 ).…”
“…Two of the first characterized members are the phenol 2-hydroxylase and the 4-hydroxyphenylacetate monooxygenase, which will be described in the first place to outline a general overview about FAD-dependent group D monooxygenases. Many group D monooxygenases that originate from Streptomyces are involved in the biosynthesis of secondary metabolites (antibiotics, antitumor agents) [ 48 , 49 , 60 , 68 ]. For example, a recently discovered enzyme (XiaF) is involved in the biosynthesis of an indolosesquiterpene (xiamycin) [ 48 ].…”
“…Many group D monooxygenases that originate from Streptomyces are involved in the biosynthesis of secondary metabolites (antibiotics, antitumor agents) [ 48 , 49 , 60 , 68 ]. For example, a recently discovered enzyme (XiaF) is involved in the biosynthesis of an indolosesquiterpene (xiamycin) [ 48 ]. Other recently characterized members are involved in the degradation and detoxification of halogenated phenols [ 58 , 59 ].…”
“…As already mentioned, the loop region in the middle domain can influence flavin as well as substrate preference but potentially also the reactivity. For instance, the hydroxylase XiaF shows hydroxylation-induced terpenoid cyclization [ 48 ]. The active site of XiaF is more open what might help to accommodate bigger substrates and absence of the loop that is required for recognition of the adenine domain might explain the promiscuity towards the flavin co-substrate ( Figure 5 ).…”
“…XiaF is displayed including surface (deep teal) with bound FAD (orange). The loop region and therefore the substrate-binding pocket (indicated by an arrow) is more open in XiaF, allowing for promiscuity towards the flavin co-substrate [ 48 ].…”
Flavoprotein monooxygenases create valuable compounds that are of high interest for the chemical, pharmaceutical, and agrochemical industries, among others. Monooxygenases that use flavin as cofactor are either single- or two-component systems. Here we summarize the current knowledge about two-component flavin adenine dinucleotide (FAD)-dependent monooxygenases and describe their biotechnological relevance. Two-component FAD-dependent monooxygenases catalyze hydroxylation, epoxidation, and halogenation reactions and are physiologically involved in amino acid metabolism, mineralization of aromatic compounds, and biosynthesis of secondary metabolites. The monooxygenase component of these enzymes is strictly dependent on reduced FAD, which is supplied by the reductase component. More and more representatives of two-component FAD-dependent monooxygenases have been discovered and characterized in recent years, which has resulted in the identification of novel physiological roles, functional properties, and a variety of biocatalytic opportunities.
“…Group D flavoprotein monooxygenases ( Table 1 ) catalyze hydroxylation of aromatic compounds but also N -hydroxylation reactions are described. Members of group D can be divided into FAD- and FMN-dependent enzymes, while some are also promiscuous towards the flavin co-substrate [ 7 , 48 , 49 ]. This clustering is also reflected by phylogenetic analysis of group D ( Figure 2 ).…”
“…Two of the first characterized members are the phenol 2-hydroxylase and the 4-hydroxyphenylacetate monooxygenase, which will be described in the first place to outline a general overview about FAD-dependent group D monooxygenases. Many group D monooxygenases that originate from Streptomyces are involved in the biosynthesis of secondary metabolites (antibiotics, antitumor agents) [ 48 , 49 , 60 , 68 ]. For example, a recently discovered enzyme (XiaF) is involved in the biosynthesis of an indolosesquiterpene (xiamycin) [ 48 ].…”
“…Many group D monooxygenases that originate from Streptomyces are involved in the biosynthesis of secondary metabolites (antibiotics, antitumor agents) [ 48 , 49 , 60 , 68 ]. For example, a recently discovered enzyme (XiaF) is involved in the biosynthesis of an indolosesquiterpene (xiamycin) [ 48 ]. Other recently characterized members are involved in the degradation and detoxification of halogenated phenols [ 58 , 59 ].…”
“…As already mentioned, the loop region in the middle domain can influence flavin as well as substrate preference but potentially also the reactivity. For instance, the hydroxylase XiaF shows hydroxylation-induced terpenoid cyclization [ 48 ]. The active site of XiaF is more open what might help to accommodate bigger substrates and absence of the loop that is required for recognition of the adenine domain might explain the promiscuity towards the flavin co-substrate ( Figure 5 ).…”
“…XiaF is displayed including surface (deep teal) with bound FAD (orange). The loop region and therefore the substrate-binding pocket (indicated by an arrow) is more open in XiaF, allowing for promiscuity towards the flavin co-substrate [ 48 ].…”
Flavoprotein monooxygenases create valuable compounds that are of high interest for the chemical, pharmaceutical, and agrochemical industries, among others. Monooxygenases that use flavin as cofactor are either single- or two-component systems. Here we summarize the current knowledge about two-component flavin adenine dinucleotide (FAD)-dependent monooxygenases and describe their biotechnological relevance. Two-component FAD-dependent monooxygenases catalyze hydroxylation, epoxidation, and halogenation reactions and are physiologically involved in amino acid metabolism, mineralization of aromatic compounds, and biosynthesis of secondary metabolites. The monooxygenase component of these enzymes is strictly dependent on reduced FAD, which is supplied by the reductase component. More and more representatives of two-component FAD-dependent monooxygenases have been discovered and characterized in recent years, which has resulted in the identification of novel physiological roles, functional properties, and a variety of biocatalytic opportunities.
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Enzym‐vermittelte Kaskadenreaktionen sind weit verbreitet. Um einen Vergleich mit den mechanistischen Kategorisierungen der komplementären Kaskadenreaktionen in der organischen Synthese zu ermöglichen sowie um die gemeinsamen Grundlagen aufzuzeigen, erörtern wir hier vier Arten von Enzymkaskadenreaktionen: vermittelt durch nucleophile, elektrophile, pericyclische und radikalische Reaktionen. Zwei Subtypen von Enzymen, die radikalische Kaskaden erzeugen, befinden sich an den entgegengesetzten Enden der Abundanzskala von Sauerstoff: Eisen‐basierte Enzyme nutzen O2, um hochvalente Eisen‐Oxo‐Spezies zu erzeugen, die nichtaktivierte C‐H‐Bindungen in Substraten homolytisch spalten und Gerüstumlagerungen einleiten. Am anaeroben Ende spalten Enzyme reversibel S‐Adenosylmethionin (SAM) unter Bildung des 5′‐Desoxyadenosyl‐Radikals als starkes Oxidans, um die homolytische Spaltung von C‐H‐Bindungen in gebundenen Substraten auszulösen. Die letztgenannten Enzyme werden als Radikal‐SAM‐Enzyme bezeichnet. Die erstgenannten Enzyme kategorisieren wir als “verhinderte Oxygenasen”.
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