Abstract:N-Hydroxylating monooxygenases (NMOs) are involved in siderophore biosynthesis. Siderophores are high affinity iron chelators composed of catechol and hydroxamate functional groups that are synthesized and secreted by microorganisms and plants. Recently, a new siderophore named albachelin was isolated from a culture of Amycolatopsis alba growing under iron-limiting conditions. This work focuses on the expression, purification, and characterization of the NMO, abachelin monooxygenase (AMO) from A. alba. This en… Show more
“…In general, the mechanism of NMOs is similar to that of group B Baeyer-Villiger monooxygenases (BVMOs) (Ryerson et al 1982 ; Sheng et al 2001 ; Ballou and Entsch 2013 ) and can be described as follows (Fig. 2a ) (Olucha and Lamb 2011 ; Bufkin and Sobrado 2017 ): Fig. 2 a Catalytic mechanism of flavin-dependent NMOs as reported for SidA and PvdA.…”
Section: Catalytic Mechanism Of Flavin-dependent Nmosmentioning
confidence: 66%
“…In general, the mechanism of NMOs is similar to that of group B Baeyer-Villiger monooxygenases (BVMOs) (Ryerson et al 1982;Sheng et al 2001;Ballou and Entsch 2013) and can be described as follows ( Fig. 2a) Bufkin and Sobrado 2017):…”
Section: Catalytic Mechanism Of Flavin-dependent Nmosmentioning
Amino groups derived from naturally abundant amino acids or (di)amines can be used as "shuttles" in nature for oxygen transfer to provide intermediates or products comprising NO functional groups such as N-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C-, S-, or N-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactorcontaining enzymes and transferred to initially obtain N-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various NO or N-N comprising molecules is also described. Overall, flavin-dependent N-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the NO motif. Natural roles as well as synthetic applications are highlighted. Key points • NO and N-N comprising natural and (semi)synthetic products are highlighted. • Flavin-based NMOs with respect to mechanism, structure, and phylogeny are reviewed. • Applications in natural product formation and synthetic approaches are provided.
“…In general, the mechanism of NMOs is similar to that of group B Baeyer-Villiger monooxygenases (BVMOs) (Ryerson et al 1982 ; Sheng et al 2001 ; Ballou and Entsch 2013 ) and can be described as follows (Fig. 2a ) (Olucha and Lamb 2011 ; Bufkin and Sobrado 2017 ): Fig. 2 a Catalytic mechanism of flavin-dependent NMOs as reported for SidA and PvdA.…”
Section: Catalytic Mechanism Of Flavin-dependent Nmosmentioning
confidence: 66%
“…In general, the mechanism of NMOs is similar to that of group B Baeyer-Villiger monooxygenases (BVMOs) (Ryerson et al 1982;Sheng et al 2001;Ballou and Entsch 2013) and can be described as follows ( Fig. 2a) Bufkin and Sobrado 2017):…”
Section: Catalytic Mechanism Of Flavin-dependent Nmosmentioning
Amino groups derived from naturally abundant amino acids or (di)amines can be used as "shuttles" in nature for oxygen transfer to provide intermediates or products comprising NO functional groups such as N-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C-, S-, or N-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactorcontaining enzymes and transferred to initially obtain N-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various NO or N-N comprising molecules is also described. Overall, flavin-dependent N-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the NO motif. Natural roles as well as synthetic applications are highlighted. Key points • NO and N-N comprising natural and (semi)synthetic products are highlighted. • Flavin-based NMOs with respect to mechanism, structure, and phylogeny are reviewed. • Applications in natural product formation and synthetic approaches are provided.
“…In particular, the flavonoids were more significantly downregulated, with the most significant downregulation and the largest fold difference being in the flavonoid epicatechin gallate. In combination with comparative transcriptome analyses, a significant downregulation of the gene encoding the FAD-binding domain-containing protein (Fla1) was found; Fla1 belongs to the FAD-binding domain superfamily and is a flavoenzyme that is widely found in nature [18]. It is capable to catalyze a variety of biochemical reactions and has been widely used as a biocatalyst for a variety of reactions, and many biochemical processes take advantage of the versatility of flavoenzymes and extremely such as flavin cofactors [19,20].…”
Section: Discussionmentioning
confidence: 99%
“…FAD-binding domain protein (Fla1) belongs to the FAD-binding domain gene superfamily and is a flavoenzyme that is widely found in nature [18]; with its ability to catalyze a variety of biochemical reactions, it has been widely used as a biocatalyst for multifarious reactions [19,20]. About 1% of eukaryotic and prokaryotic proteins are expected to encode flavin adenine dinucleotide (FAD) binding domains [21].…”
Endophytic fungi are an important source of novel antitumor substances. Previously, we isolated an endophytic fungus, Alternaria alstroemeria, from the medicinal plant Artemisia artemisia, whose crude extracts strongly inhibited A549 tumor cells. We obtained a transformant, namely AaLaeAOE26, which completely loses its antitumor activity due to overexpression of the global regulator AaLaeA. Re‐sequencing analysis of the genome revealed that the insertion site was in the noncoding region and did not destroy any other genes. Metabolomics analysis revealed that the level of secondary antitumor metabolic substances was significantly lower in AaLaeAOE26 compared with the wild strain, in particular flavonoids were more downregulated according to the metabolomics analysis. A further comparative transcriptome analysis revealed that a gene encoding FAD‐binding domain protein (Fla1) was significantly downregulated. On the other hand, overexpression of AaFla1 led to significant enhancement of antitumor activity against A549 with a sevenfold higher inhibition ratio than the wild strain. At the same time, we also found a significant increase in the accumulation of antitumor metabolites including quercetin, gitogenin, rhodioloside, liensinine, ginsenoside Rg2 and cinobufagin. Our data suggest that the global regulator AaLaeA negatively affects the production of antitumor compounds via controlling the transcription of AaFla1 in endophytic A. alstroemeria.
“…Albachelin is a hydroxamate-containing siderophore with an ornithine-based backbone that coordinates the iron. Bufkin and Sobradro report on the purification and initial characterization of albachelin monooxygenase, a novel N -hydroxylase from Amycolatopsis alba [ 2 ]. They show that the flavin adenine dinucleotide (FAD)-dependent enzyme hydroxylates ornithine and that lysine stimulates the oxidase activity of the enzyme.…”
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