Unveiling Two Consecutive Hydroxylations: Mechanisms of Aromatic Hydroxylations Catalyzed by Flavin‐Dependent Monooxygenases for the Biosynthesis of Actinorhodin and Related Antibiotics

Hashimoto, Makoto; Taguchi, Tanezo; Ishikawa, Kazuki; Mori, Ryuichiro; Hotta, Akari; Watari, Susumu; Katakawa, Kazuaki; Kumamoto, Takuya; Okamoto, Susumu; Ichinose, Koji

doi:10.1002/cbic.201900490

Cited by 14 publications

(15 citation statements)

References 24 publications

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“…This system has recently been demonstrated in vitro to catalyze an additional C-8 oxygenation (Figure ). This study also showed that Med-7 (a C-6 FMO) solely affords a trihydroxynaphthalene intermediate leading to DHK 6 (Figure ). An S. coelicolor engineered strain in which the C-6 oxygenase genes were replaced with med -7 led to produce 7 and 8 , together with KAL 4 .…”

Section: Resultsmentioning

confidence: 89%

“…24 This observation is reasonably explained by the monofunctionality at the C-6 oxygenation of Med-7 (Figure 1) to accumulate DHK 6, which is converted to its AcCys adducts as unwanted metabolites in the ACT pathway. A lactonizing conversion of DHK 6 to KAL 4 was demonstrated, 40,41 indicating its mechanism is most likely via a hydroquinone formation (Figure S5).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Identification of a C-Glycosyltransferase Involved in Medermycin Biosynthesis

et al. 2021

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C-Glycosylation in the biosynthesis of bioactive natural products is quite unique, which has not been studied well. Medermycin, as an antitumor agent in the family of pyranonaphthoquinone antibiotics, is featured with unique C-glycosylation. Here, a new C-glycosyltransferase (C-GT) Med-8 was identified to be essential for the biosynthesis of medermycin, as the first example of C-GT to recognize a rare deoxyaminosugar (angolosamine). med-8 and six genes (med-14, -15, -16, -17, -18, and -20 located in the medermycin biosynthetic gene cluster) predicted for the biosynthesis of angolosamine were proved to be functional and sufficient for C-glycosylation. A C-glycosylation cassette composed of these seven genes could convert a proposed substrate into a C-glycosylated product. In conclusion, these genes involved in the C-glycosylation of medermycin were functionally identified and biosynthetically engineered, and they provided the possibility of producing new C-glycosylated compounds.

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Section: Resultsmentioning

confidence: 89%

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification of a C-Glycosyltransferase Involved in Medermycin Biosynthesis

et al. 2021

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“…[63] Within the biosynthesis of the polyaromatic pyranonaphthoquinone antibiotic actinorhodin (23), two consecutive hydroxylations take place at the C6 and C8 positions via atwo-component FMO (Figure 8). [64] Sequential dihydroxylation within the natural product pathway of saxitoxin has recently been shown to be catalysed by two Rieske oxygenases.Each enzyme was responsible for aregioand stereoselective hydroxylation from b-saxitoxinol to yield 11-b-hydroxysaxitoxin (24). [65] Furthermore in the biosyntheses of platensimycin (25)a nd platencin (26), an on-haem diiron monooxygenase hydroxylates at the C5 b-position facilitating facile diversification of these natural products.…”

Section: Hydroxylationmentioning

confidence: 99%

Enzymatic Late‐Stage Modifications: Better Late Than Never

et al. 2021

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Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late‐stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme‐catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late‐stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.

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“…[83] Enzymvarianten wurden kürzlich für die stereoselektive Lacton-Carben-Insertion entwickelt (Schema 10). Durch die Einführung dieser funktionellen Gruppe waren zahlreiche Derivate des Sequiterpenlactonamins (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74) in hohen Enantio-und Diastereoselektivitäten zugänglich. [82] Kürzlich wurde über die Konstruktion von P411-Enzymen für die C(sp 3 )-H-Aminierung berichtet.…”

Section: Nicht-natürliche Oxyfunktionalisierungenunclassified