Mycinamicins, new macrolide antibiotics. I. Taxonomy, production, isolation, characterization and properties.

Satoi, Shūzō; Muto, Naoki; Hayashi, Masahito; Fujii, Tadashiro; Otani, Motoyasu

doi:10.7164/antibiotics.33.364

Cited by 81 publications

(47 citation statements)

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“…Mycinamicins are macrolide antibiotics produced by the actinomycete Micromonospora griseorubida (1). They are composed of a 16-membered macrolactone ring and two sugars, desosamine and mycinose, at the C-5 and C-21 positions respectively (Fig.…”

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confidence: 99%

Substrate Recognition by the Multifunctional Cytochrome P450 MycG in Mycinamicin Hydroxylation and Epoxidation Reactions

Tietz

Rutaganira

et al. 2012

Journal of Biological Chemistry

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Background: A hierarchy of catalytic steps characterizes multifunctional cytochrome P450 enzymes. Results: In the post-polyketide oxidative tailoring of mycinamicins by MycG, the two methoxy groups of mycinose are sensors that mediate initial recognition and discriminate between closely related molecules. Conclusion: Bulky and conformationally restrained macrolide substrates advance to the catalytically productive mode through multiple steps. Significance: Protein engineering facilitating substrate progression may enhance catalysis.

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confidence: 99%

Substrate Recognition by the Multifunctional Cytochrome P450 MycG in Mycinamicin Hydroxylation and Epoxidation Reactions

Tietz

Rutaganira

et al. 2012

Journal of Biological Chemistry

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“…Mycinamicin, which is produced by Micromonospora griseorubida A11725, is a 16-membered macrolide antibiotic with strong antibacterial activity against Gram-positive bacteria (29). Mycinamicin consists of a macrolactone substituted with two different sugars, desosamine and mycinose.…”

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confidence: 99%

Function of Cytochrome P450 Enzymes MycCI and MycG in Micromonospora griseorubida, a Producer of the Macrolide Antibiotic Mycinamicin

Anzai

Tsukada

Sakai

et al. 2012

Antimicrob Agents Chemother

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The cytochrome P450 enzymes MycCI and MycG are encoded within the mycinamicin biosynthetic gene cluster and are involved in the biosynthesis of mycinamicin II (a 16-membered macrolide antibiotic produced by Micromonospora griseorubida). Based on recent enzymatic studies, MycCI is characterized as the C-21 methyl hydroxylase of mycinamicin VIII, while MycG is designated multifunctional P450, which catalyzes hydroxylation and also epoxidation at C-14 and C-12/13 on the macrolactone ring of mycinamicin. Here, we confirm the functions of MycCI and MycG in M. griseorubida. Protomycinolide IV and mycinamicin VIII accumulated in the culture broth of the mycCI disruption mutant; moreover, the mycCI gene fragment complemented the production of mycinamicin I and mycinamicin II, which are produced as major mycinamicins by the wild strain M. griseorubida A11725. The mycG disruption mutant did not produce mycinamicin I and mycinamicin II; however, mycinamicin IV accumulated in the culture broth. The mycG gene was located immediately downstream of the self-resistance gene myrB. The mycG gene under the control of mycGp complemented the production of mycinamicin I and mycinamicin II. Furthermore, the amount of mycinamicin II produced by the strain complemented with the mycG gene under the control of myrBp was approximately 2-fold higher than that produced by the wild strain. In M. griseorubida, MycG recognized mycinamicin IV, mycinamicin V, and also mycinamicin III as the substrates. Moreover, it catalyzed hydroxylation and also epoxidation at C-14 and C-12/13 on these intermediates. However, C-14 on mycinamicin I was not hydroxylated. The cytochrome P450 enzymes (P450s) form a very large family of oxidative heme proteins, which are responsible for a diverse range of oxidative transformations across most life forms (12, 13). These reactions typically involve the modification of physiological and xenobiotic compounds and include the biosynthesis of various bioactive compounds (e.g., steroids, antibiotics, and signaling molecules). Approximately 40% of all known bacterial P450s are found in various species of the industrially important genus Streptomyces, which is the largest genus of the actinomycetes. Recent genome sequencing of the actinomycetes, particularly Streptomyces, has revealed an unexpectedly large number of genes encoding P450s (9,16,18,24,25). In secondary metabolic pathways, P450 genes are typically integrated within the biosynthetic cluster, where their products catalyze regiospecific and stereospecific oxidation of precursors. This results in structural diversity and also improved bioactivities of these molecules (21, 27). The P450s EryF (2) and EryK (30) are encoded within the erythromycin biosynthetic gene cluster and are involved in the biosynthesis of erythromycin A. Specifically, EryF catalyzes the hydroxylation of the macrolactone precursor 6-deoxyerthronolide B, while EryK catalyzes the formation of erythromycin D. As prototypic P450 hydroxylases involved in secondary metabolism, EryF and EryK exhibit stri...

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“…Reductive decarboxylation6) by the Barton reaction of the 19-carboxyl derivative prepared from compound1 was accomplished in the following manner. The hydroxyl groups at the C-2' and C-4' positions of compound 1 were easily acetylated with acetic anhydride at room temperature to afford a quantitative yield of I'^'-di-O-acetyldesmycosin (2). The aldehyde at the C-19 position in compound2 was readily oxidized to the corresponding carboxyl group at ambient temperature using NaClO2as an oxidant and sulfamic acid as a scavenger7), to give I'^'-di-O-acetyl-^-deformyl-^-carboxydesmycosin (3) in 80 to 90% yield.…”

Section: Resultsmentioning

confidence: 99%

19-Deformyl-4'-deoxydesmycosin (TMC-016): Synthesis and biological properties of a unique 16-membered macrolide antibiotic.

et al. 1989

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Mycinamicins, new macrolide antibiotics. I. Taxonomy, production, isolation, characterization and properties.

Cited by 81 publications

References 1 publication

Substrate Recognition by the Multifunctional Cytochrome P450 MycG in Mycinamicin Hydroxylation and Epoxidation Reactions

Substrate Recognition by the Multifunctional Cytochrome P450 MycG in Mycinamicin Hydroxylation and Epoxidation Reactions

Function of Cytochrome P450 Enzymes MycCI and MycG in Micromonospora griseorubida, a Producer of the Macrolide Antibiotic Mycinamicin

19-Deformyl-4'-deoxydesmycosin (TMC-016): Synthesis and biological properties of a unique 16-membered macrolide antibiotic.

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