A New 16-Membered Chalcomycin Type Macrolide Antibiotic, 250-144C.

Goo, Yang Mo; Lee, Youn Young; Kim, Bum Tab

doi:10.7164/antibiotics.50.85

Cited by 14 publications

(5 citation statements)

References 4 publications

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“…Extensive investigations have revealed that the sugar moieties attached to macrolide antibiotics such as chalcomycin often provide or enhance their pharmacological properties . Thus far, three congeners of chalcomycin that differ slightly with respect to the degree of saturation of the aglycone ring or the identity of the substituent attached to the 4″-hydroxyl group of mycinose have been identified. , In addition to chalcomycin, the unusual sugar mycinose has also been found attached to tylosin, an antibiotic used in veterinary medicine. − …”

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confidence: 99%

Structural and Functional Studies on a 3′-Epimerase Involved in the Biosynthesis of dTDP-6-deoxy-d-allose

et al. 2012

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Unusual deoxy sugars are often attached to natural products such as antibiotics, antifungals, and chemotherapeutic agents. One such sugar is mycinose, which has been found on the antibiotics chalcomycin and tylosin. An intermediate in the biosynthesis of mycinose is dTDP-6-deoxy-D-allose. Four enzymes are required for the production of dTDP-6-deoxy-D-allose in Streptomyces bikiniensis, a soil-dwelling microbe first isolated from the Bikini and Rongelap atolls. Here we describe a combined structural and functional study of the enzyme ChmJ, which reportedly catalyzes the third step in the pathway leading to dTDP-6-deoxy-D-allose formation. Specifically, it has been proposed that ChmJ is a 3'-epimerase that converts dTDP-4-keto-6-deoxyglucose to dTDP-4-keto-6-deoxyallose. This activity, however, has never been verified in vitro. As reported here, we demonstrate using (1)H nuclear magnetic resonance that ChmJ, indeed, functions as a 3'-epimerase. In addition, we determined the structure of ChmJ complexed with dTDP-quinovose to 2.0 Å resolution. The structure of ChmJ shows that it belongs to the well-characterized "cupin" superfamily. Two active site residues, His 60 and Tyr 130, were subsequently targeted for study via site-directed mutagenesis and kinetic analyses, and the three-dimensional architecture of the H60N/Y130F mutant protein was determined to 1.6 Å resolution. Finally, the structure of the apoenzyme was determined to 2.2 Å resolution. It has been previously suggested that the position of a conserved tyrosine, Tyr 130 in the case of ChmJ, determines whether an enzyme in this superfamily functions as a mono- or diepimerase. Our results indicate that the orientation of the tyrosine residue in ChmJ is a function of the ligand occupying the active site cleft.

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Structural and Functional Studies on a 3′-Epimerase Involved in the Biosynthesis of dTDP-6-deoxy-d-allose

et al. 2012

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“…1; compound 1), discovered in the late 1950s in a strain of Streptomyces bikiniensis (11), and mycinamicin I (compound 2) represent a group with 2,3-trans double bonds. Three congeners of chalcomycin have been recently identified (2,13,21). All contain the same polyketide backbone but differ in the degrees of oxidation or acylation.…”

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confidence: 99%

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

Ward¹,

Hu²,

Schirmer³

et al. 2004

Antimicrob Agents Chemother

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Chalcomycin, a 16-membered macrolide antibiotic made by the bacterium Streptomyces bikiniensis, contains a 2,3-trans double bond and the neutral sugar D-chalcose in place of the amino sugar mycaminose found in most other 16-membered macrolides. Degenerate polyketide synthase (PKS)-specific primers were used to amplify DNA fragments from S. bikiniensis with very high identity to a unique ketosynthase domain of the tylosin PKS. The resulting amplimers were used to identify two overlapping cosmids encompassing the chm PKS. Sequencing revealed a contiguous segment of >60 kb carrying 25 putative genes for biosynthesis of the polyketide backbone, the two deoxysugars, and enzymes involved in modification of precursors of chalcomycin or resistance to it. The chm PKS lacks the ketoreductase and dehydratase domains in the seventh module expected to produce the 2,3-double bond in chalcomycin. Expression of PKS in the heterologous host Streptomyces fradiae, from which the tyl genes encoding the PKS had been removed, resulted in production of at least one novel compound, characterized as a 3-keto 16-membered macrolactone in equilibrium with its 3-trans enol tautomer and containing the sugar mycaminose at the C-5 position, in agreement with the structure predicted on the basis of the domain organization of the chm PKS. The production of a 3-keto macrolide from the chm PKS indicates that a discrete set of enzymes is responsible for the introduction of the 2,3-trans double bond in chalcomycin. From comparisons of the open reading frames to sequences in databases, a pathway for the synthesis of nucleoside diphosphate-D-chalcose was proposed.

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“…A few congeners of chalcomycin all of which have two neutral sugar units in the molecule attached to C-5 and C-19, respectively, have been reported, e.g. swalpamycin (Kim et al, 1996;Goo et al, 1997;Asolkar et al, 2002;Chatterjee et al, 1987). In our study, two new 16-membered macrolides named chalcomycin C and D have been isolated from marine Streptomyces sp.…”

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confidence: 92%