Elucidation of the di-c-glycosylation steps during biosynthesis of the antitumor antibiotic, kidamycin

Kyung Taek Heo; Byeongsan Lee; Jae-Hyuk Jang; Young-Soo Hong

doi:10.3389/fbioe.2022.985696

Elucidation of the di-c-glycosylation steps during biosynthesis of the antitumor antibiotic, kidamycin

Front Bioeng Biotechnol. 2022 Aug 25:10:985696. doi: 10.3389/fbioe.2022.985696. eCollection 2022.

Authors

Kyung Taek Heo^{1

2}, Byeongsan Lee¹, Jae-Hyuk Jang^{1

2}, Young-Soo Hong^{1

2}

Affiliations

¹ Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, South Korea.
² Department of Bio-Molecular Science, KRIBB School of Bioscience, University of Science and Technology(UST), Daejeon, South Korea.

Abstract

Kidamycins belong to the pluramycin family of antitumor antibiotics that contain di-C-glycosylated angucycline. Owing to its interesting biological activity, several synthetic derivatives of kidamycins are currently being developed. However, the synthesis of these complex structural compounds with unusual C-glycosylated residues is difficult. In the kidamycin-producing Streptomyces sp. W2061 strain, the genes encoding the biosynthetic enzymes responsible for the structural features of kidamycin were identified. Two glycosyltransferase-coding genes, kid7 and kid21, were found in the kidamycin biosynthetic gene cluster (BGC). Gene inactivation studies revealed that the subsequent glycosylation steps occurred in a sequential manner, in which Kid7 first attached N,N-dimethylvancosamine to the C10 position of angucycline aglycone, following which Kid21 transferred an anglosamine moiety to C8 of the C10-glycosylated angucycline. Therefore, this is the first report to reveal the sequential biosynthetic steps of the unique C-glycosylated amino-deoxyhexoses of kidamycin. Additionally, we confirmed that all three methyltransferases (Kid4, Kid9, and Kid24) present in this BGC were involved in the biosynthesis of these amino-deoxyhexoses, N,N-dimethylvancosamine and anglosamine. Aglycone compounds and the mono-C-glycosylated compound obtained in this process will be used as substrates for the development of synthetic derivatives in the future.

Keywords: C-glycosyltransferase; angucycline; biosynthetic gene cluster (BGC); kidamycin; methyltransferase; streptomyces.