Divergent biosynthesis of C-Nucleoside minimycin and indigoidine in bacteria

Authors: KONG, LIYUAN - University Of Wuhan; XU, GUDAN - University Of Wuhan; LIU, XIAOQIN - University Of Wuhan; WANG, JINGWEN - University Of Wuhan; TANG, ZENGLIN - University Of Wuhan; CAI, YOUSHENG - University Of Wuhan; SHEN, KUN - University Of Wuhan; TAO, WEIXIN - Wuhan University; ZHENG, YU - Tianjin University Of Science And Technology; DENG, ZIXIN - Shanghai Jiaotong University; Price, Neil; CHEN, WENQING - University Of Wuhan

Submitted to: iScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/19/2019
Publication Date: 12/20/2019
Citation: Kong, L., Xu, G., Liu, X., Wang, J., Tang, Z., Cai, Y., Shen, K., Tao, W., Zheng, Y., Deng, Z., Price, N.P.J., Chen, W. 2019. Divergent biosynthesis of C-Nucleoside minimycin and indigoidine in bacteria. iScience. 22:430–440. https://doi.org/10.1016/j.isci.2019.11.037.
DOI: https://doi.org/10.1016/j.isci.2019.11.037

Interpretive Summary: The antibiotic minimycin and the naturally-occurring blue coloring agent indigoidine are both produced by the soil bacterium Streptomyces. In the present study, we show that these natural products share a biosynthetic pathway. It was determined that five genes are needed to produce minimycin, and the first gene in this pathway, called MinA, is also required for making indigoidine. Our work shows how the Streptomyces switches between making the two natural products. Finding the MIN genes will allow us to better control synthesis of each of these products and will help us to discover other minimycin-type antibiotics, which we expect to have potential uses as antibacterial agents for health and agriculture.

Technical Abstract: Minimycin (MIN, also called oxazinomycin) is a carbon-linked nucleoside antibiotic structurally related to uridine and pseudouridine, in which a 1,3-oxazine 2,4-dione ring and ribose are linked via a C-glycoside bond. Indigoidine is a naturally-occurring 3, 3’-bipyridyl blue pigment produced by several bacteria, which also contains a C-nucleoside core structure. Although MIN and indigoidine have been known for decades, the logic underlying the divergent biosynthesis of these interesting molecules has long been obscure. Here, we report the identification of a minimal 5-gene cluster (min) essential for MIN biosynthesis. We demonstrated that a non-ribosomal peptide synthetase, MinA, that selectively converts L-Gln to compound 1 via sequential steps, also governs “the switch” for the divergent biosynthesis of MIN and the cryptic indigoidine (blue pigment). We also demonstrate that MinCN (the N-terminal phosphatase domain of MinC), MinD (uracil phosphoribosyltransferase), and MinT (transporter) function together as the safeguard enzymes, which collaboratively constitute an unusual self-resistance mechanism during MIN biosynthesis. Finally, we established that MinD, utilizing an unprecedented substrate-competition strategy for self-resistance of the producer cell, maintains the competition advantage over the active molecule MIN-MP (MIN-5’-monophosphate) by increasing the UMP pool in vivo. These findings greatly expand our current knowledge regarding natural product biosynthesis.