Location: Renewable Product Technology ResearchTitle: Coordinated biosynthesis of the purine nucleoside antibiotics aristeromycin and coformycin in the actinomycetes
|XU, GUDAN - UNIVERSITY OF WUHAN|
|KONG, LIYUAN - UNIVERSITY OF WUHAN|
|XU, LIUDONG - SHANGHAI JIAOTONG UNIVERSITY|
|GAO, YAOJIE - SHANGHAI JIAOTONG UNIVERSITY|
|JIANG, MING - SHANGHAI JIAOTONG UNIVERSITY|
|CAI, YOU-SHENG - UNIVERSITY OF WUHAN|
|HONG, KUI - UNIVERSITY OF WUHAN|
|DENG, ZIXIN - UNIVERSITY OF WUHAN|
|CHEN, WENQING - UNIVERSITY OF WUHAN|
|YU, YOUCAI - PEKING UNION MEDICAL COLLEGE HOSPITAL|
Submitted to: Applied and Environmental Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2018
Publication Date: 9/14/2018
Citation: Xu, G., Kong, L., Xu, L., Gao, Y., Jiang, M., Cai, Y., Hong, K., Deng, Z., Price, N.P.J., Chen, W., Yu, Y. 2018. Coordinated biosynthesis of the purine nucleoside antibiotics aristeromycin and coformycin in the actinomycetes. Applied and Environmental Microbiology. 34(22):e01860-18. https://doi.org/10.1128/aem.01860-18.
Interpretive Summary: Antimicrobial resistance is a major concern for both human and veterinary medicine. Aristeromycin (ARM) and coformycin (COF) are two antiviral agents that are currently made by chemical synthesis. In the present paper we report two soil bacteria (Micromonospora haikouensis and Streptomyces citricolor) that produce these antiviral agents when grown in fermentation. We have also studied the biosynthetic pathway for how these compounds are made by the organisms, and report the functions for several of the mac genes involved. The results will help us to understand how ARM and COF are produced by these organism, and may provide an alternative to the current chemical preparation of them.
Technical Abstract: Purine nucleoside antibiotic pairs are an important group of Actinomycete-derived natural products. Here, we report a target-directed genome mining approach to elucidate the biosynthesis of the purine nucleoside antibiotic pair aristeromycin (ARM) and coformycin (COF) in Micromonospora haikouensis DSM 45626 (a new producer for ARM and COF) and Streptomyces citricolor NBRC 13005 (a new COF producer). We also provided biochemical data that MacI and MacT function as unusual phosphorylases, catalyzing an irreversible reaction for the tailoring assembly of neplanocin A (NEP-A) and ARM. Unexpectedly, MacI/MacT also catalyze a reversible hydrolysis of adenosine to provide adenine as substrate. Moreover, mutation of the macQ gene decreases production of ARM, and functionally MacQ is shown to be an adenosine-specific deaminase, likely relieving the “excess adenosine” stress for producing cells. Finally, we report that MacR, an annotated IMP (inosine monophosphate) dehydrogenase, is actually an NADPH-dependent GMP (guanosine monophosphate) reductase, which plays a probable salvage role for the efficient supply of the precursor pool. Hence, these findings illustrate a fine-tuned pathway for the biosynthesis of ARM, and also open the way for the rational search for purine antibiotic pairs.