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Scientists Elucidate Long Mystery on Late Rifamycin Biosynthesis

Jun 19, 2018

The most effective drug to treat tuberculosis is the specific broad spectrum antibiotic. Rifamycins, the first and the most commercially successful antibiotics, show the wide spectrum of antimicrobial activities against tuberculosis bacteria. Their semisynthetic derivatives have long been used as first-line therapies for the treatment of tuberculosis, leprosy, and AIDS-related mycobacterial infections. 

Although a majority of rifamycin B biosynthetic steps have been elucidated, the late biosynthetic steps leading from rifamycin SV to the end product rifamycin B remains elusive to date. 

Recently, a research team led by Prof. LI Shengying from the Qingdao Institute of Bioenergy and Bioprocess Technology of the Chinese Academy of Sciences and their collaborators completely elucidated the long mystery on late rifamycin biosynthesis. Their findings were published in Nature Communications. 

Scientists elucidated the late steps of rifamycin biosynthesis for the first time by reconstitution of the in vitro activities of transketolase Rif15 and P450 enzyme Rif16, 13C chasing experiments, and resolution of the Rif16 crystal structure. This work revises the previous biosynthetic model that was proposed by Ghisalba et al. 36 years ago (J. Antibiot. 1982, 35, 74-80). 

Rifamycin SV can be oxidized to rifamycin S spontaneously. The transketolase Rif15 is responsible for transferring a C2 keto-containing fragment from a 2-ketose to rifamycin S giving rise to rifamycin L. Subsequently, the P450 enzyme Rif16 catalyzes the transformation from rifamycin L to rifamycin O. 

Rifamycin O is non-enzymatically reduced to rifamycin B by NADPH. These transformations revealed a unique C-O bond formation reaction mediated by a transketolase and an atypical P450 reaction of ester-to-ether transformation. 

These uncommon biosynthetic mechanisms add two new reactions to the toolkit of available biosynthetic tools. It will likely have significant implications for strain engineering relating to the industrial production of rifamycins and the new derivatives thereof.  

This work was supported by the Shandong Provincial Key Laboratory of Synthetic Biology, Shandong Natural Science Foundation, the National Natural Science Foundation of China, Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality. 

 

The biosynthetic network of late rifamycin derivatives. (Imaged by Qi Feifei) 

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