Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5 |
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| Authors: | Lilan Zhang Prof Dr Chun‐Chi Chen Dr Tzu‐Ping Ko Jian‐Wen Huang Prof Dr Yingying Zheng Prof Dr Weidong Liu Dr Iren Wang Dr Satish R Malwal Dr Xinxin Feng Dr Ke Wang Prof Dr Chun‐Hsiang Huang Prof Dr Shang‐Te Danny Hsu Prof Dr Andrew H‐J Wang Prof Dr Eric Oldfield Prof Dr Rey‐Ting Guo |
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| Institution: | 1. Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China;2. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan;3. AsiaPac Biotechnology Co., Ltd., Dongguan, China;4. Department of Chemistry, University of Illinois, Urbana, IL, USA |
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| Abstract: | The structure of MoeN5, a unique prenyltransferase involved in the biosynthesis of the antibiotic moenomycin, is reported. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis‐farnesyl group in phosphoglycolipid 5 to form the (C25) moenocinyl‐sidechain‐containing lipid 7 . GPP binds to an allylic site (S1) and aligns well with known S1 inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 and a second site, S2. Long sidechains in S2 are “bent” and co‐locate with the homoallylic substrate isopentenyl diphosphate in other prenyltransferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6–C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, with the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics. |
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| Keywords: | biosynthesis drug discovery enzyme mechanisms isoprenoids protein structure |
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