“Head‐to‐Middle” and “Head‐to‐Tail” cis‐Prenyl Transferases: Structure of Isosesquilavandulyl Diphosphate Synthase |
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| Authors: | Jian Gao Dr Tzu‐Ping Ko Lu Chen Dr Satish R Malwal Jianan Zhang Xiangying Hu Fiona Qu Dr Weidong Liu Dr Jian‐Wen Huang Dr Ya‐Shan Cheng Dr Chun‐Chi Chen Yunyun Yang Prof?Dr Yonghui Zhang 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. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA;4. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA;5. School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA;6. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China;7. Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA |
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| Abstract: | We report the first X‐ray crystallographic structure of the “head‐to‐middle” prenyltransferase, isosesquilavandulyl diphosphate synthase, involved in biosynthesis of the merochlorin class of antibiotics. The protein adopts the ζ or cis‐prenyl transferase fold but remarkably, unlike tuberculosinol adenosine synthase and other cis‐prenyl transferases (e.g. cis‐farnesyl, decaprenyl, undecaprenyl diphosphate synthases), the large, hydrophobic side chain does not occupy a central hydrophobic tunnel. Instead, it occupies a surface pocket oriented at 90° to the hydrophobic tunnel. Product chain‐length control is achieved by squeezing out the ligand from the conventional allylic S1 binding site, with proton abstraction being achieved using a diphosphate‐Asn‐Ser relay. The structures revise and unify our thinking as to the mechanism of action of many other prenyl transferases and may also be of use in engineering new merochlorin‐class antibiotics. |
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| Keywords: | antibiotics enzymes isoprenoids protein structures X-ray diffraction |
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