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Co-option of Sulphur-Transfer Machinery from Primary Metabolism for 2-Thiosugar Biosynthesis
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Title:Co-option of Sulphur-Transfer Machinery from Primary Metabolism for 2-Thiosugar Biosynthesis 

Presenter:Prof. Hung-wen (Ben) Liu

University: Department of Chemistry and Biochemistry at the University of Texas, Austin 



Host:Prof. Yihua Chen

Resume:Professor Hung-wen (Ben) Liu was born in Taipei, Taiwan. He graduated with a B.S. degree in Chemistry from Tunghai University (Taiwan).  After two years of military service, he began his graduate study at Columbia University where he carried out research under Professor Koji Nakanishi.  His work on the additivity relation in exciton-split circular dichroism curves and its application in structural studies of oligosaccharides earned him a Ph.D. in 1981.  He then joined Professor Christopher Walsh's group at MIT as a postdoctoral fellow.  There he became involved in the field of mechanistic enzymology. In 1984, he became an Assistant Professor in the Department of Chemistry at the University of Minnesota.  He was promoted through the ranks becoming the Distinguished McKnight University Professor in 1999.  In the summer of 2000, Liu moved to the University of Texas at Austin.  He currently holds the George Hitchings Regent Chair in Drug Design, and is a Professor in the Medicinal Chemistry Division of the College of Pharmacy and the Department of Chemistry and Biochemistry at the University of Texas, Austin. 

  Liu's research lies at the crossroads of chemistry and biology, and focuses on the elucidation of the chemical mechanisms of enzymes that catalyze mechanistically unusual and physiologically important steps in the biosynthetic pathways of natural products. Over the years, his group has studied many intriguing chemical transformations in a wide variety of natural product classes. His multi-faceted approach in studying bioorganic problems, especially the biosynthesis of unusual sugars and radicals in enzyme catalysis, has earned him many awards including the National Institutes of Health Research Career Development Award (1990), the Horace S. Isbell Award from the American Chemical Society Carbohydrate Division (1993), the MERIT Award from the National Institute of General Medicine (1999), the Nakanishi Prize from the American Chemical Society Organic Division (2007), the Repligen Award from the American Chemical Society Biological Division (2008), the A. I. Scott Medal (2011), and the Arthur C. Cope Late Career Scholars Award from the American Chemical Society (2014). He is a Fellow of the American Association for the Advancement of Science, the American Academy of Microbiology, the Japan Society for the Promotion of Science, the American Chemical Society, and an academician of Academia Sinica. He was an Honorary Professor of the University of Hong Kong, National Tsing Hua University, and Tunghai University. He serves on many review panels and editorial boards. He is currently an Associate Editor of Organic Letters since 2004. He is also an active member in many professional societies, and was the chair of the American Chemical Society Biological Division during 2013-2014. 

Abstract:Sulfur is an essential element for life and exists ubiquitously in living systems. Yet, how the sulfur atom is incorporated in many sulfur-containing secondary metabolites remains poorly understood. For C-S bond formation in primary metabolites, the major ionic sulfur sources are the protein-persulfide and protein-thiocarboxylate. In each case, the persulfide and thiocarboxylate group on these sulfur-carrier (donor) proteins are post-translationally generated through the action of a specific activating enzyme.  In all bacterial cases reported thus far, the genes encoding the enzyme that catalyzes the actual C-S bond formation reaction and its cognate sulfur-carrier protein co-exist in the same gene cluster. To study 2-thiosugar production in BE-7585A, an antibiotic from Amycolatopsis orientalis, we identified a putative 2-thioglucose synthase, BexX, whose protein sequence and mode of action appear similar to those of ThiG, the enzyme catalyzing thiazole formation in thiamin biosynthesis. However, no sulfur-carrier protein gene could be located in the BE-7585A cluster. Subsequent genome sequencing revealed the presence of a few sulfur-carrier proteins likely involved in the biosynthesis of primary metabolites, but surprisingly only a single activating enzyme gene in the entire genome of A. orientalis. Further experiments showed that this activating enzyme is capable of adenylating each of these sulfur-carrier proteins, and likely also catalyzing the subsequent thiolation taking advantage of its rhodanese activity.  A proper combination of these sulfur delivery systems is effective for BexX-catalyzed 2-thioglucose production. The ability of BexX to selectively distinguish sulfur-carrier proteins is given a structural basis using X-ray crystallography. These studies represent the first complete characterization of a thiosugar formation in nature and also demonstrate the receptor promiscuity of the sulfur-delivery system in A. orientalis. Our results also provide evidence that exploitation of sulfur-delivery machineries of primary metabolism for thte biosynthesis of sulfur-containing natural products is likely a general strategy found in nature. 

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