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Abstract:

Radical S-adenosyl-L-methionine (SAM) enzymes are currently the largest known group of metalloenzymes and catalyze an extraordinarily broad range of radical-mediated chemical reactions. All radical SAM enzymes are unified by the presence of an active site [Fe4S4] cluster that can reductively cleave SAM and thus initiate the catalytic cycle. Radical SAM enzymes are also found in the biosynthesis of nucleoside natural products with oxetanocin A and albomycin 未2 being two notable examples. OxsB is a cobalamin-dependent radical SAM enzyme that participates in the biosynthetic conversion of 2'-deoxyadenosine 5'-monophosphate (2'-dAMP) to the antiviral and antibiotic agent oxetanocin A, which contains a four-membered oxetane ring. Recent findings indicate that OxsB catalyzes an oxidative, intramolecular C鈥扖 bond formation in 2'-dAMP to yield a highly unstable bicyclic intermediate. This intermediate undergoes regioselective bond cleavage catalyzed by OxsA to afford oxetanocin A aldehyde phosphate. Albomycin 未2 is a nucleoside antibiotic possessing a unique thiofuranose moiety. Biosynthesis of the thiofuranose ring requires an unprecedented, radical-mediated, sulfur-for-oxygen swapping reaction catalyzed by the twitch radical SAM enzyme AbmM. Recent studies have provided evidence that the sulfur is donated by the radical SAM [Fe4S4] cluster in this reaction. Furthermore, the immediate product of the AbmM catalyzed reaction undergoes a dehydration reaction involving a phosphorylated intermediate generated by the multifunctional kinase AbmG. The biosynthetic roles of these enzymes, their mechanisms of catalysis, and the insights they can offer for furthering our understanding of radical SAM enzymology will be discussed in this presentation.

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Bio:

Hun-wen (Ben) Liu was born in Taiwan and graduated with a BS degree in chemistry from Tunghai University (Taichung) in 1974. He completed his Ph.D. at Columbia University under the supervision of Koji Nakanishi, where he studied the additivity relation in exciton-split circular dichroism curves and its application in structural studies of oligosaccharides. In 1981, he joined Christopher Walsh at MIT as a postdoctoral fellow, where he became involved in mechanistic enzymology. In 1984, he became an assistant professor in the Department of Chemistry at the University of Minnesota, where he achieved the rank of Distinguished McKnight University Professor in 1999. Since 2000, he has held the George H. Hitchings Regents Chair in Drug Design at the University of Texas at Austin, where he is Professor of Medicinal Chemistry, Chemistry, and Biochemistry. His research lies at the crossroads of biological and organic chemistry, with particular emphasis on enzyme reaction mechanisms, natural product biosynthesis, protein function regulation, enzyme inhibitor design and synthesis, and metabolic pathway engineering. His work has been recognized by many awards, including the Horace S. Isbell Award (1993), the Nakanishi Prize (2007), the Repligen Award in Chemistry of Biological Processes (2008), the A. I. Scott Medal for Excellence in Biological Chemistry Research (2011), the Arthur C. Cope Late Career Scholars Award (2014), and the Gordon Hammes Lectureship Award (2023), among many others. He is an elected fellow of the American Association for the Advancement of Science (2005), the American Academy of Microbiology (2006), and the Academia Sinica (2008). He is an active member of a number of professional societies, and serves on many advisory boards, review panels, and editorial boards.