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Biosynthesis and Chemical Diversity of Β-Lactone Natural Products 20Xx, Serina L Natural Product Reports Biosynthesis and Chemical Diversity of β-Lactone Natural Products Journal: Natural Product Reports Manuscript ID NP-REV-06-2018-000052.R1 Article Type: Review Article Date Submitted by the Author: 14-Aug-2018 Complete List of Authors: Robinson, Serina; University of Minnesota BioTechnology Institute Christenson, James; University of Minnesota BioTechnology Institute; Bethel University, Chemistry Wackett, Lawrence; University of Minnesota BioTechnology Institute Page 1 of 22 PleaseNatural do notProduct adjust Reports margins Natural Product Reports ARTICLE Received 00th January Biosynthesis and Chemical Diversity of β-Lactone Natural Products 20xx, Serina L. Robinson,a James K. Christenson,a,b and Lawrence P. Wacketta Accepted 00th January Covering: up to 2018 20xx DOI: 10.1039/x0xx00000x β-Lactones are strained rings that are useful organic synthons and pharmaceutical www.rsc.org/ warheads. Over 30 core scaffolds of β-lactone natural products have been described to date, many with potent bioactivity against bacteria, fungi, or human cancer cell lines. β-Lactone natural products are chemically diverse and have high clinical potential, but production of derivatized drug leads has been largely restricted to chemical synthesis partly due to gaps in biochemical knowledge about β-lactone biosynthesis. Here we review recent discoveries in enzymatic β-lactone ring closure via ATP-dependent synthetases, intramolecular cyclization from seven-membered rings, and thioesterase-mediated cyclization during release from nonribosomal peptide synthetase assembly lines. We also comprehensively cover the diversity and taxonomy of source organisms for β-lactone natural products including their isolation from bacteria, fungi, plants, insects, and marine sponges. This work identifies computational and experimental bottlenecks and highlights future directions for genome-based discovery of biosynthetic gene clusters that may produce novel compounds with β-lactone rings. 1. Background and Reactivity 5. Conflicts of interest 2. Mechanisms of β-lactone biosynthesis 6. Acknowledgements 2.1. Known mechanisms 7. References 2.2. Proposed mechanisms 2.3. Comparisons with β-lactam biosynthesis Serina L. Robinson is a National Science Foundation 3. Diversity of β-lactone natural products Graduate Research Fellow in the lab of Dr. Lawrence P. 3.1. Microbial β-lactones Wackett at the University of Minnesota. She is 3.1.1. Amino acid β-lactones concurrently pursuing a Ph.D. in Microbiology and a 3.1.2. Fatty acid β-lactones M.S. in Bioinformatics and Computational Biology. 3.1.3. Polyketide β-lactones Prior to beginning her 3.1.4. Hybrid pathway β-lactones β graduate studies, Serina 3.1.5. Other -lactones studied chemistry at St. Olaf β 3.2. Plant and animal -lactones College and received a β 3.2.1. Terpenoid -lactones Fulbright Scholarship to 3.2.2. Alkaloid β-lactones Norway in the lab of Dr. 3.3. β-Lactones as pathway intermediates Mette M. Svenning. Her 4. Future directions thesis research is focused on the biosynthesis of β-lactone natural products. aBioTechnology Institute, University of Minnesota – Twin Cities 140 Gortner Laboratory, 1479 Gortner Avenue, Saint Paul, MN, 55108, USA bDepartment of Chemistry, Bethel University 3900 Bethel Drive, Saint Paul, MN, 55112, USA Email: [email protected] PleaseNatural do notProduct adjust Reports margins Page 2 of 22 ARTICLE Journal Name James K. Christenson is a professor of Biochemistry at 80 Bethel University in St. Paul, Minnesota. He completed his Ph.D. at the University of 70 Minnesota in the laboratory 60 of Dr. Lawrence P. Wackett where he published on 50 enzymes that synthesize and 40 decarboxylate β-lactones. 30 He is passionate about the Publications# of integration of research into 20 undergraduate course work 10 and is currently exploring new enzymes capable of β- 0 lactone biosynthesis. 1897 1902 1910 1918 1924 1931 1938 1944 1949 1954 1959 1964 1969 1974 1979 1984 1989 1994 1999 2004 2009 2014 Year Lawrence P. Wackett received his Ph.D. at the University Figure 1. Number of publications in SciFinder Scholar of Texas at Austin, working with David T. Gibson on with the word ‘beta-lactone’ in the title or keyword by enzymes that metabolize aromatic hydrocarbons. He year up to 2017. went on to do postdoctoral studies at MIT with Christopher T. Walsh. He then travelled to the ETH- wave, corresponding largely to a surge in β-lactone Zürich, collaborating with Thomas Leisinger, and natural product discovery, that the potential clinical, started thereafter as an assistant professor at the synthetic, and chemoproteomic applications of β- University of Minnesota in the Department of lactones began to emerge. Interestingly, most β-lactone Biochemistry, Molecular natural products were not reported until long after the Biology and Biophysics and post-World War II ‘golden age’ of antibiotic discovery. the BioTechnology Institute. Only three distinct β-lactone natural product scaffolds In 2001, he became (anisatin,6 hymeglusin,7 and oxazolomycin8) were Distinguished McKnight discovered before 1975. From the 1980’s through the University Professor at 2000’s, however, nearly 30 novel bioactive compounds Minnesota. His research is with β-lactone functional groups were isolated from the in two main areas, novel culture broth of fungi and bacteria. As recently as 2015 microbial enzymes that and later, several distinct β-lactone analogs of known biodegrade organic natural product scaffolds were discovered, including the compounds and natural cystargolides,9 ostalactones,10 bisoxazolomycins,11 and product biosynthesis. vibralactoximes.12 The wave of β-lactone natural product discovery may have been delayed partly due to the 1 Background and Reactivity instability of β-lactone rings to chemical workup β-Lactones (2-oxetanones) are often referred to as following biological extractions. β-Lactones readily ‘privileged’ structures as they have highly-reactive undergo acid or base hydrolysis and are subject to β electrophilic scaffolds and serve as versatile synthetic thermal degradation. That may have caused -lactone intermediates. The first synthesis of a β-lactone was natural products to elude discovery by traditional described by Einhorn in 1883,1 but it was not until the extraction methods and they may represent an understudied class of compounds with regards to their mid-1950’s that the first β-lactone natural product, the biosynthesis. Recent developments in genome-based potent neurotoxin, anisatin, was isolated from the fruit of natural product discovery and synthetic biology a Japanese spice tree.2 The first complete asymmetric techniques offer new potential to uncover the gene synthesis of a β-lactone was later reported in 1982,3 clusters encoding ‘orphan’ β-lactone compounds and laying the foundation for the use of chiral β-lactones in β the total synthesis of natural products and their promote discovery of novel -lactone natural products. β derivatives. A query of SciFinder revealed two spikes in Although overshadowed by the success of the - β the publication record of β-lactones (Fig. 1). The first lactams, -lactones have received significant attention in spike in the 1960’s – 1970’s corresponded to commercial their own right for their antimicrobial, anticancer, and interest in β-lactones as building blocks to make antiobesity properties. Notably, in 1999, the β-lactone biodegradable polyesters.4,5 It was not until the second natural product derivative tetrahydrolipstatin (Xenical, 2 | Nat. Prod. Rep.., 2018, 00, 1-3 This journal is © The Royal Society of Chemistry 2018 Please do not adjust margins Page 3 of 22 PleaseNatural do notProduct adjust Reports margins Journal Name ARTICLE Alli) was approved by the U.S. Food and Drug Administration (FDA) as a weight loss drug.13 Another β-lactone secondary metabolite, salinosporamide A, completed phase II clinical trials for multiple myeloma and glioblastoma and is currently in phase III clinical trials for combination treatment of glioblastoma.14 Despite these few successes, the therapeutic potential for this potent class of molecules remains underexplored relative to the β-lactams, which comprise greater than 50% of antibiotics on the market today.15 The β-lactams and β-lactones belong to a class of Figure 2. Dual sites of nucleophilic attack by cysteine, strained four-membered heterocycles. The release of the threonine, or serine residues results in two modes of ring inherent ring strain facilitates nucleophilic attack from opening. catalytic serine, threonine, or cysteine residues in enzyme nucleophilic attack exclusively at the acyl (C2) position. active sites (Fig. 2). Enzymes with these activated The diversity of cellular targets is both a boon and a catalytic nucleophiles are susceptible to inhibition by pitfall as the high reactivity can also cause off-target forming a stable covalent adduct with an opened β- effects. Rational drug design and testing is paramount to lactam or β-lactone ring. The major physiological targets realize the potential of this reactive but powerful class of of β-lactams are the penicillin-binding proteins (PBPs) molecules. For further insight into the mode of action of involved in polymerization and cross-linking of β-lactones we refer readers to in-depth reviews on peptidoglycan.16-18 In contrast, chemical profiling studies targeted covalent inhibitors.20,21 have revealed that β-lactones target >20 different Organic chemists have long used β-lactones as enzymes representing four different enzyme classes: intermediates
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