Principal Investigator: Dr. Guohui Pan   Telephone/Fax： E-mail：panguohui@im.ac.cn Add.:NO.1 West Beichen Road, Chaoyang District, Beijing 100101, China

Research area Microbial natural product discovery, biosynthesis and synthetic biology

Research interests Natural products are well-known for their various biological activities and remarkable structural diversity. Natural products have a proven track record of success in the history of drug discovery and development. More than half of the new drugs developed over the last several decades are natural product and their derivatives. The rise in multi-drug resistant pathogens further highlight the urgency to discover more new natural product drugs. On the other hand, the intriguing chemical structures of natural products inspire and promote the field of natural product biosynthesis and total synthesis, triggering the discovery of novel enzymatic reactions, new chemical reactions, et al. Our group take a multi-disciplinary approach, including genomics/bioinformatics, molecular biology, genetics, biochemistry and organic chemistry, to study the natural products from actinomycetes and human microbiome. We aim to understand: what type of natural products the microbial genomes encode, what are the enzymatic reactions leading to the assembly of the final natural product structures, and how can we manipulate and reconstruct the biosynthetic pathways for drug discovery and development.   (1) Natural product discovery by genome mining Microbial genomes encode dramatic amount of natural product biosynthetic gene clusters (BGCs, >30 BGCs per typical bacterial genome), and the products of the vast majority of these BGCs are not characterized, which represent a great source of new natural products. By analyzing the microbial genomic information and prioritizing the BGCs, we aim to identify the corresponding natural products of interests with a combination of strategies. We will focus on the BGCs that have the potential to produce analogues of natural product drugs on market, which may be developed as new therapeutic agents in the future.   (2) Biosynthetic pathway refactoring with synthetic biology tools and application in drug development One key challenge in natural product discovery field is that most of the BGCs are cryptic under standard laboratory conditions. We aim to (i) reconstruct the biosynthetic pathway using modern synthetic biology tools, to active the cryptic BGCs, and increase the yield of targeted natural products; (ii) design and construct new biosynthetic pathways for generating structurally diverse natural products for drug development.   (3) Natural product biosynthesis and protein engineering The tremendous chemical diversity of natural products is generated by the diverse enzymes in the biosynthetic machinery, which use simple building blocks to assemble the final complex structures. We aim to characterize these novel enzymes, and elucidate their catalytic mechanisms with biochemical and structural biology tools. We are also very interested in developing these enzymes into biocatalyst through protein engineering.

Group Members     Principle investigator Guohui Pan, Ph.D., Associate Professor   Education Sep. 2008 – Jan. 2014, Ph.D. Biochemistry and Molecular Biology, Institute of Microbiology, Chinese Academy of Sciences (IMCAS) & University of the Chinese Academy Sciences, Beijing, China.   Sep. 2004 – Sep. 2008, B.S. Biological Engineering, School of Chemical & Enviromental Engineering, China University of Mining and Technology-Beijing (CUMTB), Beijing, China.   Professional Experience Aug. 2019 – present, Principle investigator, Associate Professor State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences   Feb. 2014 – Aug. 2019, Postdoctoral Research Associate Department of Chemistry, The Scripps Research Institute – Florida, Jupiter, Florida, USA.

Recent Publications 1. Steele AD, Kalkreuter E, Pan G, Meng S, Shen B*. (2019) "Hybrid Peptide-Polyketide Natural Product Biosynthesis" in Comprehensive Natural Products: Chemistry and Biology, Vol I, Elsevier, in press. 2. McAlpine et al. (2019) The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research. Nat Prod Rep. 36, 35-107. 3. Xu Z#, Pan G#, Zhou H, Shen B*. (2018) Discovery and characterization of 1-aminocyclopropane-1-carboxylic acid synthase of bacterial origin. J Am Chem Soc. 140, 16957-61. (Hot off the press) 4. Kwong T#, Ma M#, Pan G, Hindra, Yang D, Yang C, Lohman JR, Rudolf JD, Cleveland JL, Shen B*. (2018) P450-catalyzed tailoring steps in leinamycin biosynthesis featuring regio- and stereoselective hydroxylations and substrate promiscuities. Biochemistry. 57, 5005–13. 5. Pan G#, Xu Z#, Guo Z, Hindra, Ma M, Yang D, Zhou H, Gansemans Y, Zhu X, Huang Y, Zhao LX, Jiang Y, Cheng J, Van Nieuwerburgh F, Suh JW, Duan Y, Shen B*. (2017) Discovery of the leinamycin family of natural products by mining actinobacterial genomes. Proc Natl Acad Sci U S A. 114, E11131-40. (Highlighted by F1000) 6. Zhang B#, Xu Z#, Teng Q#, Pan G, Ma M, Shen B*. (2017) A Long-range effecting dehydratase domain as the missing link for C17-dehydration in iso-migrastatin biosynthesis. Angew. Chem. Int. Ed. 56, 7247-51. 7. Li L#, Pan G#, Zhu X, Fan K, Gao W, Ai G, Ren J, Shi M, Olano C, Salas J, Yang K*. (2017) Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase. Appl Microbiol Biotechnol. 101:5291-300. 8. Pan G#, Gao X#, Fan K#, Liu J, Meng B, Gao J, Wang B, Zhang C, Han H, Ai G, Chen Y, Wu D*, Liu ZJ*, Yang K*. (2017) Structure and function of a C-C bond cleaving oxygenase in atypical angucycline biosynthesis. ACS Chem Biol. 12, 142-52. 9. Guo Z, Pan G, Xu Z, Yang D, Hindra, Zhu X, Huang Y, Zhao LX, Jiang Y, Duan Y, Shen B*. (2017) New isofuranonaphthoquinones and isoindolequinones from Streptomyces sp. CB01883. J Antibiot. 70, 414-22. 10. Huang Y#, Yang D#, Pan G, Tang GL, Shen B*. (2016) Characterization of LnmO as a pathway-specific Crp/Fnr-type positive regulator for leinamycin biosynthesis in Streptomyces atroolivaceus and its application for titer improvement. Appl Microbiol Biotechnol. 100, 10555-62. 11. Huang Y, Tang GL, Pan G, Chang CY, Shen B. (2016) Characterization of the Ketosynthase and Acyl Carrier Protein Domains at the LnmI Nonribosomal Peptide Synthetase-Polyketide Synthase Interface for Leinamycin Biosynthesis. Org Lett. 18, 4288-91.  12. Zhang B#, Yang D#, Yan Y, Pan G, Xiang W*, Shen B*. (2016) Overproduction of lactimidomycin by cross-overexpression of genes encoding Streptomyces antibiotic regulatory proteins. Appl Microbiol Biotechnol. 100, 2267-77. 13. Medema MH et al. (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol. 11, 625-31. (Highlighted by F1000) 14. Wang B#, Ren J#, Li L, Guo F, Pan G, Ai G, Aigle B, Fan K*, Yang K*. (2015) Kinamycin biosynthesis employs a conserved pair of oxidases for B-ring contraction. Chem Commun. 51, 8845-8. 15. Liu Y, Ryu H, Ge B, Pan G, Sun L, Park K, Zhang K*. (2014) Improvement of wuyiencin biosynthesis in Streptomyces wuyiensis CK-15 by identification of a key regulator, WysR. J Microbiol Biotechnol. 24, 1644-53. 16. Wang W#, Ji J#, Li X, Wang J, Li S, Pan G, Fan K, Yang K*. (2014) Angucyclines as signals modulate the behaviors of Streptomyces coelicolor. Proc Natl Acad Sci U S A. 111, 5688-93. 17. Zhang Y#, Pan G#, Zou Z, Fan K, Yang K*, Tan H*. (2013) JadR*-mediated feed-forward regulation of cofactor supply in jadomycin biosynthesis. Mol Microbiol. 90, 884-97. 18. Fan K#, Pan G#, Peng X, Zheng J, Gao W, Wang J, Wang W, Li Y, Yang K*. (2012) Identification of JadG as the B ring opening oxygenase catalyzing the oxidative C-C bond cleavage reaction in jadomycin biosynthesis. Chem Biol. 19, 1381-90.