张骊駻 - 西湖大学

个人简介

Lihan was originally born in Jilin, China, later grew up in Nagano, Japan, where he became interested in science as a high school student. After entering the University of Tokyo, he started working in the laboratory of Professor Ikuro Abe, and obtained his B.S. (2012) and Ph.D.(2017) in Pharmaceutical Sciences. He then moved to the laboratory of Professor Emily Balskus at Harvard University to pursue postdoctoral research till 2019. He has awarded multiple honors and fellowships, including The University of Tokyo Fellowship, the JSPS Research Fellowship, and the JSPS Overseas Research Fellowship. Lihan joined School of Science, Westlake University in September 2019.

研究领域

Natural products have been the major source of antibiotics. As we enter the era of antibiotic resistance crisis, there is a keen need for discovery of new antibiotics. How much do new drugs remain to be discovered from nature? How can we create new “unnatural” natural products? Our lab applies evolutionary perspective to understand the diversity of natural products and their biosynthesis, and aims to accelerate natural product evolution by synthetic biology. 1. Evolution-guided Nature Product Discovery Hundreds of thousands of natural products, or specialized metabolites, have been recorded nowadays. However, recent (meta)genomic analysis suggested the existence of vast amount of “microbial dark matter” that remain unexplored but potentially encode enzymes for new natural products. We are interested in the distribution and diversity of natural products. To better characterize these “dark matters”, we take interdisciplinary approach integrating bioinformatics, metabolomics, and traditional natural product chemistry for the discovery of new natural products. Our group is working on global analysis of the entire natural products world, and at the same time pursuing big-data and evolution driven targeted discovery of clinically important class of molecules. 2. Assembly Line Biosynthesis and Bioengineering Assembly line enzymes are the most sophisticated biosynthetic machinery that produce numerous structural varieties. Among these products, polyketides and nonribosomal peptides are the leading class of natural products in antibiotics discovery and development. The biosynthesis of polyketides, for example in macrolide antibiotics erythromycin, is catalyzed by a set of multimodular polyketide synthase (PKS) megaenzymes in a sequential manner. This assembly line biosynthesis has been a target for rational bioengineering since their discovery in 1990s, though we are still far from flexible reprogramming of these assembly line enzymes. Interestingly, the exponentially accumulating sequences of biosynthetic genes now offers opportunity to understand the evolution of multimodular PKSs and NRPSs in nature. Our group aims to understand the evolution of polyketide and nonribosomal peptide biosynthesis and apply it for evolution-guided engineering to realize plug-and-play reprogramming of assembly line biosynthesis.

近期论文

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Chen, S.#; Zhang, C.#; Zhang, L. "Investigation of the Molecular Landscape of Bacterial Aromatic Polyketides by Global Analysis of Type II Polyketide Synthases." Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202202286 Zhang, L.*; Awakawa, T.; Abe, I.* "Understanding and manipulating assembly line biosynthesis by heterologous expression in Streptomyces" Methods in Molecular Biology 2022 in press Xie, S.; Zhang, L. "A specialized role played by a redox cofactor" Engineering Microbiology 2022, 2, 100010. Liu, G.#; Li, S.#; Shi, Q.; Li, H.; Guo, J.; Ouyang J.; Jia, X.; Zhang, L.*; You, S.*; Qin, B.* "Engineering of Sccharomyces pastorianus Old Yellow Enzyme 1 for the Synthesis of Pharmacologically Active (S)-Profen Derivatives." Mol. Catal. 2021, 507, 111568. Wang, W.-G.#*; Wang, H.#; Du, L.-Q.#; Li, M.; Chen, L.; Yu, J.; Cheng, G.-G.; Zhan, M.-T.; Hu, Q.-F.; Zhang, L.; Yao., M.; Matsuda, Y.* "Molecular Basis for the Biosynthesis of an Unusual Chain-Fused Polyketide, Gregatin A." J. Am. Chem. Soc. 2020, 142, 8464-8472. Acknowledgement Awakawa, T.; Fujioka, T.; Zhang, L.; Hoshino, S.; Hu, Z.; Hashimoto, J.; Kozone, I.; Ikeda, H.; Shin-ya, K.; Liu, W.; Abe, I. “Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution.” Nat. Commun. 2018, 9, 3534 Zhang, L.#; Hashimoto, T.#; Qin, B.; Hashimoto, J.; Kozone, I.; Kawahara, T.; Okada, M.; Awakawa, T.; Ito, T.; Asakawa, Y.; Ueki, M.; Takahashi, S.; Osada, H.; Wakimoto, T.; Ikeda, H.; Shin-ya, K.; Abe, I. “Characterization of giant modular PKSs provides insight into genetic mechanism for structural diversification of aminopolyol polyketides.” Angew. Chem. Int. Ed., 2017, 56, 1740-1745. Zhang, L.; Hoshino, S.; Awakawa, T.; Wakimoto, T.; Abe, I. “Structural Diversification of Lyngbyatoxin A by Host-Dependent Heterologous Expression of the tleABC Biosynthetic Gene Cluster.” ChemBioChem 2016, 17, 1407–1411. Mori, T.; Zhang, L.; Awakawa, T.; Hoshino, S.; Okada, M.; Morita, H.; Abe, I. “Manipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases.” Nat. Commun. 2016, 7, 10849. Zhang, L.; Mori, T.; Zheng, Q.; Awakawa, T.; Yan, Y.; Liu, W.; Abe, I. “Rational control of polyketide extender units by structure-based engineering of a crotonyl-CoA carboxylase/reductase in antimycin biosynthesis.” Angew. Chem. Int. Ed. 2015, 54, 13462–13465. Hoshino, S.; Zhang, L.; Awakawa, T.; Wakimoto, T.; Onaka, H.; Abe, I. “Arcyriaflavin E, a new cytotoxic indolocarbazole alkaloid isolated by combined-culture of mycolic acid- containing bacteria and Streptomyces cinnamoneus NBRC 13823.” J. Antibiot. 2015, 68, 342–344. Awakawa, T.; Zhang, L.; Wakimoto, T.; Hoshino, S.; Mori, T.; Ito, T.; Ishikawa, J.; Tanner, M. E.; Abe, I. “A methyltransferase initiates terpene cyclization in teleocidin B biosynthesis.” J. Am. Chem. Soc. 2014, 136, 9910–9913. Zhang, L.; Chen, J.; Mori, T.; Yan, Y.; Liu, W.; Abe, I. “Crystallization and preliminary X-ray diffraction analysis of AntE, a crotonyl-CoA carboxylase/reductase from Streptomyces sp. NRRL 2288.” Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. 2014, 70, 734–737. Yan Y.; Chen, J.; Zhang, L.; Zheng, Q.; Han, Y.; Zhang, H.; Awakawa, T.; Abe, I.; Liu, W. “Multiplexing of combinatorial chemistry in antimycin biosynthesis expands the molecular diversity and utility.” Angew. Chem. Int. Ed. 2013, 52, 12308–12312. Chen, D.; Zhang, L.; Pang, B.; Chen, J.; Xu, Z.; Abe, I.; Liu, W. “FK506 maturation involves a cytochrome P450 protein-catalyzed four-electron C-9 oxidation in parallel with a C-31 O-methylation.” J. Bacteriol. 2013, 195, 1931–1939. Yan, Y.; Zhang, L.; Ito, T.; Qu, X.; Asakawa, Y.; Awakawa, T.; Abe, I.; Liu, W. “Biosynthetic pathway for high structural diversity of a common dilactone core in antimycin production.” Org. Lett. 2012, 14, 4142–4145.