Prof. Dr.Ya-Jie Tang,UniversityDistinguished Professor of Biochemical Engineering
Email：yajietang@sdu.edu.cn
Professor Ya-Jie Tang
Ya-Jie Tang,UniversityDistinguished Professor and doctoral supervisor at the State Key Laboratory of Microbial Technology (Shandong University, Qingdao, China). He received PhD degree of Biochemical Engineering from the State Key Laboratory of Bioreactor Engineering (East China University of Science and Technology, Shanghai, China) in 2003. After postdoctoral work at MIT, he returned to China in 2005. Prof. Tang has been devoting himself to the teaching and scientific research about Biomanufacture of Natural Product. His project of “The theory and method for the biomanufacture of natural product” was awarded the First Prize Natural Science by Hubei Province in 2016, and “The key technology for industrial microbial fermentation and its industrialization” was awarded the First Prize of Science and Technology Progress by Hubei Province in 2014. Prof. Tang was selected to be the State Class Persons of National Talents Engineering of Ministry of Personnel in 2009, the National Outstanding Professional and Technical Personnel and the China National High-level Talents Special Support Plan (Million Plan) in 2014, then he was invited to take part in the holiday in Beidaihe and spoke as a representative in 2015, and was granted the Outstanding Scholar by National Natural Science Foundation of China (NSFC) in 2016, was granted De-Bang Hou Innovation Prize for the Chemical Engineering of Science and Technology, Chemical Industry and Engineering Society of China in 2017. Furthermore, Prof. Tang is an Associate Editor of the Springer journalBioprocess and Biosystems Engineering.
Prize 2016 The First Prize Natural Science by Hubei Province
The theory and method for the biomanufacture of natural product
Winner：Ya-Jie Tang, Jian-Jiang Zhong, Li-Wen Zhu, Rui-Sang Liu, Wei Zhao
2014 The First Prize of Science and Technology Progress by Hubei Province
The key technology for industrial microbial fermentation and its industrialization
Winner：Ya-Jie Tang, Duan-Ji Wang, Jun Cai, Wang-Jun Li, Feng Gao, Feng He, Fei-Zhong Duan, Li-Wen Zhu, Zhu Li, Chang-Gao Wang, Rui-Sang Liu, You Li, Wei Zhao
2014 The First Prize of Natural Science by the Ministry of Education
Fermentation process regulation for production of valuable secondary metabolites by higher fungi and plant cells
Winner：Jian-Jiang Zhong,Ya-Jie Tang, Zhi-Gang Qian, Jian-Wen Liu, Wen Tang, Jian-Hui Xiao
2011 The Second Prize of Natural Science by Hubei Province
Edible fungi submerged fermentation
Winner：Ya-Jie Tang, Dong-Sheng Li, Duan-Ji Wang, Rui-Sang Liu, Li-Wen Zhu
2010 The Second Prize of Natural Science by Shanghai City
Theory and method for the regulation of biochemical reaction engineering
Winner：Jian-Jiang Zhong, Jian-He Xu, Xu-Hong Qian,Ya-Jie Tang, You-Yan Liu
2004 The First Prize of Natural Science by the Ministry of Education
Study on the cell culture in bioreactor engineering
Winner：Jian-Jiang Zhong, Jing-Si Wang,Ya-Jie Tang, Yi-Heng Zhang, Qing-Hua Fang
Grant
1 2017.1-2021.12 Biomanufacture of natural product,the National Natural Science Foundation for Distinguished Young Scholars (Grant No. 21625602)
2 2019.1-2023.12In vivo assembly of artificial synthesis pathway of drug candidates’ nitrogen-containing heterocyclic podophyllum derivatives,National Natural Science Foundation of China (Grant No. 21838002).
Research Interest 1: The Development of New Anti-tumor Natural Drugs
Natural productis the main sourcefor the discoveryof new drug. The rich resource of natural product in China providea unique advantage for the development of new drug.In orderto develop the new anti-tumor drug with novel structure and unique activity, we intend to studythetraditional Chinese medicine herbs by usingthecurrent biologicalscience and technology.
1. Molecular structure design for natural medicine. By taking podophyllotoxin as the research object, the research model of "analyze the target protein structure → establish the pharmacophore model with high activity and low toxicity → screen the molecular fragment with high affinity of target protein → molecular structure design of leading compounds → summarize the structure-activity relationship"will be developed. To explore two binding active domains of target protein such as tubulin, topoisomerase II and IGF1R, the affinity target fragmentswill be assembled by using drug hybridization principles. The method of drug molecular structure design for dual-target inhibitory target proteinswill be established, and the "target compound library" will be designed and constructed.
2. Molecular structure modification of natural medicine. According to the molecular structure characteristics of target compounds, the biocatalysis reactions types of target productwill berationally designed. An effective strategy for screening biocatalystswill bedeveloped, and a biocatalyst library with various functionswill be established. Novel methods of tandem biotransformation and combined biotransformationwill be established for modifying the molecular structure of natural products. Meanwhile, the target compoundswill be synthesized rapidly by chemical synthesis, biosynthesis or coupling chemical-biosynthesis methods, and podophyllotoxin derivatives library with novel molecular diversity and structure will be established.
3. The evaluation of activity and toxicity. Anti-tumor activity, toxicity and target protein inhibition ability at the cellular levelwill be evaluated and screened for discovering hit compounds. Then the validity, safety and bioavailability of the compounds will be evaluatedin vivo for discovering leading compounds. In our previous work, 4β-NH-heterocyclic podophyllotoxin derivatives with nanomolar-potency antitumor activity and 4β-S-heterocyclic podophyllotoxin derivatives with millimolar-potency low toxicity against human normal cells were screened out, while the antitumor activities and toxicities of positive control drugs such as etoposide and teniposide were all of micromolar-potency. The above candidate drugs are expected to be developed as new anti-cancer drugs with high efficiency and low toxicity.
4. Anti-tumor and toxicity mechanism. To clarify the anti-tumor mechanism of the lead compounds, the apoptotic signal transduction pathwaywas studied. The pharmacological result showed that the candidate drugs with nanomolar antitumor activity could trigger mitochondrial apoptotic pathway and regulated ROS apoptotic signal cascade pathway. Meanwhile, the intracellular DNA repair pathway was specifically activated and PI3K proliferation signal pathway was enhanced in normal cells.
Research Interest 2: Biomanufacture of Natural Product
1. Artificial design of synthetic pathway for drug nitrogen-containing heterocyclic podophyllum candidate. Molecular structure characteristics between the substrate podophyllotoxin and the target product nitrogen-containing heterocyclic podophyllotoxin candidates will be analyzed. Usingde novo design strategy, modification routes such as oxidation at C-4 site, C-NH substitution, C-S substitution and demethylation at E-4' site will be worked out, and the synthetic pathways for target product nitrogen-containing heterocyclic podophyllotoxin candidates will be designed.
2. Construction of single-step catalytic reactionin vitro. Based on the above artificial design of synthetic pathway, the enzymes involved in oxidation, imine substitution, free radicalization and demethylation reactions will be screened in the database of enzymology or biosynthetic compounds according to the principle of substrate similarity. To improve the catalytic efficiency of enzyme, substrate cognition sites and catalytic center will be reconstructed by using site redesign and directed evolution, and the construction of single-step catalytic reaction will be realizedin vitro.
3. Construction of single-step catalytic reaction inin vivo. The enzyme-coding genes will be carried out by codon optimization, and a higher expression of enzyme involved the single-step catalytic reaction will be realized in yeast chassis cells. According to the optimized culture conditions (i.e., pH, temperature etc.) for lipase, reductase and free radical enzyme in the intracellular and extracellular space, the enzyme will be evolved directionally. According to the specificity of monooxygenase to ligand recognition, the specific structural region will be mutated specifically to improve the catalytic function of intracellular enzyme. Then, the single-step catalytic reaction will be constructedin vivo.
4. Assembly of synthetic pathway in vivo. Multiple enzyme-coding genes will be localized to different organelles by using location elements, andin vivo assembly of synthetic pathways will be preliminarily realized. Then, the libraries of regulatory elements such as promoters and terminators will be constructed. By combining regulatory elements and enzyme-coding genes, the fine regulation of multi-step catalytic reaction will be implemented, thus thein vivo assembly of synthetic pathway will be realized. The adaptation mechanism between artificial synthesis pathway and chassis cells can be elucidated to realize the artificial synthesis of nitrogen-containing heterocyclic podophylloids candidate drugs.
Patents
1. Ya-Jie Tang, Wei Zhao. 4β-anilino-substituted podophyllotoxin derivatives having antitumor activity, method for preparation thereof, and use thereof (PCT/CN2018/089831)
2. Ya-Jie Tang, Wei Zhao. Sulfur-substituted heterocycles podophyllotoxin derivatives having antitumor activity, method for preparation thereof, and use thereof (PCT/CN2018/089832)
3. Ya-Jie Tang, Wei Zhao. Heterocycles-substituted teniposide derivatives, synthesis method thereof, and use thereof (PCT/CN2019)
4. Ya-Jie Tang, Jian-Long Li, Wei Zhao, Hong-Mei Li. Sulfur-substituted podophyllotoxin derivative, synthesis method thereof, and use thereof (US 9,828,386 B2)
5. Ya-Jie Tang, Yong Yang, Wei Zhao, Hong-Mei Li. Anilino podophyllin derivative having antitumor activity, method for preparation thereof, and use thereof (US 9,714,254 B2)
6. Ya-Jie Tang, Wei Zhao. 4′-Demthylepipodophyllotoxin Derivative, Preparation Method and Use Thereof II (US 8,796,279 B2)
7. Ya-Jie Tang. 4′-Demthylepipodophyllotoxin Derivative, Preparation Method and Use Thereof (US 8,569,309 B2)
8. Ya-Jie Tang, Kai-Zhi Jia, Yang-Hua Xu, Quan Zhang, Hong-Mei Li. Methionine lyase and Its gene encoding and biosynthesis method and use thereof (US 096230)
9. Ya-Jie Tang, Jian-Long Li, Wei Zhao, Hong-Mei Li. Sulfur-substituted podophyllotoxin derivative, synthesis method thereof, and use thereof (ZL201310571051.5)
10. Ya-Jie Tang, Yong Yang, Wei Zhao, Hong-Mei Li. Anilino podophyllin derivative having antitumor activity, method for preparation thereof, and use thereof (ZL201310571026.7)
Papers
1. Wei Zhao1, Long He1, Tian-Le Xiang,Ya-Jie Tang*. Discover 4β-NH-(6-aminoindole)-4-desoxy-podophyllotoxin with nanomolar-potency antitumor activity by improving the tubulin binding affinity on the basis of a potential binding site nearby colchicine domain.European Journal of Medicinal Chemistry 2019, 170:73-86. (IF=4.816) (1 with equal contribution to this work)
2. Qing-Yun Zhang1, Wei Zhao1,Ya-Jie Tang*. Discover the leading compound of 4β-S-(5-fluorobenzoxazole)-4-deoxy-4'-demethylepipodophyllotoxin with millimolar-potency toxicity by modifying the molecule structure of podophyllotoxin.European Journal of Medicinal Chemistry 2018, 158:951-964. (1 with equal contribution to this work)
3. Yang-Hua Xu1, Kai-Zhi Jia1,Ya-Jie Tang*.Regulatory networks governing methionine catabolism into volatile organic sulfur-containing compounds inClonostachys rosea. Applied and Environmental Microbiology2018, 84(22): e01840-18 (1 with equal contribution to this work)
4. Li-Wen Zhu,Ya-Jie Tang*.Current advances of succinate biosynthesis in metabolically engineeredEscherichia coli.Biotechnology Advances2017, 35:1040-1048.
5. Wei Zhao1, Chen Zhou1, Ze-Yuan Guan, Fu-Sheng Chen*, Ping Yin*,Ya-Jie Tang*. Structural insights into the inhibition of tubulin by the antitumor agent 4β-S-(1, 2, 4-triazole-3-yl)-podophyllotoxin. ACS Chemical Biology 2017,12:746-752 (1 with equal contribution to this work)
6. Li-Na Wei1, Li-Wen Zhu1,Ya-Jie Tang*. Succinate production positively correlates with the affinity of the global transcription factor Cra for its effector FBP inEscherichia coli. Biotechnology for Biofuels 2016, 9:624. (1 with equal contribution to this work)
7. Jun-Han Yu1, Li-Wen Zhu1, Shi-Tao Xia1,Hong-Mei Li, Ya-Ling Tang, Xin-Hua Liang, Tao Chen,Ya-Jie Tang*. Combinatorial optimization of CO2 transport and fixation to improve succinate production by promoter engineering.Biotechnology and Bioengineering 2016, 113:1531-1541. (1 with equal contribution to this work)
8. Li Xiao1, Wei Zhao1, Hong-Mei Li, Duan-Ji Wan, Dong-Sheng Li, Tao Chen,Ya-Jie Tang*. Design and synthesis of the novel DNA topoisomerase II inhibitors: esterification and amination substituted 4′-demethylepipodophyllotoxin derivates with anti-tumor activity by activating ATM/ATR signaling pathways. European Journal of Medicinal Chemistry2014, 80:267-277. (1 with equal contribution to this work)
9. Li-Wen Zhu1, Xiao-Hong Li1, Lei Zhang, Hong-Mei Li, Jian-Hua Liu, Zhan-Peng Yuan, Tao Chen,Ya-Jie Tang*. Activation ofglyoxylate pathway without the activation ofitsrelated gene in succinate-producing engineeredEscherichia coli.Metabolic Engineering 2013, 20:9-19. (1 with equal contribution to this work)
10. Ya-Jie Tang*, Wei Zhao, Hong-Mei Li. Novel tandem biotransformation process for the biosynthesis of a novel compound 4-(2, 3, 5, 6-tetramethylpyrazine-1)-4′-demethylepipodophyllotoxin.Applied and Environmental Microbiology 2011, 77:3023-3034.
