Short Communication
Xiwei Chen, Lu Wang, Jinmei Zhang, Tao Jiang, Changhua Hu, Dehai Li, Yi Zou. Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side chain cleavage[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1253-1258

Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side chain cleavage
Xiwei Chena, Lu Wangb, Jinmei Zhanga, Tao Jianga, Changhua Hua, Dehai Lib,c, Yi Zoua,d
a College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China;
b Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;
c Laboratory for Marine Drugs and Bioproducts of Qingdao, National Laboratory for Marine Science and Technology, Qingdao 266237, China;
d Biological Science Research Center, Southwest University, Chongqing 400715, China
Mycophenolic acid (MPA, 1) and its derivatives are first-line immunosuppressants used in organ transplantation and for treating autoimmune diseases. Despite chemical synthetic achievements, the biosynthetic formation of a seven-carbon carboxylic acid pharmacophore side chain of 1, especially the processes involving the cleavage of the prenyl side chain between DHMP (4) and DMMPA (5), remains unknown. In this work, we identified a membrane-bound prenyltransferase, PgMpaA, that transfers FPP to 4 to yield FDHMP (6). Compound 6 undergoes the first cleavage step via a new globin-like enzyme PgMpaB to form a cryptic intermediate 12. Heterologous expression of PgMpa genes in Aspergillus nidulans demonstrates that the second cleavage step (from 12 to 5) of 1 is a PgMpa cluster-independent process in vivo. Our results, especially the discovery of the broad tolerance of substrates recognized by PgMpaB, set up a strategy for the formation of "pseudo-isopentenyl" natural products using fungal globin-like enzymes.
Key words:    Biosynthesis    Mycophenolic acid    Prenylation    C-C bond cleavage    Globin enzyme   
Received: 2019-06-12     Revised: 2019-06-19
DOI: 10.1016/j.apsb.2019.06.009
Funds: We thank Prof. Blaine Pfeifer from the University at Buffalo (UB, USA), the State University of New York (USA) for a critical reading of the manuscript. This work is supported by the National Natural Science Foundation of China (31870022), the Fundamental Research Funds for the Central Universities (XDJK2018B035 and 201941001, China), and the Scientific Research Starting Foundation of Southwest University (SWU117034, China), the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology (Qingdao, China) (No. 2018SDKJ0401-2), and Taishan Scholar Youth Expert Program in Shandong Province (tsqn201812021, China). Yi Zou is supported by the Venture & Innovation Support Program for Chongqing Overseas Returnees and the Thousand Young Talents Program of China.
Corresponding author: Dehai Li, Yi Zou;
Author description:
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Xiwei Chen
Lu Wang
Jinmei Zhang
Tao Jiang
Changhua Hu
Dehai Li
Yi Zou

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