Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side chain cleavage.
10.1016/j.apsb.2019.06.009
- Author:
Xiwei CHEN
1
;
Lu WANG
2
;
Jinmei ZHANG
1
;
Tao JIANG
1
;
Changhua HU
1
;
Dehai LI
2
;
Yi ZOU
1
Author Information
1. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
2. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
- Publication Type:Journal Article
- Keywords:
Biosynthesis;
C‒C bond cleavage;
Globin enzyme;
Mycophenolic acid;
Prenylation
- From:
Acta Pharmaceutica Sinica B
2019;9(6):1253-1258
- CountryChina
- Language:English
-
Abstract:
Mycophenolic acid (MPA, ) 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 , especially the processes involving the cleavage of the prenyl side chain between DHMP () and DMMPA (), remains unknown. In this work, we identified a membrane-bound prenyltransferase, PgMpaA, that transfers FPP to to yield FDHMP (). Compound undergoes the first cleavage step a new globin-like enzyme PgMpaB to form a cryptic intermediate . Heterologous expression of genes in demonstrates that the second cleavage step (from to ) of is a cluster-independent process . 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.
