,Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side c

• 作 者: Xiwei Chen Lu Wang Jinmei Zhang Tao Jiang Changhua Hu Dehai Li Yi Zou
• 机 构: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China“,”Key Laboratory o
• 出 处: 药学学报（英文版）
• 发表日期: 2019年6期
• 关键词: Biosynthesis Mycophenolic acid Prenylation C-C bond cleavage Globin enzyme

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 clusterindependent 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.