摘要
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.
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.
基金
supported by the National Natural Science Foundation of China(31870022)
the Fundamental Research Funds for the Central Universities(XDJK2018B035 and 201941001,China)
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)
Taishan Scholar Youth Expert Program in Shandong Province(tsqn201812021,China)
supported by the Venture&Innovation Support Program for Chongqing Overseas Returnees and the Thousand Young Talents Program of China.
