Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side chain cleavage.

ABSTRACT: 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.

SUBMITTER: Chen X 

PROVIDER: S-EPMC6900556 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature