Functional Characterization of MpaG′, the O-Methyltransferase Involved in the Biosynthesis of Mycophenolic Acid

Mycophenolic acid (MPA, 1) is a clinically important immunosuppressant. In this report, a gene cluster mpa′ responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S‐adenosyl‐L‐methionine‐dependent (SAM‐dependent) O‐methyltransferase encoded by the mpaG′ gene was functionally and kinetically characterized in vitro. MpaG′ catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6) to form 1. It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis. Penicillium­ genome mining: A gene cluster—mpa′—responsible for the biosynthesis of mycophenolic acid (MPA) has been identified from P. brevicompactum NRRL 864, and the O‐methyltransferase encoded by mpaG′ has been characterized. It not only catalyzed the methylation of demethylmycophenolic acid (DMMPA) to form MPA, but also methylated two derivatives of DMMPA.