Biosynthesis of mycophenolic acid

Incorporation experiments with labelled potential biosynthetic intermediates suggest that the methyl group at C-4 of the phthalide system in mycophenolic acid is introduced at the tetraketide stage. This then gives way to the aromatic system, which is further oxidised to 5,7-dihydroxy-4- methylphthalide. The isolation of 6-farnesyl-5,7-di-hydroxy-4-methylphthalide from the culture and the high incorporation of this compound into mycophenolic acid indicate that the most important process for the biosynthesis of the side-chain is the introduction of a C15 terpene chain followed by oxidative fission at the appropriate double bond. 'Enzymic trap' experiments confirm these results. Alternative pathways for the biosynthesis of the side-chain through 6-geranyl-5.7-dihydroxy-4-methyl-phthalide are discussed.