Isolated from the plant Selaginella moellendorffii as a mutifunctional enzyme that also catalyses EC 220.127.116.11, copalyl diphosphate synthase . In the plant Salvia miltiorrhiza the two enzymes are separate entities .
expression of copalyl diphosphate synthase and miltiradiene synthase in Saccharomyces cerevisiae, results in production of 4.2 mg/l miltiradiene. Miltiradiene production increases to 8.8 mg/l by improving supply of geranylgeranyl diphosphate by over-expression of a fusion gene of farnesyl diphosphate synthase ERG20 and endogenous geranylgeranyl diphosphate synthase BTS1 together with a heterologous geranylgeranyl diphosphate synthase from Sulfolobus acidocaldarius. Combinatorial overexpression of truncated 3-hydroxyl-3-methylglutaryl-CoA reductase with a mutated global regulatory factor upc2.1 and ERG20-BTS1-geranylgeranyl diphosphate synthase genes has synergetic effects on miltiradiene production, increasing titer to 61.8 mg/l. In fed-batch fermentation 488 mg/l miltiradiene can be produced