Bifunctional premutilin synthase; part of the gene cluster that mediates the biosynthesis of pleuromutilin, a tricyclic diterpene showing antibacterial properties (PubMed:27143514, PubMed:29388775). The geranylgeranyl diphosphate (GGPP) synthase catalyzes the first step in pleuromutilin biosynthesis (PubMed:27143514, PubMed:29388775). GGPP is then substrate of the premutilin synthase (PS) to yield premutilin (PubMed:29388775). Premutilin synthase is a bifunctional enzyme composed of the fusion of a class II diterpene cyclase (DTC) and a class I diterpene synthase (DTS), with the corresponding domains and active sites containing characteristic aspartate-rich motifs. GGPP is first converted to mutildienyl-diphosphate (MPP) at the class II DTC site (PubMed:29388775). MPP is subsequently further cyclized at the class I DTS site, followed by a 1,5-hydride shift and addition of water prior to terminating deprotonation, to yield premutilin (PubMed:29388775). In addition to the aforementioned GGPP synthase and bifunctional diterpene synthase, the cluster contains also three cytochrome P450 monooxygenases, a short-chain alcohol dehydrogenase, and an acyltransferase, involved in the conversion of premutilin to pleuromutilin (PubMed:27143514, PubMed:29388775). The cytochrome P450 monooxygenases P450-1 and P450-2 hydroxylate premutilin at C-11 and C-3, respectively, producing 11-hydroxypremutilin and 3-hydroxypremutilin (By similarity). The combination of the actions of both ple5 and ple6 leads to the production of 3,11-dihydroxypremutilin (By similarity). The short chain dehydrogenase SDR further converts 3,11-dihydroxypremutilin into mutilin (By similarity). The acetyltransferase ATF then acetylates mutilin to produce 14-O-acetylmutilin (By similarity). Finally, the cytochrome P450 monooxygenase P450-3 catalyzes hydroxylation on the alpha position of the acetyl side chain of 14-O-acetylmutilin to yield pleuromutilin (By similarity). Binds 3 Mg(2+) ions per subunit. Secondary metabolite biosynthesis; terpenoid biosynthesis. Expression is up-regulated during pleuromutilin production. the class II DTC active site contains a DXDD motif from which the middle Asp acts as the catalytic acid in this protonation-initiated cyclization reaction, while the class I DTS active site contains a DDXXD motif that binds divalent magnesium cofactors required for the catalyzed allylic diphosphate ester ionization-initiated reaction, with the first Asp playing a particularly key role. Belongs to the terpene synthase family.