“…The products of both lepA (PKS-NRPS) and lepG (enoyl reductase) are responsible for fusion of phenylalanine with a hexaketide and subsequent release of the stable tetramic acid precursor, pre-leporin C. The putative cytochrome P450, LepH, an enzyme demonstrating significant homology to the ring expansion cytochrome P450s found in the 2-pyridones, tenellin and bassianin, was shown to be required for the ring expansion step. LepF, a putative short chain dehydrogenase/ reductase, was hypothesized to reduce the acyl carbonyl to an alcohol 143) . Interestingly, although lepI was predicted to encode a putative methyltransferase, elegant in vitro studies by Tang and coworkers 143) showed that LepI catalyzed an Sadenosyl-L-methionine (SAM)-dependent inverse electron demand hetero-Diels-Alder (HDA) reaction forming leporin C. In addition to the HDA reaction, LepI was shown to possess retro-Claisen activity, which allows the enzyme to convert a byproduct of the Diels-Alder reactions to leporin C. Leporin C is then further oxidized by the N-hydroxylase, LepD, to form leporin B.…”