8d7f

Structural highlights

Function

FLVF_ASPFN Terpene cyclase; part of the gene cluster that mediates the biosynthesis of flavunoidine, an alkaloidal terpenoid with a tetracyclic cage-like core connected to dimethylcadaverine via a C-N bond and acylated with 5,5-dimethyl-L-pipecolate (PubMed:31885262). The tetracyclic core is synthesized by the terpene cyclase flvE and the cytochrome P450 monooxygenase flvD (PubMed:31885262). The terpene cyclase flvE catalyzes the cyclization of farnesyl pyrophosphate (FPP) to form (1R,4R,5S)-(+)-acoradiene and the cytochrome P450 monooxygenase flvD is then responsible for oxidative conversion of (1R,4R,5S)-(+)-acoradiene into the tetracyclic cage present in the final product flavunoidine (PubMed:31885262). The cytochrome monooxygenase flvC then hydroxylates the C-10 position (PubMed:31885262). The second terpene cyclase flvF is required for attachment of the C-7 axial dimethylcadaverine which is itself produced by the N-methyltransferase flvH and the decarboxylase flvG via methylation of L-lysine to give N,N-dimethyl-L-Lysine, and decarboxylation to afford dimethylcadaverine, respectively (PubMed:31885262). The NRPS flvI acylates the terpenoid core at the hydroxylated C-10 with dimethylpipecolate to yield final flavunoidine (PubMed:31885262). The bifunctional enzyme flvA and the dehydrogenase flvB are responsible for the synthesis of the dimethylpipecolate precursor (PubMed:31885262). The PLP-dependent lyase domain of flvA might use L-O-acetyl-homoserine and alpha-keto-isovalerate to form an intermediary ketone that can cyclize intramolecularly to yield an imine (PubMed:31885262). The imine can be reduced by flvB to yield the 6-carboxylated pipecolate (PubMed:31885262). The C-terminal alpha-KG-dependent oxygenase domain of flvA is then proposed to catalyze the decarboxylation to yield dimethylpipecolate (PubMed:31885262).^[1]

References

1. ↑ Yee DA, Kakule TB, Cheng W, Chen M, Chong CTY, Hai Y, Hang LF, Hung YS, Liu N, Ohashi M, Okorafor IC, Song Y, Tang M, Zhang Z, Tang Y. Genome Mining of Alkaloidal Terpenoids from a Hybrid Terpene and Nonribosomal Peptide Biosynthetic Pathway. J Am Chem Soc. 2020 Jan 15;142(2):710-714. doi: 10.1021/jacs.9b13046. Epub 2020, Jan 3. PMID:31885262 doi:http://dx.doi.org/10.1021/jacs.9b13046