6nki

Structure of PhqB Reductase Domain from Penicillium fellutanum

spinqualitylabelsall models 6nki, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nki is a 1 chain structure with sequence from Penicillium fellutanum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: NDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PHQB_PENFE Nonribisomal peptide synthase; part of the gene cluster that mediates the biosynthesis of paraherquamide, a fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The first steps in the biosynthesis of paraherquamide is the production of the beta-methyl-proline precursor from L-isoleucine (Probable). They require oxidation of a terminally hydroxylated L-isoleucine to the corresponding aldehyde by enzymes which have still to be identified (Probable). Spontaneous cyclization and dehydration would yield the 4-methyl pyrolline-5-carboxylic acid, which is then reduced by the pyrroline-5-carboxylate reductase phqD leading to the beta-methyl-proline precursor (Probable). The next step of paraherquamide biosynthesis involves coupling of beta-methyl-proline and L-tryptophan by the bimodular NRPS phqB, to produce a monooxopiperazine intermediate (Probable). The reductase (R) domain of phqB utilizes NADPH for hydride transfer to reduce the thioester bond of the T domain-tethered linear dipeptide to a hemithioaminal intermediate, which spontaneously cleaves the C-S bond to release the aldehyde product (PubMed:31548667). This compound undergoes spontaneous cyclization and dehydration to give a dienamine which is reverse prenylated at C-2 by the reverse prenyltransferase phqJ (Probable). The other prenyltransferase present in the cluster, phqI may be a redundant gene in the pathway (Probable). During biosynthetic assembly, the key step to produce the polycyclic core is catalyzed by the bifunctional reductase and intramolecular [4+2] Diels-Alderase, phqE, resulting in formation of the [2.2.2] diazaoctane intermediate preparaherquamide (PubMed:31548667). Following formation of preparaherquamide, an indole 2,3-epoxidation-initiated pinacol-like rearrangement is catalyzed by the phqK FAD-dependent monooxygenase (Probable). The prenyltransferase phqA, the cytochrome P450 monooxygenase phqL, and the FAD-linked oxidoreductase phqH (or the cytochrome P450 monooxygenase phqM), are proposed to be involved in the formation of the pyran ring (Probable). The FAD-dependent monooxygenase phqK is likely responsible for generation of the spiro-oxindole, and the N-methylation is likely mediated by the phqN methyltransferase leading to the isolable natural product paraherquamide F (Probable). However, the order of these biosynthetic steps has still to be determined (Probable). In late-stage paraherquamide biosynthesis, the third P450 monooxygenase, phqO, is probably responsible for the C-14 hydroxylation, transforming paraherquamide F to paraherquamide G, and paraherquamide E to the final product paraherquamide A (Probable). The expansion from the 6-membered ring pyran (in paraherquamides F and G) to the 7-membered dioxepin ring (in paraherquamides A and E) represents a poorly understood but intriguing process that probably involves the 2-oxoglutarate-dependent dioxygenase phqC (Probable). Finally, the remaining members of the paraherquamide cluster, including phqI as well as phqM (or phqH), do not have a clearly prescribed role and appear to be redundant (Probable).

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