7oc5

Structural highlights

Function

ASR6_SARSH Alpha-humulene synthase; part of the gene cluster that mediates the biosynthesis of xenovulene A, an unusual meroterpenoid that has potent inhibitory effects on the human gamma-aminobutyrate A (GABAA) benzodiazepine receptor (PubMed:29773797). The first step of xenovulene A biosynthesis is the biosynthesis of 3-methylorcinaldehyde performed by the non-reducing polyketide synthase aspks1 (PubMed:17912413, PubMed:29773797, PubMed:20552126). The salicylate hydroxylase asL1 then catalyzes the oxidative dearomatization of 3-methylorcinaldehyde to yield a dearomatized hydroxycyclohexadione (PubMed:29773797). The 2-oxoglutarate-dependent dioxygenase asL3 further catalyzes the oxidative ring expansion to provide the first tropolone metabolite (PubMed:29773797). The cytochrome P450 monooxygenase asR2 allows the synthesis of tropolone hemiacetal (PubMed:29773797). In parallel, a previously unrecognised class of terpene cyclase, asR6, produces alpha-humulene from farnesylpyrophosphate (FPP) (PubMed:29773797). The putative Diels-Alderase asR5 probably catalyzes the formation of the tropolone-humulene skeleton by linking humulene and the polyketide moiety (PubMed:29773797). Oxidative-ring contractions catalyzed by asL4 and asL6 then processively remove carbon atoms from the polyketide to yield xenovulene A (PubMed:29773797).^{[1] [2] [3]}

References

1. ↑ Bailey AM, Cox RJ, Harley K, Lazarus CM, Simpson TJ, Skellam E. Characterisation of 3-methylorcinaldehyde synthase (MOS) in Acremonium strictum: first observation of a reductive release mechanism during polyketide biosynthesis. Chem Commun (Camb). 2007 Oct 21;(39):4053-5. doi: 10.1039/b708614h. Epub 2007 Jul, 25. PMID:17912413 doi:http://dx.doi.org/10.1039/b708614h
2. ↑ Fisch KM, Skellam E, Ivison D, Cox RJ, Bailey AM, Lazarus CM, Simpson TJ. Catalytic role of the C-terminal domains of a fungal non-reducing polyketide synthase. Chem Commun (Camb). 2010 Aug 7;46(29):5331-3. doi: 10.1039/c0cc01162b. Epub 2010 , Jun 16. PMID:20552126 doi:http://dx.doi.org/10.1039/c0cc01162b
3. ↑ Schor R, Schotte C, Wibberg D, Kalinowski J, Cox RJ. Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A. Nat Commun. 2018 May 17;9(1):1963. doi: 10.1038/s41467-018-04364-9. PMID:29773797 doi:http://dx.doi.org/10.1038/s41467-018-04364-9