Structural highlights
Function
[PSOF_ASPFU] Dual-functional monooxygenase/methyltransferase; part of the gene cluster that mediates the biosynthesis of pseurotin A, a competitive inhibitor of chitin synthase and an inducer of nerve-cell proliferation (PubMed:24082142, PubMed:24939566). The PKS-NRPS hybrid synthetase psoA is responsible for the biosynthesis of azaspirene, one of the first intermediates having the 1-oxa-7-azaspiro[4,4]-non-2-ene-4,6-dione core of pseurotin, via condensation of one acetyl-CoA, 4 malonyl-CoA, and a L-phenylalanine molecule (PubMed:24082142, PubMed:24939566). The dual-functional monooxygenase/methyltransferase psoF seems to be involved in the addition of the C3 methyl group onto the pseurotin scaffold (PubMed:24939566). Azaspirene is then converted to synerazol through 4 steps including oxidation of C17 by the cytochrome P450 monooxygenase psoD, O-methylation of the hydroxy group of C8 by the methyltransferase psoC, and the trans-to-cis isomerization of the C13 olefin by the glutathione S-transferase psoE (PubMed:24939566). The fourth step of synerazol production is performed by the dual-functional monooxygenase/methyltransferase psoF which seems to catalyze the epoxidation of the intermediate deepoxy-synerazol (PubMed:24939566). Synerazol can be attacked by a water molecule nonenzymatically at two different positions to yield two diol products, pseurotin A and pseurotin D (PubMed:24939566).[1] [2]
Publication Abstract from PubMed
Biosynthesis of certain fungal polyketide-peptide synthetases involves C-methyltransferase activity that adds one or more S-adenosyl-l-methionine-derived methyl groups to the carbon framework. The previously reported PsoF-MT, the stand-alone C-methyltransferase (MT) from the pseurotin biosynthetic pathway that exists as a domain within a trifunctional didomain enzyme PsoF, was characterized crystallographically and kinetically using mutants with substrate analogs to understand how a trans-acting C-MT works and compare it to known polyketide synthase-associated C-MTs. This study identified key active-site residues involved in catalysis and substrate recognition, which led us to propose the mechanism of C-methylation and substrate specificity determinants in PsoF-MT.
Functional and Structural Analyses of trans C-Methyltransferase in Fungal Polyketide Biosynthesis.,Kishimoto S, Tsunematsu Y, Matsushita T, Hara K, Hashimoto H, Tang Y, Watanabe K Biochemistry. 2019 Sep 24;58(38):3933-3937. doi: 10.1021/acs.biochem.9b00702., Epub 2019 Sep 11. PMID:31486637[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wiemann P, Guo CJ, Palmer JM, Sekonyela R, Wang CC, Keller NP. Prototype of an intertwined secondary-metabolite supercluster. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17065-70. doi:, 10.1073/pnas.1313258110. Epub 2013 Sep 30. PMID:24082142 doi:http://dx.doi.org/10.1073/pnas.1313258110
- ↑ Tsunematsu Y, Fukutomi M, Saruwatari T, Noguchi H, Hotta K, Tang Y, Watanabe K. Elucidation of pseurotin biosynthetic pathway points to trans-acting C-methyltransferase: generation of chemical diversity. Angew Chem Int Ed Engl. 2014 Aug 4;53(32):8475-9. doi: 10.1002/anie.201404804., Epub 2014 Jun 18. PMID:24939566 doi:http://dx.doi.org/10.1002/anie.201404804
- ↑ Kishimoto S, Tsunematsu Y, Matsushita T, Hara K, Hashimoto H, Tang Y, Watanabe K. Functional and Structural Analyses of trans C-Methyltransferase in Fungal Polyketide Biosynthesis. Biochemistry. 2019 Sep 24;58(38):3933-3937. doi: 10.1021/acs.biochem.9b00702., Epub 2019 Sep 11. PMID:31486637 doi:http://dx.doi.org/10.1021/acs.biochem.9b00702
