| Structural highlights
Function
[ROQN_PENRW] Glandicoline B O-methyltransferase; part of the gene cluster that mediates the biosynthesis of the mycotoxin meleagrin (PubMed:22118684, PubMed:23776469). The first stage is catalyzed by the dipeptide synthase roqA which condenses histidine and tryptophan to produce histidyltryptophanyldiketopiperazine (HTD) (PubMed:22118684, PubMed:23776469). HTD is then converted to roquefortine C through two possible pathways (PubMed:23776469). In the first pathway, prenyltransferase roqD transforms HTD to the intermediate roquefortine D, which is in turn converted to roquefortine C by the cytochrome P450 monooxygenase roqR (PubMed:23776469). In the second pathway, HTD is first converted to the intermediate dehydrohistidyltryptophanyldi-ketopiperazine (DHTD) by roqR which is then prenylated by roqD to form roquefortine C (PubMed:23776469). Roquefortine C can be further transformed to meleagrin via three more reactions including oxydation to glandicolin A by roqM, which is further reduced to glandicoline B by roqO (PubMed:23776469). Finally, glandicoline B is converted to meleagrin by the glandicoline B O-methyltransferase roqN (PubMed:22118684, PubMed:23776469). More studies identified further branching and additional metabolites produced by the roquefortine/meleagrin cluster, including roquefortine F, roquefortine L, roquefortine M, roquefortine N and neoxaline (PubMed:24225953).[1] [2] [3]
Publication Abstract from PubMed
Antimicrobial and anti-proliferative meleagrin and oxaline are roquefortine C-derived alkaloids produced by fungi of the genus Penicillium. Tandem O-methylations complete the biosynthesis of oxaline from glandicoline B through meleagrin. Currently, little is known about the role of these methylation patterns in the bioactivity profile of meleagrin and oxaline. To establish the structural and mechanistic basis of methylation in these pathways, crystal structures were determined for two late-stage methyltransferases in the oxaline and meleagrin gene clusters from Penicillium oxalicum and Penicillium chrysogenum. The homologous enzymes OxaG and RoqN were shown to catalyze penultimate hydroxylamine O-methylation to generate meleagrin in vitro. Crystal structures of these enzymes in the presence of methyl donor S-adenosylmethionine revealed an open active site, which lacks an apparent base indicating that catalysis is driven by proximity effects. OxaC was shown to methylate meleagrin to form oxaline in vitro, the terminal pathway product. Crystal structures of OxaC in a pseudo-Michaelis complex containing sinefungin and meleagrin, and in a product complex containing S-adenosyl-homocysteine and oxaline, reveal key active site residues with His313 serving as a base that is activated by Glu369. These data provide structural insights into the enzymatic methylation of these alkaloids that include a rare hydroxylamine oxygen acceptor, and can be used to guide future efforts towards selective derivatization and structural diversification and establishing the role of methylation in bioactivity.
Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway.,Newmister SA, Romminger S, Schmidt JJ, Williams RM, Smith JL, Berlinck RGS, Sherman DH Org Biomol Chem. 2018 Aug 24. doi: 10.1039/c8ob01565a. PMID:30141817[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Garcia-Estrada C, Ullan RV, Albillos SM, Fernandez-Bodega MA, Durek P, von Dohren H, Martin JF. A single cluster of coregulated genes encodes the biosynthesis of the mycotoxins roquefortine C and meleagrin in Penicillium chrysogenum. Chem Biol. 2011 Nov 23;18(11):1499-512. doi: 10.1016/j.chembiol.2011.08.012. PMID:22118684 doi:http://dx.doi.org/10.1016/j.chembiol.2011.08.012
- ↑ Ali H, Ries MI, Nijland JG, Lankhorst PP, Hankemeier T, Bovenberg RA, Vreeken RJ, Driessen AJ. A branched biosynthetic pathway is involved in production of roquefortine and related compounds in Penicillium chrysogenum. PLoS One. 2013 Jun 12;8(6):e65328. doi: 10.1371/journal.pone.0065328. Print 2013. PMID:23776469 doi:http://dx.doi.org/10.1371/journal.pone.0065328
- ↑ Ries MI, Ali H, Lankhorst PP, Hankemeier T, Bovenberg RA, Driessen AJ, Vreeken RJ. Novel key metabolites reveal further branching of the roquefortine/meleagrin biosynthetic pathway. J Biol Chem. 2013 Dec 27;288(52):37289-95. doi: 10.1074/jbc.M113.512665. Epub, 2013 Nov 13. PMID:24225953 doi:http://dx.doi.org/10.1074/jbc.M113.512665
- ↑ Newmister SA, Romminger S, Schmidt JJ, Williams RM, Smith JL, Berlinck RGS, Sherman DH. Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway. Org Biomol Chem. 2018 Aug 24. doi: 10.1039/c8ob01565a. PMID:30141817 doi:http://dx.doi.org/10.1039/c8ob01565a
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