| Structural highlights
Function
OPHMA_OMPOL Fusion protein of the methyltransferase ophM and the omphalotin core peptide; part of the gene cluster that mediates the biosynthesis of omphalotin A, a highly methylated cyclic dodecapeptide with nematodicidal activity (PubMed:28715095, PubMed:30151425, PubMed:32491837, PubMed:33574430). Omphalotin A derives from the C-terminus of the ophMA protein, and it is the ophMA protein that methylates its own C-terminus using S-adenosyl methionine (SAM) (PubMed:28715095, PubMed:30151425, PubMed:32491837, PubMed:33574430). The C-terminus is subsequently cleaved off and macrocyclized by the prolyloligopeptidase ophP to give the final product (PubMed:28715095, PubMed:30151425, PubMed:32491837).[1] [2] [3] [4]
Publication Abstract from PubMed
The methylation of amide nitrogen atoms can improve the stability, oral availability, and cell permeability of peptide therapeutics. Chemical N-methylation of peptides is challenging. Omphalotin A is a ribosomally synthesized, macrocylic dodecapeptide with nine backbone N-methylations. The fungal natural product is derived from the precursor protein, OphMA, harboring both the core peptide and a SAM-dependent peptide alpha-N-methyltransferase domain. OphMA forms a homodimer and its alpha-N-methyltransferase domain installs the methyl groups in trans on the hydrophobic core dodecapeptide and some additional C-terminal residues of the protomers. These post-translational backbone N-methylations occur in a processive manner from the N- to the C-terminus of the peptide substrate. We demonstrate that OphMA can methylate polar, aromatic, and charged residues when these are introduced into the core peptide. Some of these amino acids alter the efficiency and pattern of methylation. Proline, depending on its sequence context, can act as a tunable stop signal. Crystal structures of OphMA variants have allowed rationalization of these observations. Our results hint at the potential to control this fungal alpha-N-methyltransferase for biotechnological applications.
Substrate Plasticity of a Fungal Peptide alpha-N-Methyltransferase.,Song H, Fahrig-Kamarauskaite JR, Matabaro E, Kaspar H, Shirran SL, Zach C, Pace A, Stefanov BA, Naismith JH, Kunzler M ACS Chem Biol. 2020 Jun 19. doi: 10.1021/acschembio.0c00237. PMID:32491837[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ramm S, Krawczyk B, Mühlenweg A, Poch A, Mösker E, Süssmuth RD. A Self-Sacrificing N-Methyltransferase Is the Precursor of the Fungal Natural Product Omphalotin. Angew Chem Int Ed Engl. 2017 Aug 7;56(33):9994-9997. PMID:28715095 doi:10.1002/anie.201703488
- ↑ Song H, van der Velden NS, Shiran SL, Bleiziffer P, Zach C, Sieber R, Imani AS, Krausbeck F, Aebi M, Freeman MF, Riniker S, Kunzler M, Naismith JH. A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds. Sci Adv. 2018 Aug 24;4(8):eaat2720. doi: 10.1126/sciadv.aat2720. eCollection 2018, Aug. PMID:30151425 doi:http://dx.doi.org/10.1126/sciadv.aat2720
- ↑ Song H, Fahrig-Kamarauskaite JR, Matabaro E, Kaspar H, Shirran SL, Zach C, Pace A, Stefanov BA, Naismith JH, Kunzler M. Substrate Plasticity of a Fungal Peptide alpha-N-Methyltransferase. ACS Chem Biol. 2020 Jun 19. doi: 10.1021/acschembio.0c00237. PMID:32491837 doi:http://dx.doi.org/10.1021/acschembio.0c00237
- ↑ Matabaro E, Kaspar H, Dahlin P, Bader DLV, Murar CE, Staubli F, Field CM, Bode JW, Künzler M. Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A. Sci Rep. 2021 Feb 11;11(1):3541. PMID:33574430 doi:10.1038/s41598-021-83106-2
- ↑ Song H, Fahrig-Kamarauskaite JR, Matabaro E, Kaspar H, Shirran SL, Zach C, Pace A, Stefanov BA, Naismith JH, Kunzler M. Substrate Plasticity of a Fungal Peptide alpha-N-Methyltransferase. ACS Chem Biol. 2020 Jun 19. doi: 10.1021/acschembio.0c00237. PMID:32491837 doi:http://dx.doi.org/10.1021/acschembio.0c00237
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