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dc.contributor.authorSong, Haigang
dc.contributor.authorFahrig-Kamarauskaite, Jurate
dc.contributor.authorMatabaro, Emmanuel
dc.contributor.authorKaspar, Hannelore
dc.contributor.authorShirran, Sally L.
dc.contributor.authorZach, Christina
dc.contributor.authorPace, Amy
dc.contributor.authorStefanov, Bozhidar-Adrian
dc.contributor.authorNaismith, James H.
dc.contributor.authorKunzler, Markus
dc.date.accessioned2020-08-06T14:30:03Z
dc.date.available2020-08-06T14:30:03Z
dc.date.issued2020-07-17
dc.identifier269484747
dc.identifierb317f870-2223-4d56-9be8-09445a6c2ebc
dc.identifier000551550000023
dc.identifier85087727746
dc.identifier.citationSong , H , Fahrig-Kamarauskaite , J , Matabaro , E , Kaspar , H , Shirran , S L , Zach , C , Pace , A , Stefanov , B-A , Naismith , J H & Kunzler , M 2020 , ' Substrate plasticity of a fungal peptide α-N-methyltransferase ' , ACS Chemical Biology , vol. 15 , no. 7 , pp. 1901-1912 . https://doi.org/10.1021/acschembio.0c00237en
dc.identifier.issn1554-8929
dc.identifier.otherORCID: /0000-0003-3516-3507/work/78527686
dc.identifier.urihttps://hdl.handle.net/10023/20417
dc.descriptionThis work was financially supported by the Commission for Technology and Innovation (CTI/Innosuisse Grant No. CTI 25951.2), the Swiss National Science Foundation (Grant No. 31003A_173097), Wellcome Trust (Grant No. 094476/Z/10/ Z), and BBSRC (Grant No. BB/R018189/1).en
dc.description.abstractThe 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 α-N-methyltransferase domain. OphMA forms a homodimer and its α-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 α-N-methyltransferase for biotechnological applications.
dc.format.extent12
dc.format.extent7590820
dc.language.isoeng
dc.relation.ispartofACS Chemical Biologyen
dc.subjectQH301 Biologyen
dc.subjectNDASen
dc.subject.lccQH301en
dc.titleSubstrate plasticity of a fungal peptide α-N-methyltransferaseen
dc.typeJournal articleen
dc.contributor.sponsorThe Wellcome Trusten
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.identifier.doi10.1021/acschembio.0c00237
dc.description.statusPeer revieweden
dc.identifier.grantnumber094476/Z/10/Zen


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