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dc.contributor.author
Song, Haigang
dc.contributor.author
Fahrig-Kamarauskaitè, Ju̅ratè
dc.contributor.author
Matabaro, Emmanuel
dc.contributor.author
Kaspar, Hannelore
dc.contributor.author
Shirran, Sally L.
dc.contributor.author
Zach, Christina
dc.contributor.author
Pace, Amy
dc.contributor.author
Stefanov, Bozhidar-Adrian
dc.contributor.author
Naismith, James H.
dc.contributor.author
Künzler, Markus
dc.date.accessioned
2020-11-20T07:58:49Z
dc.date.available
2020-07-28T02:57:24Z
dc.date.available
2020-08-31T10:38:26Z
dc.date.available
2020-11-20T07:58:49Z
dc.date.issued
2020-07-17
dc.identifier.issn
1554-8929
dc.identifier.issn
1554-8937
dc.identifier.other
10.1021/acschembio.0c00237
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/428703
dc.identifier.doi
10.3929/ethz-b-000428703
dc.description.abstract
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 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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
American Chemical Society
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Substrate Plasticity of a Fungal Peptide α-N-Methyltransferase
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2020-06-03
ethz.journal.title
ACS Chemical Biology
ethz.journal.volume
15
en_US
ethz.journal.issue
7
en_US
ethz.pages.start
1901
en_US
ethz.pages.end
1912
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Molecular dissection of the chemical defense system of multicellular fungi against predation
en_US
ethz.identifier.scopus
ethz.publication.place
Columbus, OH
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02520 - Institut für Mikrobiologie / Institute of Microbiology::08838 - Künzler, Markus (Tit.-Prof.)
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02520 - Institut für Mikrobiologie / Institute of Microbiology::08838 - Künzler, Markus (Tit.-Prof.)
ethz.grant.agreementno
173097
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
Projektförderung in Biologie und Medizin (Abteilung III)
ethz.date.deposited
2020-07-28T02:57:42Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2020-08-31T10:38:59Z
ethz.rosetta.lastUpdated
2021-02-15T20:51:29Z
ethz.rosetta.versionExported
true
ethz.COinS
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