Opposed effects of enzymatic gliotoxin N- and S-methylations.
Identifieur interne : 001498 ( Main/Exploration ); précédent : 001497; suivant : 001499Opposed effects of enzymatic gliotoxin N- and S-methylations.
Auteurs : Daniel H. Scharf [Allemagne] ; Andreas Habel ; Thorsten Heinekamp ; Axel A. Brakhage ; Christian HertweckSource :
- Journal of the American Chemical Society [ 1520-5126 ] ; 2014.
Descripteurs français
- KwdFr :
- Aspergillus fumigatus (composition chimique), Aspergillus fumigatus (enzymologie), Aspergillus fumigatus (génétique), Aspergillus fumigatus (pathogénicité), Facteurs de virulence (biosynthèse), Facteurs de virulence (composition chimique), Facteurs de virulence (métabolisme), Facteurs de virulence (toxicité), Gliotoxine (biosynthèse), Gliotoxine (composition chimique), Gliotoxine (métabolisme), Gliotoxine (toxicité), Methyltransferases (métabolisme), Méthylation (MeSH).
- MESH :
- biosynthèse : Facteurs de virulence, Gliotoxine.
- composition chimique : Aspergillus fumigatus, Facteurs de virulence, Gliotoxine.
- enzymologie : Aspergillus fumigatus.
- génétique : Aspergillus fumigatus.
- métabolisme : Facteurs de virulence, Gliotoxine, Methyltransferases.
- pathogénicité : Aspergillus fumigatus.
- toxicité : Facteurs de virulence, Gliotoxine.
- Méthylation.
English descriptors
- KwdEn :
- Aspergillus fumigatus (chemistry), Aspergillus fumigatus (enzymology), Aspergillus fumigatus (genetics), Aspergillus fumigatus (pathogenicity), Gliotoxin (biosynthesis), Gliotoxin (chemistry), Gliotoxin (metabolism), Gliotoxin (toxicity), Methylation (MeSH), Methyltransferases (metabolism), Virulence Factors (biosynthesis), Virulence Factors (chemistry), Virulence Factors (metabolism), Virulence Factors (toxicity).
- MESH :
- chemical , biosynthesis : Gliotoxin, Virulence Factors.
- chemistry : Aspergillus fumigatus, Gliotoxin, Virulence Factors.
- enzymology : Aspergillus fumigatus.
- genetics : Aspergillus fumigatus.
- chemical , metabolism : Gliotoxin, Methyltransferases, Virulence Factors.
- pathogenicity : Aspergillus fumigatus.
- chemical , toxicity : Gliotoxin, Virulence Factors.
- Methylation.
Abstract
Gliotoxin (1), a virulence factor of the human pathogenic fungus Aspergillus fumigatus, is the prototype of epipoly(thiodioxopiperazine) (ETP) toxins. Here we report the discovery and functional analysis of two methyl transferases (MTs) that play crucial roles for ETP toxicity. Genome comparisons, knockouts, and in vitro enzyme studies identified a new S-adenosyl-l-methionine-dependent S-MT (TmtA) that is, surprisingly, encoded outside the gli gene cluster. We found that TmtA irreversibly inactivates ETP by S-alkylation and that this detoxification strategy appears to be not only limited to ETP producers. Furthermore, we unveiled that GliN functions as a freestanding amide N-MT. GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides. In addition, enzymatic N-alkylation constitutes the last step in gliotoxin biosynthesis and is a prerequisite for the cytotoxicity of the molecule. Thus, these specialized alkylating enzymes have dramatic and fully opposed effects: complete activation or inactivation of the toxin.
DOI: 10.1021/ja5033106
PubMed: 25062268
Affiliations:
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Brakhage</name></author><author><name sortKey="Hertweck, Christian" sort="Hertweck, Christian" uniqKey="Hertweck C" first="Christian" last="Hertweck">Christian Hertweck</name></author></analytic><series><title level="j">Journal of the American Chemical Society</title><idno type="eISSN">1520-5126</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aspergillus fumigatus (chemistry)</term><term>Aspergillus fumigatus (enzymology)</term><term>Aspergillus fumigatus (genetics)</term><term>Aspergillus fumigatus (pathogenicity)</term><term>Gliotoxin (biosynthesis)</term><term>Gliotoxin (chemistry)</term><term>Gliotoxin (metabolism)</term><term>Gliotoxin (toxicity)</term><term>Methylation (MeSH)</term><term>Methyltransferases (metabolism)</term><term>Virulence Factors (biosynthesis)</term><term>Virulence Factors (chemistry)</term><term>Virulence Factors (metabolism)</term><term>Virulence Factors (toxicity)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Aspergillus fumigatus (composition chimique)</term><term>Aspergillus fumigatus (enzymologie)</term><term>Aspergillus fumigatus (génétique)</term><term>Aspergillus fumigatus (pathogénicité)</term><term>Facteurs de virulence (biosynthèse)</term><term>Facteurs de virulence (composition chimique)</term><term>Facteurs de virulence (métabolisme)</term><term>Facteurs de virulence (toxicité)</term><term>Gliotoxine (biosynthèse)</term><term>Gliotoxine (composition chimique)</term><term>Gliotoxine (métabolisme)</term><term>Gliotoxine (toxicité)</term><term>Methyltransferases (métabolisme)</term><term>Méthylation (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Gliotoxin</term><term>Virulence Factors</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Facteurs de virulence</term><term>Gliotoxine</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Aspergillus fumigatus</term><term>Gliotoxin</term><term>Virulence Factors</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Aspergillus fumigatus</term><term>Facteurs de virulence</term><term>Gliotoxine</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Gliotoxin</term><term>Methyltransferases</term><term>Virulence Factors</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteurs de virulence</term><term>Gliotoxine</term><term>Methyltransferases</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Aspergillus fumigatus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Gliotoxin</term><term>Virulence Factors</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Facteurs de virulence</term><term>Gliotoxine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Methylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Méthylation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Gliotoxin (1), a virulence factor of the human pathogenic fungus Aspergillus fumigatus, is the prototype of epipoly(thiodioxopiperazine) (ETP) toxins. Here we report the discovery and functional analysis of two methyl transferases (MTs) that play crucial roles for ETP toxicity. Genome comparisons, knockouts, and in vitro enzyme studies identified a new S-adenosyl-l-methionine-dependent S-MT (TmtA) that is, surprisingly, encoded outside the gli gene cluster. We found that TmtA irreversibly inactivates ETP by S-alkylation and that this detoxification strategy appears to be not only limited to ETP producers. Furthermore, we unveiled that GliN functions as a freestanding amide N-MT. GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides. In addition, enzymatic N-alkylation constitutes the last step in gliotoxin biosynthesis and is a prerequisite for the cytotoxicity of the molecule. Thus, these specialized alkylating enzymes have dramatic and fully opposed effects: complete activation or inactivation of the toxin. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25062268</PMID><DateCompleted><Year>2015</Year><Month>10</Month><Day>26</Day></DateCompleted><DateRevised><Year>2014</Year><Month>08</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-5126</ISSN><JournalIssue CitedMedium="Internet"><Volume>136</Volume><Issue>33</Issue><PubDate><Year>2014</Year><Month>Aug</Month><Day>20</Day></PubDate></JournalIssue><Title>Journal of the American Chemical Society</Title><ISOAbbreviation>J Am Chem Soc</ISOAbbreviation></Journal><ArticleTitle>Opposed effects of enzymatic gliotoxin N- and S-methylations.</ArticleTitle><Pagination><MedlinePgn>11674-9</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/ja5033106</ELocationID><Abstract><AbstractText>Gliotoxin (1), a virulence factor of the human pathogenic fungus Aspergillus fumigatus, is the prototype of epipoly(thiodioxopiperazine) (ETP) toxins. Here we report the discovery and functional analysis of two methyl transferases (MTs) that play crucial roles for ETP toxicity. Genome comparisons, knockouts, and in vitro enzyme studies identified a new S-adenosyl-l-methionine-dependent S-MT (TmtA) that is, surprisingly, encoded outside the gli gene cluster. We found that TmtA irreversibly inactivates ETP by S-alkylation and that this detoxification strategy appears to be not only limited to ETP producers. Furthermore, we unveiled that GliN functions as a freestanding amide N-MT. GliN-mediated amide methylation confers stability to ETP, damping the spontaneous formation of tri- and tetrasulfides. In addition, enzymatic N-alkylation constitutes the last step in gliotoxin biosynthesis and is a prerequisite for the cytotoxicity of the molecule. Thus, these specialized alkylating enzymes have dramatic and fully opposed effects: complete activation or inactivation of the toxin. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Scharf</LastName><ForeName>Daniel H</ForeName><Initials>DH</Initials><AffiliationInfo><Affiliation>Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute , Beutenbergstrasse 11a, 07745 Jena, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Habel</LastName><ForeName>Andreas</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Heinekamp</LastName><ForeName>Thorsten</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Brakhage</LastName><ForeName>Axel A</ForeName><Initials>AA</Initials></Author><Author ValidYN="Y"><LastName>Hertweck</LastName><ForeName>Christian</ForeName><Initials>C</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>08</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Am Chem Soc</MedlineTA><NlmUniqueID>7503056</NlmUniqueID><ISSNLinking>0002-7863</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D037521">Virulence Factors</NameOfSubstance></Chemical><Chemical><RegistryNumber>67-99-2</RegistryNumber><NameOfSubstance UI="D005912">Gliotoxin</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber><NameOfSubstance UI="D008780">Methyltransferases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001232" MajorTopicYN="N">Aspergillus fumigatus</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005912" MajorTopicYN="N">Gliotoxin</DescriptorName><QualifierName UI="Q000096" MajorTopicYN="Y">biosynthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008745" MajorTopicYN="N">Methylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008780" MajorTopicYN="N">Methyltransferases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D037521" MajorTopicYN="N">Virulence Factors</DescriptorName><QualifierName UI="Q000096" MajorTopicYN="N">biosynthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>7</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>7</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>10</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25062268</ArticleId><ArticleId IdType="doi">10.1021/ja5033106</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li></country></list><tree><noCountry><name sortKey="Brakhage, Axel A" sort="Brakhage, Axel A" uniqKey="Brakhage A" first="Axel A" last="Brakhage">Axel A. Brakhage</name><name sortKey="Habel, Andreas" sort="Habel, Andreas" uniqKey="Habel A" first="Andreas" last="Habel">Andreas Habel</name><name sortKey="Heinekamp, Thorsten" sort="Heinekamp, Thorsten" uniqKey="Heinekamp T" first="Thorsten" last="Heinekamp">Thorsten Heinekamp</name><name sortKey="Hertweck, Christian" sort="Hertweck, Christian" uniqKey="Hertweck C" first="Christian" last="Hertweck">Christian Hertweck</name></noCountry><country name="Allemagne"><noRegion><name sortKey="Scharf, Daniel H" sort="Scharf, Daniel H" uniqKey="Scharf D" first="Daniel H" last="Scharf">Daniel H. Scharf</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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