Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae

CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde. In humans, TMA is produced exclusively by the intestinal microbiota, and its metabolite, trimethylamine oxide, has been associated with a hig...

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Veröffentlicht in:The Journal of biological chemistry Jg. 290; H. 35; S. 21732 - 21740
Hauptverfasser: Kalnins, Gints, Kuka, Janis, Grinberga, Solveiga, Makrecka-Kuka, Marina, Liepinsh, Edgars, Dambrova, Maija, Tars, Kaspars
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 28.08.2015
Schlagworte:
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Catalytic Domain
Choline - metabolism
Chromatography, Gel
Chymotrypsin - metabolism
Electrophoresis, Polyacrylamide Gel
Humans
Klebsiella pneumoniae - enzymology
Lyases - chemistry
Lyases - metabolism
Microbiota
Models, Molecular
Protein Multimerization
Protein Structure, Tertiary
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
choline
enzyme catalysis
radical
conformational change
enzyme structure
ISSN:1083-351X
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Abstract CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde. In humans, TMA is produced exclusively by the intestinal microbiota, and its metabolite, trimethylamine oxide, has been associated with a higher risk of cardiovascular diseases. Therefore, information about the three-dimensional structures of TMA-producing enzymes is important for microbiota-targeted drug discovery. We have cloned, expressed, and purified the CutC GRE and the activating enzyme CutD from Klebsiella pneumoniae, a representative of the human microbiota. We have determined the first crystal structures of both the choline-bound and choline-free forms of CutC and have discovered that binding of choline at the ligand-binding site triggers conformational changes in the enzyme structure, a feature that has not been observed for any other characterized GRE.
AbstractList CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde. In humans, TMA is produced exclusively by the intestinal microbiota, and its metabolite, trimethylamine oxide, has been associated with a higher risk of cardiovascular diseases. Therefore, information about the three-dimensional structures of TMA-producing enzymes is important for microbiota-targeted drug discovery. We have cloned, expressed, and purified the CutC GRE and the activating enzyme CutD from Klebsiella pneumoniae, a representative of the human microbiota. We have determined the first crystal structures of both the choline-bound and choline-free forms of CutC and have discovered that binding of choline at the ligand-binding site triggers conformational changes in the enzyme structure, a feature that has not been observed for any other characterized GRE.
Author Tars, Kaspars
Makrecka-Kuka, Marina
Kuka, Janis
Grinberga, Solveiga
Liepinsh, Edgars
Kalnins, Gints
Dambrova, Maija
Author_xml – sequence: 1
  givenname: Gints
  surname: Kalnins
  fullname: Kalnins, Gints
  email: gints@biomed.lu.lv
  organization: From the Latvian Biomedical Research and Study Center, LV-1067 Riga, gints@biomed.lu.lv
– sequence: 2
  givenname: Janis
  surname: Kuka
  fullname: Kuka, Janis
  organization: the Latvian Institute of Organic Synthesis, LV-1006 Riga, and
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  givenname: Solveiga
  surname: Grinberga
  fullname: Grinberga, Solveiga
  organization: the Latvian Institute of Organic Synthesis, LV-1006 Riga, and
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  givenname: Marina
  surname: Makrecka-Kuka
  fullname: Makrecka-Kuka, Marina
  organization: the Latvian Institute of Organic Synthesis, LV-1006 Riga, and
– sequence: 5
  givenname: Edgars
  surname: Liepinsh
  fullname: Liepinsh, Edgars
  organization: the Latvian Institute of Organic Synthesis, LV-1006 Riga, and
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  givenname: Maija
  surname: Dambrova
  fullname: Dambrova, Maija
  organization: the Latvian Institute of Organic Synthesis, LV-1006 Riga, and
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  givenname: Kaspars
  surname: Tars
  fullname: Tars, Kaspars
  organization: From the Latvian Biomedical Research and Study Center, LV-1067 Riga, the University of Latvia, LV-1586 Riga, Latvia
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Issue 35
Keywords choline
enzyme catalysis
radical
conformational change
enzyme structure
Language English
License 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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Snippet CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde....
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SubjectTerms Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Catalytic Domain
Choline - metabolism
Chromatography, Gel
Chymotrypsin - metabolism
Electrophoresis, Polyacrylamide Gel
Humans
Klebsiella pneumoniae - enzymology
Lyases - chemistry
Lyases - metabolism
Microbiota
Models, Molecular
Protein Multimerization
Protein Structure, Tertiary
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Title Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae
URI https://www.ncbi.nlm.nih.gov/pubmed/26187464
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