دورية أكاديمية
Crystal structure of cis -aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.
| العنوان: | Crystal structure of cis -aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. |
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| المؤلفون: | Chen F; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.; Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.; Research Group Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany., Lukat P; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany., Iqbal AA; Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.; Research Group Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany., Saile K; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany., Kaever V; Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany., van den Heuvel J; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany., Blankenfeldt W; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.; Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany., Büssow K; Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; konrad.buessow@helmholtz-hzi.de frank.pessler@twincore.de., Pessler F; Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany; konrad.buessow@helmholtz-hzi.de frank.pessler@twincore.de.; Research Group Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.; Centre for Individualised Infection Medicine, 30625 Hannover, Germany. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Oct 08; Vol. 116 (41), pp. 20644-20654. Date of Electronic Publication: 2019 Sep 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Mutation*, Carboxy-Lyases/*chemistry , Carboxy-Lyases/*genetics , Succinates/*metabolism, A549 Cells ; Amino Acid Sequence ; Animals ; Carboxy-Lyases/metabolism ; Catalysis ; Catalytic Domain ; Crystallography, X-Ray ; Evolution, Molecular ; Humans ; Mice ; Models, Molecular ; Mutagenesis, Site-Directed ; Protein Conformation ; Sequence Homology |
| مستخلص: | cis -Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis -aconitate to itaconate and plays central roles in linking innate immunity with metabolism and in the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated the crystal structures of human and murine CADs and compared their enzymological properties to CAD from A. terreus Recombinant CAD is fully active in vitro without a cofactor. Murine CAD has the highest catalytic activity, whereas Aspergillus CAD is best adapted to a more acidic pH. CAD is not homologous to any known decarboxylase and appears to have evolved from prokaryotic enzymes that bind negatively charged substrates. CADs are homodimers, the active center is located in the interface between 2 distinct subdomains, and structural modeling revealed conservation in zebrafish and Aspergillus We identified 8 active-site residues critical for CAD function and rare naturally occurring human mutations in the active site that abolished CAD activity, as well as a variant (Asn152Ser) that increased CAD activity and is common (allele frequency 20%) in African ethnicity. These results open the way for 1) assessing the potential impact of human CAD variants on disease risk at the population level, 2) developing therapeutic interventions to modify CAD activity, and 3) improving CAD efficiency for biotechnological production of itaconic acid. Competing Interests: The authors declare no competing interests. (Copyright © 2019 the Author(s). Published by PNAS.) |
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| فهرسة مساهمة: | Keywords: cis-aconitate; decarboxylase; enzymology; itaconic acid; macrophage |
| سلسلة جزيئية: | PDB 6R6T; 6R6U |
| المشرفين على المادة: | 0 (Succinates) EC 4.1.1.- (Carboxy-Lyases) EC 4.1.1.6 (aconitate decarboxylase) Q4516562YH (itaconic acid) |
| تواريخ الأحداث: | Date Created: 20190925 Date Completed: 20200403 Latest Revision: 20200403 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC6789909 |
| DOI: | 10.1073/pnas.1908770116 |
| PMID: | 31548418 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1908770116 |