Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 41, Pages 20644-20654Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908770116
Keywords
macrophage; enzymology; itaconic acid; cis-aconitate; decarboxylase
Categories
Funding
- Helmholtz Association's Initiative on Individualised Medicine (iMed)
- Helmholtz Association's Future Topic Aging and Metabolic Programming (AMPro)
- Helmholtz Centre for Infection Research
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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.
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