ArticleScientific reports2023
Amino acid positions near the active site determine the reduced activity of human ACOD1 compared to murine ACOD1.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.Nature reviews. Immunology · 2026Review
- Offense and defense: itaconate mediates bidirectional immune regulation of host-bacteria interaction.Journal of biomedical science · 2026Review
- Human pneumovirus induces IFN-dependent expression of the immune-responsive gene 1 and is inhibited by 4-octyl itaconate in human macrophages.NAR molecular medicine · 2026Article
- Itaconate modifications: Mechanisms and applications.Journal of intensive medicine · 2026Review
- Dissecting antimicrobial logic: species-specific strategies for intracellular pathogen defense.mSphere · 2025Review
- Effect of pH and buffer on substrate binding and catalysis by cis-aconitate decarboxylase.Scientific reports · 2025Article
- Metabolic Messengers: itaconate.Nature metabolism · 2024Review
- ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.Cell death & disease · 2024Article
- Divergent effects of itaconate isomers onFrontiers in immunology · 2024Article
- Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.Cellular and molecular life sciences : CMLS · 2023Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
cis-Aconitate decarboxylase (ACOD1, IRG1) converts cis-aconitate to the immunomodulatory and antibacterial metabolite itaconate. Although the active site residues of human and mouse ACOD1 are identical, the mouse enzyme is about fivefold more active. Aiming to identify the cause of this difference, we mutated positions near the active site in human ACOD1 to the corresponding residues of mouse ACOD1 and measured resulting activities in vitro and in transfected cells. Interestingly, Homo sapiens is the only species with methionine instead of isoleucine at residue 154 and introduction of isoleucine at this position increased the activity of human ACOD1 1.5-fold in transfected cells and 3.5-fold in vitro. Enzyme activity of gorilla ACOD1, which is almost identical to the human enzyme but has isoleucine at residue 154, was similar to the mouse enzyme in vitro. Met154 in human ACOD1 forms a sulfur-π bond to Phe381, which is positioned to impede access of the substrate to the active site. It appears that the ACOD1 sequence has changed at position 154 during human evolution, resulting in a pronounced decrease in activity. This change might have offered a selective advantage in diseases such as cancer.
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