Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis
For more than 100 years, the small molecule Itaconic acid was known as a metabolite of fungi. Due to it highly reactive double bonds and the biotechnological production of large amounts, it has played an important role in the synthesis of industrial polymers. Surprisingly, it was recently discovered as an important anti-inflammatory metabolite in the human immune system. A major obstacle to studies on itaconic acid function in human immunity was the fact that the structure of the enzyme responsible for its synthesis (cis-aconitate decarboxylase, ACOD1 [human], CAD [non-human]; also known as Irg1) was not known. In a collaboration with the Dept. Structure and Function of Proteins of the Helmholtz Centre for Infection Research we have elucidated its crystal structure, identified the active center, and found naturally occurring variants in the ACOD1 gene that increase or abolish itaconic acid synthesis. The latter are extremely rare, suggesting that itaconic acid has played an important role in human evolution.
These results will now make it possible to assess the impact of naturally occurring ACOD1 variants on the risk of infectious and inflammatory diseases in humans, and to design substances that modulate itaconic acid synthesis in the immune system for therapeutic purposes.