Abstract
Itaconate, produced as an offshoot of the TCA cycle, is a multifunctional immunometabolite possessing antibacterial, antiviral, immune regulation, and tumor progression activities. The production of itaconate in biological systems is catalyzed by cis-aconitate decarboxylase (CAD, also known as immune responsive gene 1 (IRG1) in mammals). In this study, we solved the structure of IRG1 from Mus musculus (mouse IRG1). Structural comparison analysis revealed that IRG1 can exist in either an open or closed conformation and that this is controlled by the A1 loop located proximal to the active site. Our closed form structure was maintained by an unidentified molecule in the active site, which might mimic its substrate.Protein Data Bank accession codesCoordinate and structural factors were deposited with the Protein Data Bank under PDB ID: 7BR9.
Highlights
Itaconate, the decarboxylated product of cis-aconitate, is a small immunometabolite that can control innate immunity and possesses antibacterial and antiviral activity [1,2,3]
Itaconate produced by macrophages during Salmonella enterica and Mycobacterium tuberculosis infection kills these bacteria by directly interacting with bacterial isocitrate lyase (ICL), which is a key enzyme of the glyoxylate shunt [1, 8,9,10]
A decarboxylation activity test showed that mouse immune responsive gene 1 (IRG1) and human IRG1 exhibit activity in vitro
Summary
The decarboxylated product of cis-aconitate (an intermediate metabolite in the TCA cycle), is a small immunometabolite that can control innate immunity and possesses antibacterial and antiviral activity [1,2,3]. This small metabolic intermediate has become an increasingly prominent polymer in the industry and is used for generating various resins and bioactive compounds [4, 5]. Itaconate produced by macrophages during Salmonella enterica and Mycobacterium tuberculosis infection kills these bacteria by directly interacting with bacterial isocitrate lyase (ICL), which is a key enzyme of the glyoxylate shunt [1, 8,9,10]. Zika virus-infected neurons produce itaconate, which can inhibit succinate dehydrogenase (SDH) activity and viral replication, indicating that itaconate has antiviral activity [2].
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