Abstract
Immune-responsive gene1 (IRG1), an enzyme that is overexpressed during immune reactions, catalyzes the production of itaconate from cis-aconitate. Itaconate is a multifunctional immuno-metabolite that displays antibacterial and antiviral activities. The recent resolution of its structure has enabled the mechanism underlying IRG1 function to be speculated on. However, the precise mechanism underlying the enzymatic reaction of IRG1 remains vague owing to the absence of information regarding the structure of the IRG1/substrate or the product complex. In this study, we determined the high-resolution structure of the active site mutant form of IRG1 from Bacillus subtilis (bsIRG1_H102A). Structural analysis detected unidentified electron densities around the active site. Structural comparison with the wildtype revealed that H102 was critical for the precise location of the side chain of residues around active site of IRG1. Finally, the activity of bsIRG1 was extremely low compared with that of mammalian IRG1. The current structural study will expectedly help understand the working mechanism of IRG1.
Highlights
Itaconate is an unsaturated dicarboxylic acid, which functions as an intermediate metabolite in the tricarboxylic acid (TCA) cycle [1]
To understand the precise mechanism by which Immune-responsive gene1 (IRG1) catalyzes the production of itaconate during microbial infection, we solved the structure of the active site mutant variant of IRG1 found in B. subtilis
We investigated the manner in which the structure of this variant H102 residue, critical for IRG1 activity, is mutated to alanine
Summary
Itaconate is an unsaturated dicarboxylic acid, which functions as an intermediate metabolite in the tricarboxylic acid (TCA) cycle [1]. In biology, itaconate is known for the role it plays in regulating innate immunity as well as for its antibacterial and antiviral activities [4,5,6]. Antimicrobial activity of itaconate was initially reported in fungi [7]. Aspergillus terreus, a representative fungus, produces high levels of itaconate that act against Pseudomonas indigofera and Mycobacterium tuberculosis by directly inhibiting the activity of housekeeping enzymes, such as isocitrate lyase (ICL) and fructose-6-phosphate 2-kinase [8,9,10]. The antimicrobial activity of itaconate in the mammalian system has been revealed recently [4,5,6]. Itaconate eliminates infections caused by bacteria, such as Salmonella enterica and M. tuberculosis, by targeting
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