7RBX

Crystal structure of isocitrate lyase and phosphorylmutase:isocitrate lyase from Brucella melitensis biovar Abortus 2308 bound to itaconic acid

Summary for 7RBX

• Entry DOI: 10.2210/pdb7rbx/pdb
• Descriptor: Isocitrase, 1,2-ETHANEDIOL, 2-methylidenebutanedioic acid, ... (6 entities in total)
• Functional Keywords: structural genomics, niaid, brucellosis, brucellaceae, covalent inhibitor, itn, substrate analog, icl, glyoxylate cycle, isocitrate, succinate, tca cycle bypass, seattle structural genomics center for infectious disease, ssgcid, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Brucella abortus (strain 2308)
• Total number of polymer chains: 4
• Total formula weight: 197739.18

Authors

Seattle Structural Genomics Center for Infectious Disease,Edwards, T.E.,Abendroth, J.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2021-07-06, release date: 2021-10-06, Last modification date: 2024-11-13)

Primary citation

Demars, A.,Vitali, A.,Comein, A.,Carlier, E.,Azouz, A.,Goriely, S.,Smout, J.,Flamand, V.,Van Gysel, M.,Wouters, J.,Abendroth, J.,Edwards, T.E.,Machelart, A.,Hoffmann, E.,Brodin, P.,De Bolle, X.,Muraille, E.
Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice.
Plos Pathog., 17:e1009887-e1009887, 2021

PubMed Abstract: Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, structural analysis suggests the binding of itaconate into the binding site of B. abortus isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ΔaceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ΔaceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.

PubMed: 34525130
DOI: 10.1371/journal.ppat.1009887

Experimental method

X-RAY DIFFRACTION (1.8 Å)