Abstract
Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; however, the function of BCATs in macrophages is unknown. Here we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identify ERG240 as a leucine analogue that blocks BCAT1 activity. Selective inhibition of BCAT1 activity results in decreased oxygen consumption and glycolysis. This decrease is associated with reduced IRG1 levels and itaconate synthesis, suggesting involvement of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic acid cycle in activated macrophages. ERG240 suppresses production of IRG1 and itaconate in mice and contributes to a less proinflammatory transcriptome signature. Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice and crescentic glomerulonephritis in rats, in part by decreasing macrophage infiltration. These results establish a regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions.
Highlights
Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; the function of BCATs in macrophages is unknown
This showed that messenger RNA (mRNA) levels of BCAT1 are markedly increased when compared to BCAT2, suggesting that the cytoplasmic isoform is the major source of BCAA catabolism in these cells
To examine the role of BCAT1 in macrophage metabolism and inflammatory diseases, we identified a novel BCAT1 inhibitor, ERG240, using molecular modelling approaches based on the X-ray crystal structures of BCAT1
Summary
Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; the function of BCATs in macrophages is unknown. A comprehensive integrative analysis of the transcriptome and metabolome in activated macrophages has established the importance of citrateitaconic acid axis through Irg[1] ( known as cis-aconitate decarboxylase, Acod1)[18], one of the most significantly up-regulated transcripts in LPS-stimulated macrophages, which encodes an enzyme that catalyses the aconitate-to-itaconate reaction[18,19] These studies led to the concept of the broken (or fragmented) Krebs cycle in LPS-activated macrophages (M(LPS))[18,20], in which TCA cycle intermediate metabolites function as metabolic checkpoints for the activation of LPS response genes, such as Hif1a, Il1b, Irg[1]. Using a novel selective inhibitor of BCAT1 (ERG240, a leucine analogue), we show that inhibition of BCAT1 leads to the reduction of oxygen consumption and glycolysis together with a decrease in IRG1 and itaconate, but not HIF-1a and IL-1b messenger RNA (mRNA)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
