Ergon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring, Maryland 20910, USA.
Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK.
Nat Commun. 2017 Jul 12;8:16040. doi: 10.1038/ncomms16040.
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.
支链氨基酸转氨酶（BCAT）是一种能够启动支链氨基酸（BCAA，如亮氨酸）分解代谢的酶，从而为大分子前体提供原料；然而，BCAT 在巨噬细胞中的功能尚不清楚。在这里，我们表明 BCAT1 是人类原代巨噬细胞中主要的 BCAT 同工酶。我们发现 ERG240 是一种亮氨酸类似物，可以阻断 BCAT1 的活性。选择性抑制 BCAT1 的活性会导致耗氧量和糖酵解减少。这种减少与 IRG1 水平和衣康酸合成的降低有关，提示在激活的巨噬细胞中，BCAA 分解代谢通过三羧酸循环中的 IRG1/衣康酸轴进行。ERG240 抑制了小鼠中 IRG1 和衣康酸的产生，并有助于减少促炎转录组特征。ERG240 的口服给药可降低胶原诱导性关节炎小鼠和新月体性肾小球肾炎大鼠的疾病严重程度，部分原因是减少了巨噬细胞浸润。这些结果确立了 BCAT1 在巨噬细胞功能中的调节作用，为炎症性疾病的治疗提供了依据。
