Korn Lukas, Brock Matthias, Schuster Stefan
Department of Bioinformatics, Friedrich Schiller University, Jena, Ernst-Abbe-Platz 2, 07743 Jena, Germany.
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
Microlife. 2025 May 19;6:uqaf009. doi: 10.1093/femsml/uqaf009. eCollection 2025.
The tricarboxylic acid (TCA) cycle is well known as a crucial pathway in central metabolism in many organisms. A less known analogous pathway is the methylcitrate cycle (MCC). It is present in various fungi such as species and bacteria such as , with some of them being pathogenic. The MCC catalyzes an alpha-oxidation of propionyl-CoA to pyruvate and is of interest in view of biotechnology and pharmacology. To elucidate the potential interaction of the MCC with other central metabolic pathways, we investigated the MCC by Elementary-flux-mode analysis. We first established a reaction network model, using information from both the KEGG database and literature. This reaction network contains enzymes of the MCC as well as of the TCA cycle, glyoxylate shunt, and carbon source-utilizing pathways, such as amino acid degradation. The network was then used to calculate the elementary flux modes (EFMs) by using the simulation software Metatool 4.3. We identified 76 EFMs, with 39 of them containing the MCC. In this way, some previously known pathways were confirmed theoretically and, additionally, some new EFMs were discovered. Among these, a different, but shorter version of the MCC was identified. The EFMs were systematically analyzed with respect to their ATP yield and the robustness of the network was computed. Predictions on the impact of enzyme deletion or inhibition on the network were made. From these analyses and based on the absence of the MCC in humans, we conclude that the methylcitrate synthase represents a promising drug target against various human pathogens.
三羧酸（TCA）循环作为许多生物体中心代谢的关键途径广为人知。一种鲜为人知的类似途径是甲基柠檬酸循环（MCC）。它存在于各种真菌（如某些物种）和细菌（如某些物种）中，其中一些具有致病性。MCC催化丙酰辅酶A向丙酮酸的α氧化，鉴于生物技术和药理学，它具有研究价值。为了阐明MCC与其他中心代谢途径的潜在相互作用，我们通过基本通量模式分析对MCC进行了研究。我们首先利用KEGG数据库和文献中的信息建立了一个反应网络模型。这个反应网络包含MCC以及TCA循环、乙醛酸分流和碳源利用途径（如氨基酸降解）的酶。然后使用模拟软件Metatool 4.3利用该网络计算基本通量模式（EFM）。我们确定了76种EFM，其中39种包含MCC。通过这种方式，一些先前已知的途径在理论上得到了证实，此外还发现了一些新的EFM。其中，鉴定出了一种不同但更短版本的MCC。对EFM的ATP产量进行了系统分析，并计算了网络的稳健性。对酶缺失或抑制对网络的影响进行了预测。基于这些分析以及人类中不存在MCC这一事实，我们得出结论，甲基柠檬酸合酶是针对各种人类病原体的一个有前景的药物靶点。
