Department of Inorganic Chemistry, Analytical Chemistry and Electrochemistry, Faculty of Chemistry, Silesian University of Technology, B. Krzywoustego 6, 44-100, Gliwice, Poland.
Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 6, 44-100, Gliwice, Poland.
Sci Rep. 2023 Jan 26;13(1):1473. doi: 10.1038/s41598-023-28335-3.
Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. Moreover, it has been proven that formed NTBC metabolites, such as CHD, cause a decrease in L-tyrosine, L-tryptophan, and L-phenylalanine concentrations by about 34%, 59% and 51%, respectively, compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.
尼替西农（2-(2-硝基-4-三氟甲基苯甲酰基）-1,3-环己二酮，NTBC）被认为是一种治疗与 L-酪氨酸代谢紊乱相关的各种代谢疾病的潜在有效药物，但副作用阻碍了其广泛应用。本工作旨在拓宽对 NTBC 及其代谢物 2-氨基-4-(三氟甲基)苯甲酸（ATFA）、2-硝基-4-(三氟甲基)苯甲酸（NTFA）和环己烷-1,3-二酮（CHD）对酿酒酵母中 L-酪氨酸和其他内源性化合物分解代谢影响的认识。基于通过 LC-ESI-MS/MS 进行的靶向分析，基于多重反应监测，发现母体化合物及其代谢物的耗散动力学与一级反应机制兼容。此外，已经证明形成的 NTBC 代谢物，如 CHD，与未处理的模型生物相比，分别导致 L-酪氨酸、L-色氨酸和 L-苯丙氨酸的浓度降低约 34%、59%和 51%。通过 LC-ESI-MS/MS 在离子阱扫描模式下进行非靶向分析来评估暴露于 NTBC 或其衍生物的酵母的整体代谢变化。基于主成分分析，观察到用 ATFA 或 NTFA 处理的酵母的代谢反应具有统计学上的显著相似性。这些发现有助于进一步研究 NTBC 对人体的影响及其作用机制。
