Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain.
Department of Biomedicine, Instituto de Biomedicina de Valencia (CSIC), Valencia 46010, Spain.
World J Gastroenterol. 2018 Dec 28;24(48):5454-5461. doi: 10.3748/wjg.v24.i48.5454.
The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2 (PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements, ranging from specific microRNAs to proteins that control mRNA degradation. Moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the pro-inflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.
前列腺素的生物合成参与了生理和病理过程。前列腺素内过氧化物合酶 2（PTGS2；也称为 COX-2）的表达传统上与几种病理学的发生有关，从炎症到心血管、胃肠道和肿瘤事件。因此，寻找选择性 PTGS2 抑制剂一直是治疗干预的重点。除了经典的非甾体抗炎药外，还产生了并广泛使用了选择性和特异性 PTGS2 抑制剂，称为 COXIBs。PTGS2 的活性在底物特异性方面比同源的 PTGS1 限制更少，它负责伴随几种病理学的升高的前列腺素合成。PTGS2 的主要调节发生在转录水平。除此之外，通过与几种细胞质元件的相互作用，包括特定的 microRNA 和控制 mRNA 降解的蛋白质，对 mRNA 的稳定性进行精细调节。此外，该蛋白已被确认为几种翻译后修饰的底物，这些修饰影响酶活性和靶向降解 蛋白酶体和非蛋白酶体机制。在这些修饰中，磷酸化、糖基化和由反应性脂质中间体和与炎症相关的自由基引起的共价修饰似乎是主要变化。鉴定这些翻译后修饰对于更好地了解 PTGS2 在几种病理学中的作用以及正确分析该蛋白在疾病进展中的潜在功能非常重要。最后，这些修饰可以用作生物标志物，与其他参数建立相关性，包括依赖分子病理流行病学决定因素的免疫调节，这可能为潜在的治疗干预提供更好的框架。
