School of Life Sciences, Manipal Academy of Higher Education, Manipal - 576104, India.
Curr Mol Med. 2019;19(4):247-272. doi: 10.2174/1566524019666190404155801.
The phosphoenolpyruvate carboxykinase (PEPCK) isoforms are considered as rate-limiting enzymes for gluconeogenesis and glyceroneogenesis pathways. PEPCK exhibits several interesting features such as a) organelle-specific isoforms (cytosolic and a mitochondrial) in vertebrate clade, b) tissue-specific expression of isoforms and c) organism-specific requirement of ATP or GTP as a cofactor. In higher organisms, PEPCK isoforms are intricately regulated and activated through several physiological and pathological stimuli such as corticoids, hormones, nutrient starvation and hypoxia. Isoform-specific transcriptional/translational regulation and their interplay in maintaining glucose homeostasis remain to be fully understood. Mounting evidence indicates the significant involvement of PEPCK isoforms in physiological processes (development and longevity) and in the progression of a variety of diseases (metabolic disorders, cancer, Smith-Magenis syndrome).
The present systematic review aimed to assimilate existing knowledge of transcriptional and translational regulation of PEPCK isoforms derived from cell, animal and clinical models.
Based on current knowledge and extensive bioinformatics analysis, in this review we have provided a comparative (epi)genetic understanding of PCK1 and PCK2 genes encompassing regulatory elements, disease-associated polymorphisms, copy number variations, regulatory miRNAs and CpG densities. We have also discussed various exogenous and endogenous modulators of PEPCK isoforms and their signaling mechanisms. A comprehensive review of existing knowledge of PEPCK regulation and function may enable identification of the underlying gaps to design new pharmacological strategies and interventions for the diseases associated with gluconeogenesis.
磷酸烯醇丙酮酸羧激酶（PEPCK）同工酶被认为是糖异生和甘油异生途径的限速酶。PEPCK 具有几个有趣的特征，例如 a）脊椎动物类群中具有细胞器特异性同工酶（细胞质和线粒体），b）同工酶的组织特异性表达，和 c）作为辅助因子的 ATP 或 GTP 的组织特异性需求。在高等生物中，PEPCK 同工酶通过几种生理和病理刺激（皮质激素、激素、营养饥饿和缺氧）进行复杂的调节和激活。同工酶特异性转录/翻译调节及其在维持葡萄糖稳态中的相互作用仍有待充分理解。越来越多的证据表明，PEPCK 同工酶在生理过程（发育和长寿）以及多种疾病（代谢紊乱、癌症、Smith-Magenis 综合征）的进展中具有重要作用。
本系统综述旨在综合来自细胞、动物和临床模型的 PEPCK 同工酶的转录和翻译调节的现有知识。
基于目前的知识和广泛的生物信息学分析，在本综述中，我们对 PCK1 和 PCK2 基因进行了比较（表观遗传学）理解，包括调控元件、与疾病相关的多态性、拷贝数变异、调节 miRNA 和 CpG 密度。我们还讨论了 PEPCK 同工酶的各种外源性和内源性调节剂及其信号机制。对 PEPCK 调节和功能的现有知识的全面综述，可能有助于确定潜在的差距，从而为与糖异生相关的疾病设计新的药理学策略和干预措施。
