Intricate Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Isoforms in Normal Physiology and Disease

Abstract

Background: 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). Objective: The present systematic review aimed to assimilate existing knowledge of transcriptional and translational regulation of PEPCK isoforms derived from cell, animal and clinical models. Conclusion: 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.

Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study

“…A potential decrease in PDH, VNN1, and PANK2 activities could lead to lower mitochondrial ATP production and increased lactate production from glycolysis. Accordingly, patients' cells showed higher levels of SLC16A3, the monocarboxylate transporter 4 (MCT4), which is upregulated in lactate-exporting glycolytic cells [63], along with upregulation of phosphoenolpyruvate carboxykinase 2 (PCK2), which is involved in the recycling of lactate to support cellular biosynthesis in glycolytic cells [64,65]. Dysregulated pantothenic acid and CoA metabolic pathways have already been shown in ME/CFS patients [28,66].…”

Fine Mapping of the Mouse Ath28 Locus Yields Three Atherosclerosis Modifying Sub-Regions

“…Pck1 encodes the cytosolic phosphoenolpyruvate carboxykinase 1, also known as PEPCK-C, while the unlinked gene Pck2 encodes the mitochondrial PEPCK-M. PEPCK is a gluconeogenic enzyme, and its expression is under complex hormonal control [ 17 ]. We noted one indel that differs in our two mouse strains in the 3’ UTR of Pck1 , which might alter its mRNA stability.…”

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

“…In our analysis, the identification of this pathway was defined by several genes. Interestingly, all pNEN cases, including family 1 with only one gene recognized in this pathway, encompassed signal transduction factors that are, among others, related to insulin signalling and glucose metabolism: PCK2 catalyses the rate-limiting step in the metabolic pathway that produces glucose from precursors [35]. TSC2 is a tumour suppressor that functions as a negative regulator of mTOR signalling, which is a signalling network induced by several molecules including insulin [36], and TSC2 deletion has been shown to be responsible for the hypertrophy of pancreatic beta cells…”