Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis

Abstract

Background: Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans.

Scope of review: Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction.

Major conclusions: In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions.

Keywords: Epigenetic regulation; Gluconeogenesis; Glyceroneogenesis; Phosphoenolpyruvate carboxykinase (PCK); Posttranscription regulation; Protein kinase; Transcription regulation.

Figure 1

Comparison of PCK conservation. (A) Amino acid alignment of PCK1 among different species. Different amino acids are highlighted in red. Conservation is scaled at the bottom, in which blue stands for less conserved. The Genome Workbench was applied to calculate the conservation score. (B) Amino acid alignment of PCK2 among different species. (C) 3D protein structure (SWISS-MODEL) and amino acid alignment of human PCK1 and PCK2.

Figure 2

Relative expression of PCK1 and PCK2 in multiple human organs. Raw data were retrieved from the TiGER (A) and GTEx (B) databases.

Figure 3

Schematic representation of metabolic pathways. Glycolysis requires the three rate-limiting enzymes shown in the green ovals. Gluconeogenesis needs the four key enzymes shown in the red ovals. Glyceroneogenesis is a truncated version of gluconeogenesis sharing the same enzymes. Abbreviations: 3-PG, 3-phosphoglycerate; DHAP, dihydroxyacetone phosphate; F-1,6-P, fructose-1,6-biphosphate; F-6-P, fructose-6-phosphate; FBP, fructose-1,6-bisphosphatase; FFA, free fatty acid; G-3-P, glyceraldehyde-3-phosphate; G-6-P, glucose-6-phosphate; G6PC, glucose-6-phosphatase; HK, hexokinase; MDH, malate dehydrogenase; OAA, oxaloacetate; PC, pyruvate carboxylase; PCK, phosphoenolpyruvate carboxykinase; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; PK, pyruvate kinase; R-5-P, ribose-5-phosphate; TG, triglyceride.

Figure 4

Illustrative representation of PCK's regulatory mechanism at different levels, from histone modification at the epigenetic level, interaction of transcriptional factors and promoter elements at the transcription level, ARE and miR-mediated mRNA degradation, and ubiquitinylation-mediated protein degradation. Abbreviations: AF, accessory factor; ARE, adenine-uridine rich elements; ATF, activating transcription factor; AUF, AU-rich element RNA-binding protein; C/EBP, CAAT/enhancer-binding protein; COUP-TF, chicken ovalbumin upstream promoter transcription factor; CRE, cAMP regulatory element; CREB, cAMP regulatory element-binding protein; FOXO1, forkhead transcription factor; GR, glucocorticoid receptor; GRE, glucocorticoid regulatory element; HNF, hepatic nuclear factor; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor coactivator; SRE, SREBP regulatory element; SREBP, sterol regulatory element-binding protein; UBR5, E3 ubiquitin-protein ligase.