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Cell Metabolism Sep 2023Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8)....
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
Topics: Mice; Animals; Phosphoenolpyruvate; Diabetes Mellitus, Type 2; Proteins; Liver; Lysine; Glucose
PubMed: 37541251
DOI: 10.1016/j.cmet.2023.07.003 -
Nature Metabolism Oct 2023Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we...
Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of β-catenin and activates the β-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.
Topics: Humans; Animals; Mice; beta Catenin; Phosphoenolpyruvate; Histone Deacetylase 1; Phosphopyruvate Hydratase
PubMed: 37667133
DOI: 10.1038/s42255-023-00883-y -
The Journal of Clinical Investigation Jul 2023Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the...
Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency-induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 KO in vivo and in vitro. These findings reveal the availability of the key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.
Topics: Humans; Carcinoma, Hepatocellular; S-Adenosylmethionine; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Epigenesis, Genetic; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins
PubMed: 37166978
DOI: 10.1172/JCI161713 -
Journal of the American Society of... Aug 2023Renal gluconeogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). Proximal tubular phosphoenolpyruvate carboxykinase1 (PEPCK1) is the...
SIGNIFICANCE STATEMENT
Renal gluconeogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). Proximal tubular phosphoenolpyruvate carboxykinase1 (PEPCK1) is the rate-limiting enzyme in gluconeogenesis. However, the functions of PEPCK1 have not been elucidated. We describe the novel role of PEPCK1 as a mitoribosomal protector using Pck1 transgenic (TG) mice and knockout mice. Pck1 blocks excessive glycolysis by suppressing the upregulation of excess HK2 (the rate-limiting enzyme of glycolysis). Notably, Pck1 overexpression retains mitoribosomal function and suppresses renal fibrosis. The renal and mitoribosomal protective roles of Pck1 may provide important clues for understanding DN pathogenesis and provide novel therapeutic targets.
BACKGROUND
Phosphoenolpyruvate carboxykinase (PEPCK) is part of the gluconeogenesis pathway, which maintains fasting glucose levels and affects renal physiology. PEPCK consists of two isoforms-PEPCK1 and PEPCK2-that the Pck1 and Pck2 genes encode. Gluconeogenesis increases in diabetic nephropathy (DN), escalating fasting and postprandial glucose levels. Sodium-glucose cotransporter-2 inhibitors increase hepatic and renal gluconeogenesis. We used genetically modified mice to investigate whether renal gluconeogenesis and Pck1 activity are renoprotective in DN.
METHODS
We investigated the expression of Pck1 in the proximal tubule (PTs) of streptozotocin (STZ)-treated diabetic mice. We studied the phenotypic changes in PT-specific transgenic (TG) mice and PT-specific Pck1 conditional knockout (CKO) mice.
RESULTS
The expression of Pck1 in PTs was downregulated in STZ-treated diabetic mice when they exhibited albuminuria. TG mice overexpressing Pck1 had improved albuminuria, concomitant with the mitigation of PT cell apoptosis and deposition of peritubular type IV collagen. Moreover, CKO mice exhibited PT cell apoptosis and type IV collagen deposition, findings also observed in STZ-treated mice. Renal fibrotic changes in CKO mice were associated with increasing defects in mitochondrial ribosomes (mitoribosomes). The TG mice were protected against STZ-induced mitoribosomal defects.
CONCLUSION
PCK1 preserves mitoribosomal function and may play a novel protective role in DN.
Topics: Mice; Animals; Diabetic Nephropathies; Diabetes Mellitus, Experimental; Collagen Type IV; Albuminuria; Diabetes Mellitus, Type 2; Phosphoenolpyruvate; Phosphoenolpyruvate Carboxykinase (GTP); Sodium-Glucose Transporter 2 Inhibitors; Disease Models, Animal; Mice, Transgenic; Fibrosis; Mice, Knockout; Glucose
PubMed: 37199399
DOI: 10.1681/ASN.0000000000000156 -
Plant Communications Sep 2023JUJUNCAO (Cenchrus fungigraminus; 2n = 4x = 28) is a Cenchrus grass with the highest biomass production among cultivated plants, and it can be used for mushroom...
JUJUNCAO (Cenchrus fungigraminus; 2n = 4x = 28) is a Cenchrus grass with the highest biomass production among cultivated plants, and it can be used for mushroom cultivation, animal feed, and biofuel production. Here, we report a nearly complete genome assembly of JUJUNCAO and reveal that JUJUNCAO is an allopolyploid that originated ∼2.7 million years ago (mya). Its genome consists of two subgenomes, and subgenome A shares high collinear synteny with pearl millet. We also investigated the genome evolution of JUJUNCAO and suggest that the ancestral karyotype of Cenchrus split into the A and B ancestral karyotypes of JUJUNCAO. Comparative transcriptome and DNA methylome analyses revealed functional divergence of homeologous gene pairs between the two subgenomes, which was a further indication of asymmetric DNA methylation. The three types of centromeric repeat in the JUJUNCAO genome (CEN137, CEN148, and CEN156) may have evolved independently within each subgenome, with some introgressions of CEN156 from the B to the A subgenome. We investigated the photosynthetic characteristics of JUJUNCAO, revealing its typical C Kranz anatomy and high photosynthetic efficiency. NADP-ME and PEPCK appear to cooperate in the major C decarboxylation reaction of JUJUNCAO, which is different from other C photosynthetic subtypes and may contribute to its high photosynthetic efficiency and biomass yield. Taken together, our results provide insights into the highly efficient photosynthetic mechanism of JUJUNCAO and provide a valuable reference genome for future genetic and evolutionary studies, as well as genetic improvement of Cenchrus grasses.
Topics: Cenchrus; Plant Leaves; Photosynthesis; Poaceae; Phosphoenolpyruvate Carboxylase
PubMed: 37271992
DOI: 10.1016/j.xplc.2023.100633 -
Nature Communications Jul 2023Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2...
Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a glycolytic enzyme known to be involved in metabolic reprogramming and gene transcription in many immune cell types, its role in neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production and microbial killing by neutrophils. Zymosan-activated neutrophils showed increased cytoplasmic expression of PKM2. Pharmacological inhibition or genetic deficiency of PKM2 in neutrophils reduced ROS production and Staphylococcus aureus killing in vitro. In addition, this also resulted in phosphoenolpyruvate (PEP) accumulation and decreased dihydroxyacetone phosphate (DHAP) production, which is required for de novo synthesis of diacylglycerol (DAG) from glycolysis. In vivo, PKM2 deficiency in myeloid cells impaired the control of infection with Staphylococcus aureus. Our results fill the gap in the current knowledge of the importance of lower glycolysis for ROS production in neutrophils, highlighting the role of PKM2 in regulating the DHAP and DAG synthesis to promote ROS production in neutrophils.
Topics: Pyruvate Kinase; Reactive Oxygen Species; Neutrophils; Phosphorylation; Glycolysis
PubMed: 37460614
DOI: 10.1038/s41467-023-40021-6 -
Cell Metabolism Jun 2024The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown....
The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.
Topics: PPAR alpha; Animals; Fasting; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Humans; Mice; Liver Neoplasms; Mice, Inbred C57BL; Male; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins; Liver; Liver Cirrhosis; Signal Transduction; Intermittent Fasting
PubMed: 38718791
DOI: 10.1016/j.cmet.2024.04.015 -
Insect Biochemistry and Molecular... Sep 2023The fat body is responsible for a variety of functions related to energy metabolism in arthropods, by controlling the processes of de novo glucose production... (Review)
Review
The fat body is responsible for a variety of functions related to energy metabolism in arthropods, by controlling the processes of de novo glucose production (gluconeogenesis) and glycogen metabolism. The rate-limiting factor of gluconeogenesis is the enzyme phosphoenolpyruvate carboxykinase (PEPCK), generally considered to be the first committed step in this pathway. Although the study of PEPCK and gluconeogenesis has been for decades restricted to mammalian models, especially focusing on muscle and liver tissue, current research has demonstrated particularities about the regulation of this enzyme in arthropods, and described new functions. This review will focus on arthropod PEPCK, discuss different aspects to PEPCK regulation and function, its general role in the regulation of gluconeogenesis and other pathways. The text also presents our views on potentially important new directions for research involving this enzyme in a variety of metabolic adaptations (e.g. diapause), discussing enzyme isoforms, roles during arthropod embryogenesis, as well as involvement in vector-pathogen interactions, contributing to a better understanding of insect vectors of diseases and their control.
Topics: Animals; Arthropods; Phosphoenolpyruvate Carboxykinase (GTP); Phosphoenolpyruvate Carboxykinase (ATP); Glucose; Homeostasis; Mammals
PubMed: 37454751
DOI: 10.1016/j.ibmb.2023.103986 -
Natural Product Reports Apr 2024Covering: 1997 to 2023The shikimate pathway is the metabolic process responsible for the biosynthesis of the aromatic amino acids phenylalanine, tyrosine, and... (Review)
Review
Covering: 1997 to 2023The shikimate pathway is the metabolic process responsible for the biosynthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. Seven metabolic steps convert phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E4P) into shikimate and ultimately chorismate, which serves as the branch point for dedicated aromatic amino acid biosynthesis. Bacteria, fungi, algae, and plants (yet not animals) biosynthesize chorismate and exploit its intermediates in their specialized metabolism. This review highlights the metabolic diversity derived from intermediates of the shikimate pathway along the seven steps from PEP and E4P to chorismate, as well as additional sections on compounds derived from prephenate, anthranilate and the synonymous aminoshikimate pathway. We discuss the genomic basis and biochemical support leading to shikimate-derived antibiotics, lipids, pigments, cofactors, and other metabolites across the tree of life.
Topics: Shikimic Acid; Molecular Structure; Chorismic Acid; Phosphoenolpyruvate; Sugar Phosphates; Bacteria; Fungi; Plants; Cyclohexanecarboxylic Acids; Cyclohexenes
PubMed: 38170905
DOI: 10.1039/d3np00037k -
Molecular Therapy Oncolytics Dec 2023Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into... (Review)
Review
Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into phosphoenolpyruvate. In mammals, enolases exist in three isoforms, encoded by the genes , , and . The altered expression of enolases is a common occurrence in various types of cancer. Although most published studies on enolases have predominantly focused on the role of ENO1 in cancer, ENO2 and ENO3 have recently emerged as crucial regulatory molecules in cancer development. Significant progress has been made in understanding their multifaceted roles in oncogenesis. In this comprehensive review, we provide an overview of the structure, subcellular localization, diagnostic and prognostic significance, biological functions, and molecular mechanisms of ENO2 and ENO3 in cancer progression. The importance of enolase in cancer development makes it a novel therapeutic target for clinical applications. Furthermore, we discuss anticancer agents designed to target enolases and summarize their anticancer efficacy in both and studies.
PubMed: 38075246
DOI: 10.1016/j.omto.2023.100750