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Frontiers in Neuroscience 2018The Embden-Meyerhof-Parnas (EMP) pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CHCH(OH)COO]. Glycolysis is largely... (Review)
Review
The Embden-Meyerhof-Parnas (EMP) pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CHCH(OH)COO]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CHCOCOO). We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway. In this review, we consider the flow of metabolites to be coupled to a flow of energy that is irreversible and sufficient to form ordered structures. This latter principle is highlighted by discussing that lactate dehydrogenase (LDH) complexes irreversibly reduce pyruvate/H to lactate [CHCH(OH)COO], or irreversibly catalyze the opposite reaction, oxidation of lactate to pyruvate/H. However, both LDH complexes are considered to be driven by postulated proton transport chains. Metabolism of glucose to two lactic acids is introduced as a unidirectional, continuously flowing pathway. In an organism, cell membrane-located proton-linked monocarboxylate transporters catalyze the final step of glycolysis, the release of lactic acid. Consequently, both pyruvate and lactate are discussed as intermediate products of glycolysis and substrates of regulated crosscuts of the glycolytic flow.
PubMed: 29962930
DOI: 10.3389/fnins.2018.00404 -
Cell Death & Disease Feb 2024Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle,...
Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle, which is called the Warburg effect. However, the detailed mechanisms of abnormal activation of the glycolysis pathway in colorectal cancer are largely unknown. In this study, we reveal that the protein arginine methyltransferase 1 (PRMT1) promotes glycolysis, proliferation, and tumorigenesis in CRC cells. Mechanistically, PRMT1-mediated arginine asymmetric dimethylation modification of phosphoglycerate kinase 1 (PGK1, the first ATP-producing enzyme in glycolysis) at R206 (meR206-PGK1) enhances the phosphorylation level of PGK1 at S203 (pS203-PGK1), which inhibits mitochondrial function and promotes glycolysis. We found that PRMT1 and meR206-PGK1 expression were positively correlated with pS203-PGK1 expression in tissues from colorectal cancer patients. Furthermore, we also confirmed that meR206-PGK1 expression is positively correlated with the poor survival of patients with colorectal cancer. Our findings show that PRMT1 and meR206-PGK1 may become promising predictive biomarkers for the prognosis of patients with CRC and that arginine methyltransferase inhibitors have great potential in colorectal cancer treatment.
Topics: Humans; Phosphoglycerate Kinase; Arginine; Cell Line, Tumor; Carcinogenesis; Cell Transformation, Neoplastic; Methylation; Colorectal Neoplasms; Glycolysis; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 38402202
DOI: 10.1038/s41419-024-06544-6 -
Acta Pharmacologica Sinica Apr 2021Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than...
Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than oxidative phosphorylation pathway. Preliminary evidence shows that inhibition of phosphoglycerate kinase 1 (PGK1) kinase activity would reverse the Warburg effect and make tumor cells lose the metabolic advantage for fueling the proliferation through restoration of the pyruvate dehydrogenase (PDH) activity and subsequently promotion of pyruvic acid to enter the Krebs cycle in glioma. However, due to the lack of small molecule inhibitors of PGK1 kinase activity to treat glioma, whether PGK1 could be a therapeutic target of glioma has not been pharmacologically verified yet. In this study we developed a high-throughput screening and discovered that NG52, previously known as a yeast cell cycle-regulating kinase inhibitor, could inhibit the kinase activity of PGK1 (the IC = 2.5 ± 0.2 μM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC values of 7.8 ± 1.1 and 5.2 ± 0.2 μM, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5-50 μM) effectively inhibited the phosphorylation of PDHK1 at Thr338 site and the phosphorylation of PDH at Ser293 site in U87 and U251 cells, resulting in more pyruvic acid entering the Krebs cycle with increased production of ATP and ROS. Therefore, NG52 could reverse the Warburg effect by inhibiting PGK1 kinase activity, and switched cellular glucose metabolism from anaerobic mode to aerobic mode. In nude mice bearing patient-derived glioma xenograft, oral administration of NG52 (50, 100, 150 mg· kg·d, for 13 days) dose-dependently suppressed the growth of glioma xenograft. Together, our results demonstrate that targeting PGK1 kinase activity might be a potential strategy for glioma treatment.
Topics: Adenine; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Female; Glioma; Humans; Mice, Nude; Phosphoglycerate Kinase; Protein Kinase Inhibitors; Warburg Effect, Oncologic; Xenograft Model Antitumor Assays; Mice
PubMed: 32737469
DOI: 10.1038/s41401-020-0465-8 -
BMC Microbiology Aug 2023Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental...
BACKGROUND
Colorectal cancer (CRC) is a public health concern and the second most common disease worldwide. This is due to genetic coding and is influenced by environmental aspects, in which the gut microbiota plays a significant role. The purpose of this study was to compare the microbiota makeup of CRC patients with that of healthy control and to identify upregulated and downregulated proteins and metabolites in CRC patients. Using a next-generation sequencing approach, fecal samples of five females (4 CRC patients and one healthy control) were analyzed by BGI DNBSEQ-T7, Hong Kong, China. Furthermore, proteomics and metabolomics analysis were performed using LC-MS/MS technique.
RESULTS
Dysbiosis of gut microbiota has been observed in patients with CRC, with an increase in microbiota diversity at all taxonomic levels relative to healthy control. Where, at the functional level the bacterial species participate in many different pathways among them de novo nucleotide synthesis and amino acids pathways were aberrantly upregulated in CRC patients. Proteomics and metabolomics profiles of CRC patients showed different proteins and metabolites, a total of 360 and 158 proteins and metabolites, respectively were highly expressed compared to healthy control with fold change ≥ 1.2. Among the highly expressed proteins were transketolase, sushi domain-containing protein, sulfide quinone oxidoreductase protein, AAA family ATPase protein, carbonic anhydrase, IgG Fc-binding protein, nucleoside diphosphate kinase protein, arylsulfatase, alkaline phosphatase protein, phosphoglycerate kinase, protein kinase domain-containing protein, non-specific serine/threonine protein kinase, Acyl-CoA synthetase and EF-hand domain-containing protein. Some of the differential metabolites, Taurine, Taurocholic acid, 7-ketodeoxycholic acid, Glycochenodeoxycholic acid, Glycocholic acid, and Taurochenodeoxycholic acid that belong to bile acids metabolites.
CONCLUSIONS
Some bacterial species, proteins, and metabolites could be used as diagnostic biomarkers for CRC. Our study paves an insight into using multi-omics technology to address the relationship between gut microbiota and CRC.
Topics: Female; Humans; Pilot Projects; Chromatography, Liquid; Multiomics; Tandem Mass Spectrometry; Protein Kinases; Colorectal Neoplasms
PubMed: 37644393
DOI: 10.1186/s12866-023-02991-x -
Scientific Reports Oct 2023Numerous studies have been conducted on long non-coding RNAs (lncRNAs) in human tumors like gastric cancer (GC). Our research uncovers how aerobic glycolysis and cell...
Numerous studies have been conducted on long non-coding RNAs (lncRNAs) in human tumors like gastric cancer (GC). Our research uncovers how aerobic glycolysis and cell proliferation in gastric cancer cells are related to H19. We discovered that H19 was highly expressed in tumor tissues and that patients with higher H19 expression have a poorer prognosis. Intriguingly, we applied the subcellular isolation, luciferase reporter, western blot analysis, MTT, colony formation experiments, and CDX Model in Mice to verify that H19 regulates aerobic glycolysis towards GC cell growth by H19/microRNA (miR)-19a-3p/phosphoglycerate kinase 1 (PGK1) axis. Together, our research offers proof that the H19/miR-19a-3p/PGK1 pathway aids in the regulation of aerobic glycolysis and cell proliferation in GC. This may offer an opportunity for novel therapeutic approaches to the treatment of GC.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glycolysis; MicroRNAs; Phosphoglycerate Kinase; RNA, Long Noncoding; Stomach Neoplasms
PubMed: 37821504
DOI: 10.1038/s41598-023-43744-0 -
RNA (New York, N.Y.) Nov 2022About three decades ago, researchers suggested that metabolic enzymes participate in cellular processes that are unrelated to their catalytic activity, and the term... (Review)
Review
About three decades ago, researchers suggested that metabolic enzymes participate in cellular processes that are unrelated to their catalytic activity, and the term "moonlighting functions" was proposed. Recently developed advanced technologies in the field of RNA interactome capture now unveil the unexpected RNA binding activity of many metabolic enzymes, as exemplified here for the enzymes of glycolysis. Although for most of these proteins a precise binding mechanism, binding conditions, and physiological relevance of the binding events still await in-depth clarification, several well explored examples demonstrate that metabolic enzymes hold crucial functions in post-transcriptional regulation of protein synthesis. This widely conserved RNA-binding function of glycolytic enzymes plays major roles in controlling cell activities. The best explored examples are glyceraldehyde 3-phosphate dehydrogenase, enolase, phosphoglycerate kinase, and pyruvate kinase. This review summarizes current knowledge about the RNA-binding activity of the ten core enzymes of glycolysis in plant, yeast, and animal cells, its regulation and physiological relevance. Apparently, a tight bidirectional regulation connects core metabolism and RNA biology, forcing us to rethink long established functional singularities.
Topics: Animals; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Phosphoglycerate Kinase; Pyruvate Kinase; RNA; Saccharomyces cerevisiae; Transcription, Genetic
PubMed: 35973722
DOI: 10.1261/rna.079210.122 -
Biodesign Research 2022All living organisms share similar reactions within their central metabolism to provide precursors for all essential building blocks and reducing power. To identify...
All living organisms share similar reactions within their central metabolism to provide precursors for all essential building blocks and reducing power. To identify whether alternative metabolic routes of glycolysis can operate in , we complementarily employed design, rational engineering, and adaptive laboratory evolution. First, we used a genome-scale model and identified two potential pathways within the metabolic network of this organism replacing canonical Embden-Meyerhof-Parnas (EMP) glycolysis to convert phosphosugars into organic acids. One of these glycolytic routes proceeds via methylglyoxal and the other via serine biosynthesis and degradation. Then, we implemented both pathways in strains harboring defective EMP glycolysis. Surprisingly, the pathway via methylglyoxal seemed to immediately operate in a triosephosphate isomerase deletion strain cultivated on glycerol. By contrast, in a phosphoglycerate kinase deletion strain, the overexpression of methylglyoxal synthase was necessary to restore growth of the strain. Furthermore, we engineered the "serine shunt" which converts 3-phosphoglycerate via serine biosynthesis and degradation to pyruvate, bypassing an enolase deletion. Finally, to explore which of these alternatives would emerge by natural selection, we performed an adaptive laboratory evolution study using an enolase deletion strain. Our experiments suggest that the evolved mutants use the serine shunt. Our study reveals the flexible repurposing of metabolic pathways to create new metabolite links and rewire central metabolism.
PubMed: 37850128
DOI: 10.34133/2022/9859643 -
Genomics, Proteomics & Bioinformatics Aug 2022As a novel post-translational modification (PTM), lysine 2-hydroxyisobutyrylation (Khib) is considered to regulate gene transcriptional activities in eukaryotic cells;...
As a novel post-translational modification (PTM), lysine 2-hydroxyisobutyrylation (Khib) is considered to regulate gene transcriptional activities in eukaryotic cells; however, the functions of Khib-modified proteins in plants remain unknown. Here, we report that Khib is an evolutionarily-conserved PTM in wheat and its progenitors. A total of 3348 Khib sites on 1074 proteins are identified in common wheat (Triticum aestivum L.) by using affinity purification and mass spectroscopy of 2-hydroxyisobutyrylome. Bioinformatic data indicate that Khib-modified proteins participate in a wide variety of biological and metabolic pathways. Immunoprecipitation confirms that Khib-modified proteins are present endogenously. A comparison of Khib and other main PTMs shows that Khib-modified proteins are simultaneously modified by multiple PTMs. Using mutagenesis experiments and co-immunoprecipitation assays, we demonstrate that Khib on K206 of phosphoglycerate kinase (PGK) is a key regulatory modification for its enzymatic activity, and mutation on K206 affects the interactions of PGK with its substrates. Furthermore, Khib modification of low-molecular-weight proteins is a response to the deacetylase inhibitors nicotinamide and trichostatin. This study provides evidence to promote our current understanding of Khib in wheat plants, including the cooperation between Khib and its metabolic regulation.
Topics: Triticum; Histones; Protein Processing, Post-Translational; Proteome; Mass Spectrometry
PubMed: 33581340
DOI: 10.1016/j.gpb.2020.06.008 -
AIMS Neuroscience 2020Since formulation of the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis in 1994, the hypothesis has provoked criticism and debate. Our review does not criticise, but... (Review)
Review
Since formulation of the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis in 1994, the hypothesis has provoked criticism and debate. Our review does not criticise, but rather integrates experimental data characterizing proton-linked monocarboxylate transporters (MCTs) into the ANLS. MCTs have wide substrate specificity and are discussed to be in protein complex with a proton donor (PD). We particularly focus on the proton-driven transfer of l-lactic acid (l-lacH) and pyruvic acid (pyrH), were PDs link MCTs to a flow of energy. The precise nature of the PD predicts the activity and catalytic direction of MCTs. By doing so, we postulate that the MCT4·phosphoglycerate kinase complex exports and at the same time in the same astrocyte, MCT1·carbonic anhydrase II complex imports monocarboxylic acids. Similarly, neuronal MCT2 preferentially imports pyrH. The repertoire of MCTs in astrocytes and neurons allows them to communicate via monocarboxylic acids. A change in imported pyrH/l-lacH ratio in favour of l-lacH encodes signals stabilizing the transit of glucose from astrocytes to neurons. The presented astrocyte neuron communication hypothesis has the potential to unite the community by suggesting that the exchange of monocarboxylic acids paves the path of glucose provision.
PubMed: 32607414
DOI: 10.3934/Neuroscience.2020007 -
Frontiers in Bioscience (Landmark... Mar 2024Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5'-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1's expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.
Topics: Humans; Adenosine; Adenosine Triphosphate; Cell Line, Tumor; Colonic Neoplasms; Phosphoglycerate Kinase; Phosphorylation
PubMed: 38538272
DOI: 10.31083/j.fbl2903092