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BioRxiv : the Preprint Server For... Oct 2023Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer...
Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is a rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction and modest changes in PGK1 activity dramatically suppressed hypometabolic synapse dysfunction . Furthermore, PGK1 is cross-regulated by PARK7 (DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.
PubMed: 37873141
DOI: 10.1101/2023.10.10.561760 -
Pharmacological Research Nov 2023Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However,...
Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1α)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Histones; Hypoxia; Cell Transformation, Neoplastic; Neoplastic Stem Cells; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37865128
DOI: 10.1016/j.phrs.2023.106964 -
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 -
Frontiers in Plant Science 2023Southern corn rust (SCR) caused by Underw is a major disease leading to severe yield losses in China Summer Corn Belt. Using six multi-locus GWAS methods, we identified...
Southern corn rust (SCR) caused by Underw is a major disease leading to severe yield losses in China Summer Corn Belt. Using six multi-locus GWAS methods, we identified a set of SCR resistance QTNs from a diversity panel of 140 inbred lines collected from China Summer Corn Belt. Thirteen QTNs on chromosomes 1, 2, 4, 5, 6, and 8 were grouped into three types of allele effects and their associations with SCR phenotypes were verified by post-GWAS case-control sampling, allele/haplotype effect analysis. Relative resistance (RR) and relative susceptibility (RRs) catering to its inbred carrier were estimated from single QTN and QTN-QTN combos and epistatitic effects were estimated for QTN-QTN combos. By transcriptomic annotation, a set of candidate genes were predicted to be involved in transcriptional regulation (, transcription factor GTE4), phosphorylation (, phosphoglycerate kinase 2), and temperature stress response (, and ). The breeding implications of the above findings were discussed.
PubMed: 37810381
DOI: 10.3389/fpls.2023.1221395 -
Frontiers in Molecular Biosciences 2023Tatridin A (TatA) is a germacrane sesquiterpenoid containing one E-double bond and one Z-double bond in its 10-membered ring, which is fused to a...
Tatridin A (TatA) is a germacrane sesquiterpenoid containing one E-double bond and one Z-double bond in its 10-membered ring, which is fused to a 3-methylene-dihydrofuran-2-one moiety. Tatridin A bioactivity has been poorly investigated despite its interesting chemical structure. Here, a functional proteomic platform was adapted to disclose its most reliable targets in leukemia monocytic cells, and phosphoglycerate kinases were recognized as the most affine enzymes. Through a combination of limited proteolysis and molecular docking, it has been discovered that tatridin A interacts with the active domains of phosphoglycerate kinase 1, altering its hinge region, and it can be accountable for tatridin A inhibition potency on enzyme activity. A more detailed tatridin A biological profile showed that it is also fully active against gastric cancer cells, downregulating the mRNA levels of chemokine receptor 4 and β-catenin and inhibiting the invasiveness of living KATO III cells as a direct consequence of phosphoglycerate kinase 1 antagonism.
PubMed: 37767160
DOI: 10.3389/fmolb.2023.1212541 -
Microorganisms Aug 2023Gossypol, generally found in the roots, stems, leaves, and, especially, the seeds of cotton plants, is highly toxic to animals and humans, which inhibits the use of...
Gossypol, generally found in the roots, stems, leaves, and, especially, the seeds of cotton plants, is highly toxic to animals and humans, which inhibits the use of cotton stalks as a feed resource. Here, a promising fungal strain for biodegrading gossypol was successfully isolated from the soil of cotton stalk piles in Xinjiang Province, China, and identified as -YJ01 with the analysis of ITS. Initial gossypol of 250 mg·L could be removed by 97% within 96 h by YJ01, and initial gossypol of 150 mg·L could also be catalyzed by 98% or 99% within 36 h by the intracellular or extracellular crude enzymes of YJ01. Sucrose and sodium nitrate were found to be the optimal carbon and nitrogen sources for the growth of YJ01, and the optimal initial pH and inoculum size for the growth of YJ01 were 6.0 and 1%, respectively. To further elucidate the mechanisms underlying gossypol biodegradation by YJ01, the draft genome of YJ01 was sequenced using Illumina HiSeq, which is 31,566,870 bp in length with a GC content of 52.27% and a total of 9737 genes. Eight genes and enzymes were predicted to be involved in gossypol biodegradation. Among them, phosphoglycerate kinase, citrate synthase, and other enzymes are related to the energy supply process. With sufficient energy, β-1, 4-endo-xylanase may achieve the purpose of biodegrading gossypol. The findings of this study provide valuable insights into both the basic research and the application of -YJ01 in the biodegradation of gossypol in cotton stalks.
PubMed: 37763992
DOI: 10.3390/microorganisms11092148 -
Biomolecules Aug 2023A protein fold is defined as a structural arrangement of a secondary structure in a three-dimensional space. It would be interesting to know whether a particular fold...
A protein fold is defined as a structural arrangement of a secondary structure in a three-dimensional space. It would be interesting to know whether a particular fold can be assigned to certain features of the corresponding folding/unfolding transitions. To understand the underlying principles of the manifold folding transitions in more detail, single-molecule FRET is the method of choice. Taking the two-domain protein phosphoglycerate kinase (PGK) as an example, we investigated denaturant-induced unfolded states of PGK using the above method. For this purpose, different intramolecular distances within the two domains were measured. In addition to the known two-state transition, a transition with a compact folding intermediate was also identified in each of the two domains. Based on the structural homology of the domains (characterized by a Rossmann fold) and the striking similarity in the features of the measured distance changes during unfolding, clear evidence emerged that the underlying domain topology plays an important role in determining the observed structural changes.
PubMed: 37759680
DOI: 10.3390/biom13091280 -
MBio Oct 2023is a model filamentous fungus that can produce aflatoxins when it infects agricultural crops. This study evaluated the protein phosphatase 2C (PP2C) family as a...
is a model filamentous fungus that can produce aflatoxins when it infects agricultural crops. This study evaluated the protein phosphatase 2C (PP2C) family as a potential drug target with important physiological functions and pathological significance in . We found that two redundant PP2C phosphatases, Ptc1 and Ptc2, regulate conidia development, aflatoxin synthesis, autophagic vesicle formation, and seed infection. The target protein phosphoglycerate kinase 1 (PGK1) that interacts with Ptc1 and Ptc2 is essential to regulate metabolism and the autophagy process. Furthermore, Ptc1 and Ptc2 regulate the phosphorylation level of PGK1 S203, which is important for influencing aflatoxin synthesis. Our results provide a potential target for interdicting the toxicity of .
Topics: Aspergillus flavus; Protein Phosphatase 2C; Phosphoric Monoester Hydrolases; Aflatoxins; Autophagy
PubMed: 37754565
DOI: 10.1128/mbio.00977-23 -
Cell Research Nov 2023Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether...
Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.
Topics: Animals; Mice; Phosphoglycerate Dehydrogenase; Tumor Suppressor Protein p53; Carcinoma, Hepatocellular; Serine; Liver Neoplasms; Cell Line, Tumor
PubMed: 37726403
DOI: 10.1038/s41422-023-00874-4 -
Cell Communication and Signaling : CCS Sep 2023Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis.... (Review)
Review
Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis. This phenomenon is called the "Warburg effect". Phosphoglycerate kinase 1 (PGK1) is a key enzyme in aerobic glycolysis. PGK1 is involved in glucose metabolism as well as a variety of biological activities, including angiogenesis, EMT, mediated autophagy initiation, mitochondrial metabolism, DNA replication and repair, and other processes related to tumorigenesis and development. Recently, an increasing number of studies have proven that PGK1 plays an important role in cancer. In this manuscript, we discussed the effects of the structure, function, molecular mechanisms underlying PGK1 regulation on the initiation and progression of cancer. Additionally, PGK1 is associated with chemotherapy resistance and prognosis in tumour patients. This review presents an overview of the different roles played by PGK1 during tumorigenesis, which will help in the design of experimental studies involving PGK1 and enhance the potential for the use of PGK1 as a therapeutic target in cancer. Video Abstract.
Topics: Humans; Phosphoglycerate Kinase; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Autophagy
PubMed: 37723547
DOI: 10.1186/s12964-023-01256-4