-
Biochemistry and Biophysics Reports Sep 2023Although it was traditionally believed that gluconeogenesis enzymes were absent from cancers that did not originate in gluconeogenic organs, numerous investigations have... (Review)
Review
Although it was traditionally believed that gluconeogenesis enzymes were absent from cancers that did not originate in gluconeogenic organs, numerous investigations have shown that they are functionally expressed in a variety of tumors as mediators of shortened forms of Gluconeogenesis. One of the isomers of PEPCK, the first-rate limiting enzyme in gluconeogenesis, is PCK 1, which catalyzes the conversion of oxaloacetate (OAA) and GTP into PEP, CO2, and GDP. It is also known as PEPCK-C or PCK1, and it is cytosolic. Despite being paradoxical, it has been demonstrated that, in addition to its enzymatic role in normal metabolism, this enzyme also plays a role in tumors that arise in gluconeogenic and non-gluconeogenic organs. According to newly available research, it has metabolic and non-metabolic roles in tumor progression and development. Thus, this review will give insight into relationship, function, and mechanism in or with different types of cancer using contemporary findings.
PubMed: 37637941
DOI: 10.1016/j.bbrep.2023.101528 -
Plant Signaling & Behavior Dec 2022Plant organisms assimilate CO through the photosynthetic pathway, which facilitates in the synthesis of sugar for plant development. As environmental elements including... (Review)
Review
Plant organisms assimilate CO through the photosynthetic pathway, which facilitates in the synthesis of sugar for plant development. As environmental elements including water level, CO concentration, temperature and soil characteristics change, the plants may recruit series of genes to help adapt the hostile environments and challenges. C4 photosynthesis plants are an excellent example of plant evolutionary adaptation to diverse condition. Compared with C3 photosynthesis plants, C4 photosynthesis plants have altered leaf anatomy and new metabolism for CO capture, with multiple related enzymes such as phosphoenolpyruvate carboxylase (PEPCase), pyruvate orthophosphate dikinase (PPDK), NAD(P)-malic enzyme (NAD(P)-ME), NAD(P) - malate dehydrogenase (NAD(P)-MDH) and carbonic anhydrases (CA), identified to participate in the carbon concentrating mechanism (CCM) pathway. Recently, great achievements about C4 CCM-related genes have been made in the dissection of C3 plant development processes involving various stresses. In this review, we describe the functions of C4 CCM-related homologous genes in carbon and nitrogen metabolism in C3 plants. We further summarize C4 CCM-related homologous genes' functions in response to stresses in C3 plants. The understanding of C4 CCM-related genes' function in response to abiotic stress in plant is important to modify the crop plants for climate diversification.
Topics: Carbon; Carbon Dioxide; NAD; Phosphoenolpyruvate Carboxylase; Plants; Stress, Physiological
PubMed: 36102341
DOI: 10.1080/15592324.2022.2115634 -
FEBS Letters Feb 2023Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the reversible reaction of decarboxylation and phosphorylation of oxaloacetate (OAA) to generate phosphoenolpyruvate...
Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the reversible reaction of decarboxylation and phosphorylation of oxaloacetate (OAA) to generate phosphoenolpyruvate (PEP) and CO playing mainly a gluconeogenic role in green algae. We found two PEPCK isoforms in Chlamydomonas reinhardtii and we cloned, purified and characterised both enzymes. ChlrePEPCK1 is more active as decarboxylase than ChlrePEPCK2. ChlrePEPCK1 is hexameric and its activity is affected by citrate, phenylalanine and malate, while ChlrePEPCK2 is monomeric and it is regulated by citrate, phenylalanine and glutamine. We postulate that the two PEPCK isoforms found originate from alternative splicing of the gene or regulated proteolysis of the enzyme. The presence of these two isoforms would be part of a mechanism to finely regulate the biological activity of PEPCKs.
Topics: Phosphoenolpyruvate; Chlamydomonas reinhardtii; Phosphoenolpyruvate Carboxykinase (ATP); Protein Isoforms; Phenylalanine; Citrates
PubMed: 36708098
DOI: 10.1002/1873-3468.14590 -
Molecular Metabolism Dec 2022Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose...
OBJECTIVES
Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation.
METHODS
RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR.
RESULTS
We found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells.
CONCLUSIONS
We conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.
Topics: Adult; Animals; Humans; Mice; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Proliferation; Glucose; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Phosphoenolpyruvate; Phosphoenolpyruvate Carboxykinase (GTP); Receptors, Thyroid Hormone; Transcription Factors; Thyroid Hormones; Triiodothyronine; Insulin-Secreting Cells
PubMed: 36455788
DOI: 10.1016/j.molmet.2022.101646 -
Cancer Cell International Apr 2023Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme in gluconeogenesis. PCK1 is considered an anti-oncogene in several human cancers. In this study,...
Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme in gluconeogenesis. PCK1 is considered an anti-oncogene in several human cancers. In this study, we aimed to determine the functions of PCK1 in colorectal cancer (CRC). PCK1 expression in CRC tissues was tested by western blot and immunohistochemistry analyses and associations of PCK1 level with clinicopathological characteristics and disease survival evaluated. Further, we studied the effect of PCK1 on CRC cell proliferation and the underlying mechanisms. Our results show that PCK1 is expressed at significantly lower levels in CRC than in control tissues. High PCK1 expression was correlated with smaller tumor diameter and less bowel wall invasion (T stage). Overexpression and knockdown experiments demonstrated that PCK1 inhibits CRC cell growth both in vitro and in vivo. Mechanistically, PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454 and enhancing autophagy. Overall, our findings reveal a novel molecular mechanism involving PCK1 and autophagy, and highlight PCK1 as a promising candidate therapeutic target in CRC.
PubMed: 37062825
DOI: 10.1186/s12935-023-02894-x -
Genes & Diseases Jan 2023The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming. One of the most important... (Review)
Review
The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming. One of the most important cancer hallmarks, including aerobic glycolysis (the Warburg effect), the central carbon pathway, and multiple-branch metabolic pathway remodeling, enables tumor growth, progression, and metastasis. Phosphoenolpyruvate carboxykinase 1 (PCK1), a key rate-limiting enzyme in gluconeogenesis, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PCK1 expression in gluconeogenic tissues is tightly regulated during fasting. In tumor cells, PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment. Interestingly, PCK1 has an anti-oncogenic role in gluconeogenic organs (the liver and kidneys), but a tumor-promoting role in cancers arising from non-gluconeogenic organs. Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways. Aberrant PCK1 expression results in the activation of oncogenic pathways, accompanied by metabolic reprogramming, to maintain tumorigenesis. In this review, we summarize the mechanisms underlying PCK1 expression and regulation, and clarify the crosstalk between aberrant PCK1 expression, metabolic rewiring, and signaling pathway activation. In addition, we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.
PubMed: 37013052
DOI: 10.1016/j.gendis.2022.02.010 -
Tropical Parasitology 2023Cystic echinococcosis (CE), caused by , is a major zoonotic disease that causes significant human morbidity and mortality. This cosmopolitan disease is difficult to...
BACKGROUND
Cystic echinococcosis (CE), caused by , is a major zoonotic disease that causes significant human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat, and control. So far, crude extracts of hydatid cyst fluid containing antigen B or antigen 5 have been used as the primary antigenic source for its immunodiagnosis. The main issue is that it reacts with sera from people infected with other helminths. There is currently no standard, specific, or sensitive test for disease diagnosis, and no human vaccine has been reported.
AIMS AND OBJECTIVES
Considering the need for efficient immunization and/or immunodiagnosis, six antigens, antigen 5, antigen B, heat shock proteins such as Hsp-8 and Hsp-90, phosphoenolpyruvate carboxykinase, and tetraspanin-1, were chosen.
MATERIALS AND METHODS
Using various tools, T cell and B cell epitopes (promiscuous peptides) were predicted by targeting antigen 5, antigen B, heat shock proteins such as Hsp-8 and Hsp-90, phosphoenolpyruvate carboxykinase, and tetraspanin-1.
RESULTS
There are twelve promiscuous peptides with overlapping human leukocyte antigen (HLA) class-I, class-II, and conformational B cell epitopes. Such immunodominant peptides could be useful as subunit vaccines. Furthermore, six peptides specific for were also discovered, which may prove to be important markers in the diagnosis of CE, potentially preventing misdiagnosis and mismanagement.
CONCLUSION
These epitopes may be the most important vaccine targets in because they have the most promiscuous peptides and B cell epitopes, as well as the highest affinity for different alleles, as determined by docking scores. However, additional research using models is undertaken.
PubMed: 37415750
DOI: 10.4103/tp.tp_70_22 -
Metabolites Dec 2022Early detection of oral candidiasis is essential. However, most currently available methods are time-consuming and useful only for screening patients. Previous studies...
Early detection of oral candidiasis is essential. However, most currently available methods are time-consuming and useful only for screening patients. Previous studies on the relationship between oral candidiasis and saliva have focused on saliva volume and not on its components. Therefore, to clarify the effects of oral candidiasis on salivary metabolites, the relationship between salivary components and oral candidiasis was investigated by comparing the salivary metabolites of oral candidiasis patients and those not previously diagnosed with candidiasis. Forty-five participants visiting our university hospital were included and classified into two groups, the group and the control group, based on the detection test results. The unstimulated saliva was collected using the spitting method over 15 min, and the stimulated saliva was collected using the gum-chewing method over 10 min. The saliva volume was measured, and the saliva samples were frozen and analyzed metabolomically. Metabolome analysis revealed 51 metabolites with peak detection rates exceeding 50%. There was no significant difference in age and sex between the and control groups. In the group, five metabolites (tyrosine, choline, phosphoenolpyruvate, histidine, and 6-phosphogluconate) were significantly elevated in the unstimulated, two (octanoic acid and uridine monophosphate(UMP)) were significantly increased, and four (ornithine, butyrate, aminovalerate and aminolevulinate) were significantly decreased in the stimulated saliva. This study suggests the possibility of identifying metabolites specific to patients with oral candidiasis, which could aid prompt diagnosis.
PubMed: 36557332
DOI: 10.3390/metabo12121294 -
Journal of Clinical and Experimental... 2019Diabetes mellitus is a rising epidemic in most part of the world and is often associated with multiple organ disorders such as kidney, liver, and cardiovascular... (Review)
Review
Diabetes mellitus is a rising epidemic in most part of the world and is often associated with multiple organ disorders such as kidney, liver, and cardiovascular diseases. Liver is a major metabolic hub, and the metabolic disorders associated with diabetes result in liver dysfunctions culminating in spectrum of liver diseases such as fatty liver disorders, cirrhosis, and hepatocellular carcinoma. The intervention strategies to prevent diabetes-associated liver injury require an overall understanding of the key factors and molecular pathways which can be strategically targeted. The present review focuses on some of the key aspects of fatty acid metabolism, fetuin-A regulation, inflammatory pathways, and genetic factors associated with insulin resistance, dyslipidemia, hyperglycemia, oxidative stress, and so on involved in the nexus between diabetes and liver injury. Further recent interventions, pharmacological target, and newer therapeutic agents are discussed briefly for the better clinical management of diabetes-associated hepatic disorders.
PubMed: 31695251
DOI: 10.1016/j.jceh.2018.10.004 -
Frontiers in Molecular Biosciences 2022Peptidoglycan is a cross-linked polymer responsible for maintaining the bacterial cell wall integrity and morphology in Gram-negative and Gram-positive bacteria. The... (Review)
Review
Peptidoglycan is a cross-linked polymer responsible for maintaining the bacterial cell wall integrity and morphology in Gram-negative and Gram-positive bacteria. The peptidoglycan pathway consists of the enzymatic reactions held in three steps: cytoplasmic, membrane-associated, and periplasmic. The Mur enzymes (MurA-MurF) are involved in a cytoplasmic stage. The UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme is responsible for transferring the enolpyruvate group from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine (UNAG) to form UDP-N-acetylglucosamine enolpyruvate (EP-UNAG). Fosfomycin is a natural product analogous to PEP that acts on the MurA target enzyme via binding covalently to the key cysteine residue in the active site. Similar to fosfomycin, other MurA covalent inhibitors have been described with a warhead in their structure that forms a covalent bond with the molecular target. In MurA, the nucleophilic thiolate of Cys115 is pointed as the main group involved in the warhead binding. Thus, in this minireview, we briefly describe the main recent advances in the design of MurA covalent inhibitors.
PubMed: 35936791
DOI: 10.3389/fmolb.2022.889825