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Kidney International Jan 2023Acute kidney injury (AKI) is a worldwide public health problem characterized by excessive inflammation with no specific therapy in clinic. Inflammation is not only a...
Acute kidney injury (AKI) is a worldwide public health problem characterized by excessive inflammation with no specific therapy in clinic. Inflammation is not only a feature of AKI but also an essential promoter for kidney deterioration. Phosphoglycerate mutase 5 (PGAM5) was up-regulated and positively correlated with kidney dysfunction in human biopsy samples and mouse kidneys with AKI. PGAM5 knockout in mice significantly alleviated ischemia/reperfusion-induced kidney injury, mitochondrial abnormality and production of inflammatory cytokines. Elevated PGAM5 was found to be mainly located in kidney tubular epithelial cells and was also related to inflammatory response. Knockdown of PGAM5 inhibited the hypoxia/reoxygenation-induced cytosolic release of mitochondrial DNA (mtDNA) and binding of mtDNA with the cellular DNA receptor cGAS in cultured cells. cGAS deficiency also attenuated the inflammation and kidney injury in AKI. Mechanistically, as a protein phosphatase, PGAM5 was able to dephosphorylate the pro-apoptotic protein Bax and facilitate its translocation to mitochondrial membranes, and then initiate increased mitochondrial membrane permeability and release of mtDNA. Leaked mtDNA recognized by cGAS then initiated its downstream-coupled STING pathway, a component of the innate immune system that functions to detect the presence of cytosolic DNA. Thus, our results demonstrated mtDNA release induced by PGAM5-mediated Bax dephosphorylation and the activation of cGAS-STING pathway as critical determinants of inflammation and kidney injury. Hence, targeting this axis may be useful for treating AKI.
Topics: Humans; Mice; Animals; DNA, Mitochondrial; Apoptosis Regulatory Proteins; Phosphoglycerate Mutase; bcl-2-Associated X Protein; Acute Kidney Injury; Inflammation; Reperfusion Injury; Nucleotidyltransferases
PubMed: 36089186
DOI: 10.1016/j.kint.2022.08.022 -
Cell Metabolism Dec 2019Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like...
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.
Topics: Actins; Animals; Anthracenes; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Enzyme Inhibitors; Female; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Phosphoglycerate Mutase; Sulfonamides
PubMed: 31607564
DOI: 10.1016/j.cmet.2019.09.014 -
IUBMB Life Oct 2019Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to... (Review)
Review
Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer-specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.
Topics: Cell Proliferation; Glyceric Acids; Glycolysis; Humans; Molecular Targeted Therapy; Neoplasms; Phosphoglycerate Mutase
PubMed: 31169978
DOI: 10.1002/iub.2100 -
Aging Cell Feb 2022Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced,...
Decline in ovarian reserve with aging is associated with reduced fertility and the development of metabolic abnormalities. Once mitochondrial homeostasis is imbalanced, it may lead to poor reproductive cell quality and aging. However, Phosphoglycerate translocase 5 (PGAM5), located in the mitochondrial membrane, is associated with necroptosis, apoptosis, and mitophagy, although the underlying mechanisms associated with ovarian aging remain unknown. Therefore, we attempted to uncover whether the high phosphoglycerate mutant enzyme family member 5 (PGAM5) expression is associated with female infertility in cumulus cells, and aims to find out the underlying mechanism of action of PGAM5. We found that PGAM5 is highly expressed and positively associated with aging, and has the potential to help maintain and regulate mitochondrial dynamics and metabolic reprogramming in aging granulosa cells, ovaries of aged female mice, and elderly patients. PGAM5 undergoes activation in the aging group and translocated to the outer membrane of mitochondria, co-regulating DRP1; thereby increasing mitochondrial fission. A significant reduction in the quality of mitochondria in the aging group, a serious imbalance, and a significant reduction in energy, causing metabolism shift toward glycolysis, were also reported. Since PGAM5 is eliminated, the mitochondrial function and metabolism of aging cells are partially reversed. A total of 70 patients undergoing in vitro fertilization (IVF) treatment were recruited in this clinical study. The high expression of PGAM5 in the cumulus cells is negatively correlated with the pregnancy rate of infertile patients. Hence, PGAM5 has immense potential to be used as a diagnostic marker.
Topics: Aged; Animals; Family; Female; Humans; Mice; Mitochondrial Dynamics; Mitochondrial Proteins; Oocytes; Phosphoglycerate Mutase; Phosphoprotein Phosphatases; Pregnancy
PubMed: 34995407
DOI: 10.1111/acel.13546 -
Drug Resistance Updates : Reviews and... May 2023Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the...
A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.
Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.
Topics: Humans; Erlotinib Hydrochloride; Lung Neoplasms; Interleukin-6; Phosphoglycerate Mutase; Drug Resistance, Neoplasm; Adenocarcinoma of Lung; ErbB Receptors; Signal Transduction; Protein Kinase Inhibitors; Mutation; Cell Line, Tumor; Janus Kinase 2
PubMed: 36990047
DOI: 10.1016/j.drup.2023.100957 -
International Immunopharmacology Mar 2023Spinal cord injury (SCI) is a high incidence worldwide that causes a heavy physical and psychological burden to patients. It is urgent to further reveal the pathological...
Spinal cord injury (SCI) is a high incidence worldwide that causes a heavy physical and psychological burden to patients. It is urgent to further reveal the pathological mechanism and effective treatment of SCI. Mitochondrial dysfunction plays an important role in the disease progression of SCI. As a mitochondrial membrane protein, phosphoglycerate mutase 5 (PGAM5) is mainly involved in mitochondrial function and mitosis to modulate cellular physiological functions, but the roles of PGAM5 in spinal tissues remain to be unreported after SCI. The purpose of this study was to evaluate the role of PGAM5 in SCI mice and its relationship with neuroinflammation. The results showed that the mitochondrial membrane protein PGAM5 was involved in microglia activation after SCI, and PGAM5 deletion could improve mitochondrial dysfunction (including abnormal mtDNA, ATP synthases, and ATP levels, Cyt C expression, and ROS and rGSH levels) in spinal cord tissue after SCI, Arg1/iNOS mRNA level, iNOS expression, and pro-inflammatory cytokines TNF-α, IL-1β, and IL-18 levels. In vitro, HO increased TNF-α, IL-1β, and IL-18 levels in BV2 cells, and PGAM5-sh and Nrf2 activators significantly reversed HO-induced iNOS expression and proinflammatory cytokine production. Furthermore, IP/Western blotting results revealed that PGAM5-sh treatment significantly reduced the interaction of PGAM5 with Nrf2 and enhanced the nuclear translocation of Nrf2 in BV2 cells. The data suggested that PGAM5 was involved in the cascade of oxidative stress and inflammatory response in microglia via facilitating the expression level of Nrf2 in the nucleus after SCI. It provided a reference for clarifying the pathological mechanism and therapeutic target of SCI.
Topics: Animals; Mice; Adenosine Triphosphate; Hydrogen Peroxide; Interleukin-18; Mitochondria; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Phosphoglycerate Mutase; Spinal Cord; Spinal Cord Injuries; Tumor Necrosis Factor-alpha
PubMed: 36773566
DOI: 10.1016/j.intimp.2023.109773 -
Microbes and Infection 2020Stenotrophomonas maltophilia biofilm formation is of increasing medical concern, particularly for lung infections. However, the molecular mechanisms facilitating the...
Stenotrophomonas maltophilia biofilm formation is of increasing medical concern, particularly for lung infections. However, the molecular mechanisms facilitating the biofilm lifestyle in S. maltophilia are poorly understood. We generated and screened a transposon mutant library for mutations that lead to altered biofilm formation compared to wild type. One of these mutations, in the gene for glycolytic enzyme phosphoglycerate mutase (gpmA), resulted in impaired attachment on abiotic and biotic surfaces. As adherence to a surface is the initial step in biofilm developmental processes, our results reveal a unique factor that could affect S. maltophilia biofilm initiation and, possibly, subsequent development.
Topics: Bacterial Adhesion; Bacterial Proteins; Biofilms; Cells, Cultured; Epithelial Cells; Humans; Mutation; Phosphoglycerate Mutase; Plastics; Stenotrophomonas maltophilia
PubMed: 31430538
DOI: 10.1016/j.micinf.2019.08.001 -
Parasite (Paris, France) 2022Schistosomiasis is a debilitating parasitic disease caused by intravascular flatworms called schistosomes (blood flukes) that affects >200 million people worldwide....
Schistosomiasis is a debilitating parasitic disease caused by intravascular flatworms called schistosomes (blood flukes) that affects >200 million people worldwide. Proteomic analysis has revealed the surprising presence of classical glycolytic enzymes - typically cytosolic proteins - located on the extracellular surface of the parasite tegument (skin). Immunolocalization experiments show that phosphoglycerate mutase (PGM) is widely expressed in parasite tissues and is highly expressed in the tegument. We demonstrate that live Schistosoma mansoni parasites express enzymatically active PGM on their tegumental surface. Suppression of PGM using RNA interference (RNAi) diminishes S. mansoni PGM (SmPGM) gene expression, protein levels, and surface enzyme activity. Sequence comparisons place SmPGM in the cofactor (2,3-bisphosphoglycerate)-dependent PGM (dPGM) family. We have produced recombinant SmPGM (rSmPGM) in an enzymatically active form in Escherichia coli. The Michaelis-Menten constant (K) of rSmPGM for its glycolytic substrate (3-phosphoglycerate) is 0.85 mM ± 0.02. rSmPGM activity is inhibited by the dPGM-specific inhibitor vanadate. Here, we show that rSmPGM not only binds to plasminogen but also promotes its conversion to an active form (plasmin) in vitro. This supports the hypothesis that host-interactive tegumental proteins (such as SmPGM), by enhancing plasmin formation, may help degrade blood clots around the worms in the vascular microenvironment and thus promote parasite survival in vivo.
Topics: Animals; Fibrinolysin; Host-Parasite Interactions; Humans; Phosphoglycerate Mutase; Proteomics; Schistosoma mansoni; Schistosomiasis
PubMed: 36083036
DOI: 10.1051/parasite/2022042 -
Philosophical Transactions of the Royal... Jun 1981The structure of yeast phosphoglycerate mutase determined by X-ray crystallographic and amino acid sequence studies has been interpreted in terms of the chemical,... (Review)
Review
The structure of yeast phosphoglycerate mutase determined by X-ray crystallographic and amino acid sequence studies has been interpreted in terms of the chemical, kinetic and mechanistic observations made on this enzyme. There are two histidine residues at the active site, with imidazole groups almost parallel to each other and approximately 0.4 nm apart, positioned close to the 2 and 3 positions of the substrate. The simplest interpretation of the available information suggests that a ping-pong type mechanism operates in which at least one of these histidine residues participates in the phosphoryl transfer reaction. The flexible C-terminal region also plays an important role in the enzymic reaction.
Topics: Amino Acid Sequence; Animals; Binding Sites; Catalysis; Chemical Phenomena; Chemistry; Kinetics; Macromolecular Substances; Models, Biological; Models, Molecular; Phosphoglycerate Mutase; Phosphotransferases; X-Ray Diffraction
PubMed: 6115412
DOI: 10.1098/rstb.1981.0066 -
Archives of Microbiology Jun 2023Candida albicans colonizes oral tissues and causes infectious diseases. Colonization of C. albicans on the oral mucosa and tooth enamel surfaces is established via the...
Candida albicans colonizes oral tissues and causes infectious diseases. Colonization of C. albicans on the oral mucosa and tooth enamel surfaces is established via the interaction between C. albicans adhesins and salivary proteins, forming a film on the oral tissues. Deleted in malignant brain tumors 1 (DMBT1), also known as salivary agglutinin or gp-340, belongs to the scavenger receptor cysteine-rich (SRCR) superfamily. In the oral cavity, immobilized DMBT1 on oral tissues causes microbial adherence. Recently, we demonstrated that C. albicans binds to DMBT1 and isolated a 25-kDa C. albicans adhesin involved in the interaction with the binding domain of DMBT1, namely, SRCRP2. In the present study, we searched for additional DMBT1-binding adhesins in C. albicans. The component isolated here had a molecular mass of 29 kDa and was found to be phosphoglycerate mutase (Gpm1). Isolated Gpm1 inhibited C. albicans binding to SRCRP2 and directly bound to SRCRP2 in a dose-dependent manner. Gpm1 localization on the C. albicans cell wall surface was confirmed by immunostaining. These results suggest that surface-expressed Gpm1 functions as an adhesin for the establishment of C. albicans cells on the oral mucosa and tooth enamel by binding to DMBT1.
Topics: Candida albicans; Phosphoglycerate Mutase; Adhesins, Bacterial; Cell Membrane; Cell Wall
PubMed: 37316743
DOI: 10.1007/s00203-023-03605-w