Effect of pH on the Kinetics of Frog Muscle Phosphofructokinase

Trivedi, Bakula; Danforth, William H.

doi:10.1016/s0021-9258(18)99819-4

Cited by 600 publications

(63 citation statements)

References 11 publications

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“…Kinetic parameters were generated by nonlinear regression analysis using Prism (GraphPad Software) and are the mean of a minimum of three measurements from two independent preparations of protein. One unit of activity was defined as the amount of enzyme that catalyzed the formation of 1 mmol of fructose 1,6-bisphosphate per min at 25 C. Assays for PFKM were performed at pH 7.0 due to the pH-dependence of ATP inhibition (Trivedi and Danforth, 1966).…”

Section: Generation Of Recombinant Pfk1 and In Vitro Kinase Assaysmentioning

confidence: 99%

Selective activation of PFKL suppresses the phagocytic oxidative burst

Amara¹,

Cooper

Voronkova

et al. 2021

Cell

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Section: Generation Of Recombinant Pfk1 and In Vitro Kinase Assaysmentioning

confidence: 99%

Selective activation of PFKL suppresses the phagocytic oxidative burst

Amara¹,

Cooper

Voronkova

et al. 2021

Cell

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“…Lactate is secreted in the extracellular environment, favouring its acidification, which is a phenomenon associated with cancer invasiveness, aggressiveness, angiogenesis, suppression of the immune response, and resistance to therapies [ 49 , 50 ]. Importantly, the concomitantly decreased mitochondrial functioning favours the establishment of an alkaline cytosolic pH, a condition enhancing PFK1 activity [ 8 , 51 ]. Moreover, the downregulation of oxidative metabolism limits the production of reactive oxygen species (ROS) in an adequate range with active proliferation [ 52 ], while the limited synthesis of ATP and citrate avoids the negative allosteric inhibition exercised by these molecules on PFK1 and PFK2 [ 8 ].…”

Section: The Central Role Of Citrate In the Warburg Effectmentioning

confidence: 99%

“…Here, lactate is converted into pyruvate by a reverse LDH-A reaction, and in turn pyruvate fuels the TCA cycle to produce energy and sustain biosynthesis [ 107 , 108 ]. In this setting, cancer cells chronically exposed to extracellular acidosis (due, for example, to excess protons secreted by glycolytic cancer cells that saturate bicarbonate buffer) would reprogram their metabolism, arresting glycolysis (proton H + is a well-known inhibitor of PFK1 [ 8 , 51 ]), and enhancing reductive carboxylation of glutamine sustaining FAS and promoting FAO [ 109 ]. The latter pathway provides acetyl-CoA for the functioning of the TCA cycle and for the acetylation of mitochondrial proteins, particularly of complex I, this process restraining ATP and ROS production [ 109 ].…”

Section: The Central Place Of Citrate In Cancer Cells Relying On Oxidative Metabolismmentioning

confidence: 99%

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

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“…However, under anaerobic conditions, cells are unable to rely on oxidative phosphorylation to balance their redox state, and pyruvate is preferentially converted to lactic acid through an enzymatic reaction catalyzed by cytosolic lactate dehydrogenase (LDH) (18). Within cells, lactic acid almost completely dissociates to lactate and H + , and lactic acid accumulation leads to acidification of the cytoplasm and potent inhibition of further glycolysis (18,19). As such, proper physiological functioning depends on the efflux of lactate out of the cell, and transport across mitochondrial and cellular membranes requires MCTs.…”

Section: Lactate Pathwaymentioning

confidence: 99%

Harnessing Lactate Metabolism for Radiosensitization

et al. 2021

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Cancer cells rewire their metabolism to promote cell proliferation, invasion, and metastasis. Alterations in the lactate pathway have been characterized in diverse cancers, correlate with outcomes, and lead to many downstream effects, including decreasing oxidative stress, promoting an immunosuppressive tumor microenvironment, lipid synthesis, and building chemo- or radio-resistance. Radiotherapy is a key modality of treatment for many cancers and approximately 50% of patients with cancer will receive radiation for cure or palliation; thus, overcoming radio-resistance is important for improving outcomes. Growing research suggests that important molecular controls of the lactate pathway may serve as novel therapeutic targets and in particular, radiosensitizers. In this mini-review, we will provide an overview of lactate metabolism in cancer, discuss three important contributors to lactate metabolism (lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier), and present data that inhibition of these three pathways can lead to radiosensitization. Future research is needed to further understand critical regulators of lactate metabolism and explore clinical safety and efficacy of inhibitors of lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier alone and in combination with radiation.

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Effect of pH on the Kinetics of Frog Muscle Phosphofructokinase

Cited by 600 publications

References 11 publications

Selective activation of PFKL suppresses the phagocytic oxidative burst

Selective activation of PFKL suppresses the phagocytic oxidative burst

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Harnessing Lactate Metabolism for Radiosensitization

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