Regulation of mammalian muscle type 6‐phosphofructo‐1‐kinase and its implication for the control of the metabolism

Sola‐Penna, Mauro; Silva, Daniel da; Coelho, Wagner Santos; Marinho-Carvalho, Monica M.; Zancan, Patrícia

doi:10.1002/iub.393

Cited by 123 publications

(138 citation statements)

References 49 publications

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“…The major isoforms expressed in the heart are HK-1 and HK-2 (14,16). Similarly, there are three known PFK isoforms, PFK-M, PFK-L, and PFK-C (also known as PFK-P) (17).…”

Section: Introductionmentioning

confidence: 99%

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva¹,

Ausina²,

Alencar³

et al. 2012

IUBMB Life

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SummaryDiabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects.

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“…The major isoforms expressed in the heart are HK-1 and HK-2 (14,16). Similarly, there are three known PFK isoforms, PFK-M, PFK-L, and PFK-C (also known as PFK-P) (17).…”

Section: Introductionmentioning

confidence: 99%

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva¹,

Ausina²,

Alencar³

et al. 2012

IUBMB Life

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“…In particular, a role for O-GlcNAc modification has been described at Ser-529 of PFK1 (phosphofructokinase 1), which catalyzes the rate-limiting step of glycolysis to generate fructose 1,6-bisphosphate from fructose 6-phosphate (36). Ser-529 is vital for allosteric activation of PFK1 by fructose 1,6-bisphosphate (37). O-GlcNAcylation of PFK1 at Ser-529 inhibits its kinase activity in cancer cells, possibly resulting from the O-GlcNAc moiety blocking the binding of fructose 1,6-bisphosphate to PFK1 and disrupting activating oligomerization of PFK1 (36), leading to increased levels of glycolytic intermediates.…”

mentioning

confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

171

132

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O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

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“…On the other hand, the absence of both modulators also diminished the activity of the enzyme since ATP would be acting, in addition to negative allosteric modulator, as substrate in low concentrations, and AMP would be required for the enzymatic activity. In concordance with these results, in somatic and tumoral cells, it has been demonstrated that ATP has a dual effect on PFK, where the enzyme is activated at concentrations of 1 mM of ATP and inhibited at higher concentration (Leite et al, 2007;Zancan et al, 2007;Sola-Penna et al, 2010). Thus, PFK has two binding sites for ATP, a catalytic binding site (with a binding constant of ~0.15 mM) and an allosteric inhibitor binding site (with a binding constant of ~2.5 mM; Leite et al, 2007;Marinho-Carvalho et al, 2009;Marcondes et al, 2010;Al Hasawi et al, 2014 lactate production and oocyte nuclear maturation confirmed the inhibition of the enzyme during IVM and the relation between the pathway and the maturation process.…”

Section: Discussionmentioning

confidence: 60%

Regulation of key enzymes of glucose metabolism in bovine COCs

Gutnisky¹,

Breininger²,

Dalvit³

et al. 2017

Anim Reprod

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The aim of this work was to study the regulation of PFK 1 and G6PDH, two key enzymes involved in glucose metabolism in cumulus oocytecomplexes (COCs), and its relationship with the oocyte maturation process. It was observed that the activity of PFK 1 in the presence of ATP was inhibited whereas the addition of AMP increased the activity (P < 0.05). To verify the effect of the physiological modulators on the COC glycolytic pathway, the lactate production during IVM and the maturation rate were evaluated. In accordance with the enzymatic activity, the glycolytic activity evaluated by lactate production and the maturation rate diminished (P < 0.05) with the addition of ATP. While the AMP had a dose response effect on the lactate production, the maturation rate remained unaltered. It was observed that NADPH inhibited the activity of the G6PDH and the addition of NADP increased the activity of the enzyme (P < 0.05). To verify the effect of the physiological modulators on the COC pentose phosphate pathway (PPP), the proportion of colourless oocytes evaluated by brilliant cresyl blue (BCB) and the maturation rate were carried out. In presence of NADPH an inhibition (P < 0.05) on PPP and maturation rate was observed. On the other hand, NADP had no effect on PPP activity and maturation rate. The present study shows that the regulation of key enzymes of glucose metabolism in bovine COCs are regulated mainly by the energetic charge and the redox status. We also reported a tight relation between the activity of the PFK 1 and G6PDH enzymes, glycolytic and PPP activities and the oocyte maturation process.

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Regulation of mammalian muscle type 6‐phosphofructo‐1‐kinase and its implication for the control of the metabolism

Cited by 123 publications

References 49 publications

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Regulation of key enzymes of glucose metabolism in bovine COCs

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