Functional Linkage of Adenine Nucleotide Binding Sites in Mammalian Muscle 6-Phosphofructokinase

Brüser, Antje; Kirchberger, Jürgen; Kloos, Marco; Sträter, Norbert; Schöneberg, Torsten

doi:10.1074/jbc.m112.347153

Cited by 26 publications

(28 citation statements)

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“…The decrease in nucleotide triphosphates in yap −/− mutants coincided with an increase in adenosine monophosphate (AMP), guanosine monophosphate (GMP), cytidine monophosphate (CMP), and uridine monophosphate (UMP) (Appendix Fig S5B). Surprisingly, we observed an increase in FBP levels in yap −/− mutant embryos; however, this may be due to allosteric activation of phosphofructokinase (PFK) activity by elevated AMP (Bruser et al , ). Collectively, the decrease in glycolytic intermediates and concomitant increase in nucleotide monophosphates could be a manifestation of energetic stress, caused by abnormal glucose metabolism.…”

Section: Resultsmentioning

confidence: 79%

“…ª 2018 The Authors The EMBO Journal 37: e100294 | 2018 embryos; however, this may be due to allosteric activation of phosphofructokinase (PFK) activity by elevated AMP (Bruser et al, 2012). Collectively, the decrease in glycolytic intermediates and concomitant increase in nucleotide monophosphates could be a manifestation of energetic stress, caused by abnormal glucose metabolism.…”

Section: Yap Regulates Glucose Metabolism and Nucleotide Biosynthesismentioning

confidence: 99%

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Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

et al. 2018

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The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap−/− mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap−/− mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose‐fueled nucleotide biosynthesis. Yap‐regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.

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Section: Resultsmentioning

confidence: 79%

Section: Yap Regulates Glucose Metabolism and Nucleotide Biosynthesismentioning

confidence: 99%

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

et al. 2018

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“…PFK1 activity was determined using an auxiliary enzyme assay (Brüser et al, 2012) with kinetic analysis using 200-µl reactions containing 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 10 mM MgCl 2 , 0.15 mM NADH, 0.675 U/ml aldolase, 5 U/ml triosephosphate isomerase, and 2 U/ml glycerol phosphate dehydrogenase. ATP and F6P were used as indicated.…”

Section: Pfk1 Activity Assaysmentioning

confidence: 99%

The Glycolytic Enzyme Phosphofructokinase-1 Assembles into Filaments

Webb

Dosey

Wittmann

et al. 2018

Biophysical Journal

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“…By contrast, PFK1 can be activated by metabolites which are elevated with energy deprivation. AMP (adenosine monophosphate) and ADP (adenosine diphosphate) activate PFK1 via a binding site that is dependent upon the amino acids Ser 377, Lys 678, Asn 341 (Bruser et al , 2012). …”

Section: Phosphofructokinase 1 (Pfk1) Allosteric Regulationmentioning

confidence: 99%

Stress eating and tuning out: Cancer cells re-wire metabolism to counter stress

Stine¹,

Dang²

2013

Critical Reviews in Biochemistry and Molecular Biology

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Cancer cells reprogram metabolism to maintain rapid proliferation under often stressful conditions. Glycolysis and glutaminolysis are two central pathways that fuel cancer metabolism. Allosteric regulation and metabolite driven post-translational modifications of key metabolic enzymes allow cancer cells glycolysis and glutaminolysis to respond to changes in nutrient availability and the tumor microenvironment. While increased aerobic glycolysis (the Warburg effect) has been a noted part of cancer metabolism for over 80 years, recent work has shown that the elevated levels of glycolytic intermediates are critical to cancer growth and metabolism due to their ability to feed into the anabolic pathways branching off glycolysis such as the pentose phosphate pathway and serine biosynthesis pathway. The key glycolytic enzymes phosphofructokinase-1 (PFK1), pyruvate kinase (PKM2) and phosphoglycerate mutase 1 (PGAM1) are regulated by upstream and downstream metabolites to balance glycolytic flux with flux through anabolic pathways. Glutamine regulation is tightly controlled by metabolic intermediates that allosterically inhibit and activate glutamate dehydrogenase, which fuels the tricarboxylic acid cycle by converting glutamine derived glutamate to α-ketoglutarate. The elucidation of these key allosteric regulatory hubs in cancer metabolism will be essential for understanding and predicting how cancer cells will respond to drugs that target metabolism. Additionally, identification of the structures involved in allosteric regulation will inform the design of anti-metabolism drugs which bypass the off-target effects of substrate mimics. Hence, this review aims to provide an overview of allosteric control of glycolysis and glutaminolysis.

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Functional Linkage of Adenine Nucleotide Binding Sites in Mammalian Muscle 6-Phosphofructokinase

Cited by 26 publications

References 28 publications

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

The Glycolytic Enzyme Phosphofructokinase-1 Assembles into Filaments

Stress eating and tuning out: Cancer cells re-wire metabolism to counter stress

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