Phosphofructokinase

Uyeda, Kosaku

doi:10.1002/9780470122938.ch4

Cited by 246 publications

(73 citation statements)

References 219 publications

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“…In most cases, the conclusions were drawn from kinetic measurements alone, since in most eukaryotic systems each phosphofructokinase protomer has multiple binding sites for both substrates. Conclusions hence are complicated by the fact that a given substrate can also act as an inhibitor or an activator of the enzymatic reaction [14,15].…”

Section: Catalytic Mechanismmentioning

confidence: 99%

Regulatory Properties of Phosphofructokinase 2 from Escherichia coli

Kotlarz

Buc

1981

European Journal of Biochemistry

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Escherichia coli K12 contains two phosphofructokinases: phosphofructokinase 1, the most studied one, appears to behave as an allosteric enzyme, while phosphofructokinase 2 presents the features of a Michaelian enzyme.We show in the present paper that, in fact, phosphofructokinase 2 also presents some regulatory properties in vitro: at high concentrations, ATP is an inhibitor of phosphofructokinase 2 and it provokes the tetramerization of the dimeric native enzyme.The binding of the two substrates to phosphofructokinase 2 is sequential and ordered as for phosphofructokinase 1, but in the former case fructose 6-phosphate is the first substrate to be bound and ADP the first product to be released. Each dimer of phosphofructokinase 2 binds two molecules of fructose 6-phosphate but only one molecule of the product fructose 1,6-bisphosphate.Although both phosphofructokinases of E. coli K12 present regulatory properties in vitro, the mechanism of regulation of the activity of the two enzymes is strikingly different, It can be asked whether or not these mechanisms operate in vivo.

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Section: Catalytic Mechanismmentioning

confidence: 99%

Regulatory Properties of Phosphofructokinase 2 from Escherichia coli

Kotlarz

Buc

1981

European Journal of Biochemistry

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“…Phosphofructokinase (PFK) is a key regulator of glycolysis and serves as the rate-limiting glycolytic enzyme in metabolism (51). This enzyme has several isoforms (52), including PFK-M, -L, and -P. To isolate the effects of glycolysis on retinal degeneration from the effects of Sirt6 deficiency, we injected a lentivirus expressing shRNA for one of the 3 isoforms into Pde6b H620Q/H620Q mice.…”

Section: Pfk Shrna Viral Knockdown Exacerbates Retinal Degeneration Imentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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“…The eukaryotic enzyme has complex regulatory properties that are mediated by the interaction of allosteric ligands with a number of distinct binding sites and presents one of the principal regulatory steps in glycolysis (4,30). Eukaryotic phosphofructo-1-kinases (PFK1s) are more than twice the size of prokaryotic PFKs and are under regulatory control by a wider array of effectors than seen with the simpler bacterial enzymes.…”

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confidence: 99%

Citrate Inhibition-Resistant Form of 6-Phosphofructo-1-Kinase fromAspergillus niger

Mlakar

Legiša

2006

Appl Environ Microbiol

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Two forms of Aspergillus niger 6-phosphofructo-1-kinase (PFK1) have been described recently, the 85-kDa native enzyme and 49-kDa shorter fragment that is formed from the former by posttranslational modification. So far, kinetic characteristics have never been determined on the enzyme purified to near homogeneity. For the first time, kinetic parameters were determined for individual enzymes with respect to citrate inhibition. The native 85-kDa enzyme was found to be moderately inhibited by citrate, with the K i value determined to be 1.5 mM, in the system with 5 mM Mg 2؉ ions, while increasing magnesium concentrations relieved the negative effect of citrate. An identical inhibition coefficient was determined also in the presence of ammonium ions, although ammonium acted as a strong activator of enzyme activity. On the other hand, the shorter fragment of PFK1 proved to be completely resistant to inhibition by citrate. Allosteric citrate binding sites were most probably lost after the truncation of the C-terminal part of the native protein, in which region some binding sites for inhibitor are known to be located. At near physiological conditions, characterized by low fructose-6-phosphate concentrations, a much higher efficiency of the shorter fragment was observed during an in vitro experiment. Since the enzyme became more susceptible to the positive control by specific ligands, while the negative control was lost after posttranslational modification, the shorter PFK1 fragment seems to be the enzyme most responsible for generating undisturbed metabolic flow through glycolysis in A. niger cells.Phosphofructokinase (EC 2.7.1.11) catalyzes the first essentially irreversible reaction of glycolysis, the phosphorylation of fructose-6-phosphate to form fructose-1,6-bisphosphate using MgATP as the phosphoryl donor and releasing MgADP as a by-product. The eukaryotic enzyme has complex regulatory properties that are mediated by the interaction of allosteric ligands with a number of distinct binding sites and presents one of the principal regulatory steps in glycolysis (4, 30). Eukaryotic phosphofructo-1-kinases (PFK1s) are more than twice the size of prokaryotic PFKs and are under regulatory control by a wider array of effectors than seen with the simpler bacterial enzymes. Sequencing data of amino acid residues indicated an evolutionary relationship between bacterial and eukaryotic PFKs that suggests duplication, tandem fusion, and divergence of catalytic and effector binding sites of a prokaryotic ancestor to yield in eukaryotes a total of six organic ligand binding sites (22). One of these allosteric ligands is citrate, which acts as a potent allosteric inhibitor of the eukaryotic PFK enzymes. Studies on citrate allosteric sites of rabbit muscle PFK concluded that they developed from the phosphoenolpyruvate (PEP)/ADP allosteric site of Escherichia coli PFK and are scattered both on N-terminal and C-terminal parts of the enzyme (11, 18). On the other hand, the strict conservation between active site residues in the N-termi...

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Phosphofructokinase

Cited by 246 publications

References 219 publications

Regulatory Properties of Phosphofructokinase 2 from Escherichia coli

Regulatory Properties of Phosphofructokinase 2 from Escherichia coli

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Citrate Inhibition-Resistant Form of 6-Phosphofructo-1-Kinase fromAspergillus niger

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