Disease relevance of PFK1

• The deduced amino acid sequences showed: (i) 20% homology between the N- and the C-terminal halves of each subunit, (ii) 55% homology between the two subunits, and (iii) significant homologies to the PFK sequences from human and rabbit muscle (42%), Escherichia coli (34%), and Bacillus (36%) [1].
• Deficiency of muscle PFK (PFK-M), glycogenosis type VII (Tarui disease), is an autosomal recessive disorder characterized by an exertional myopathy and hemolytic syndrome [2].
• The phosphofructokinase from Spiroplasma citri, which has an Asp187, has been purified and its properties follow this pattern [3].
• Epitope mapping of a monoclonal antibody directed against the alpha-subunit of phosphofructokinase-1 from Saccharomyces cerevisiae by screening phage display libraries [4].

High impact information on PFK1

• The results agree with the predictions of an allosteric model for phosphofructokinase (EC 2.7.1.11; ATP:D-fructose-6-phosphate 1-phosphotransferase), which is the enzyme responsible for periodic operation of glycolysis [5].
• When the mRNAs are ordered with respect to the glycolytic pathway, two peaks of maximal induction are observed at phosphofructokinase and pyruvate kinase [6].
• By in vitro mutagenesis, we introduced this mutation in either PFK1 or PFK2 and found that the exchange in either subunit drastically reduced the sensitivity of the holoenzyme to ATP inhibition [7].
• A mutation in the PFK1 gene, encoding the larger -subunits, rendering the enzyme insensitive to allosteric inhibition by ATP was found to be caused by an exchange of proline 728 for a leucine residue [7].
• Yeast phosphofructokinase is a heterooctameric enzyme subject to a complex allosteric regulation [7].

Chemical compound and disease context of PFK1

• Experiments and calculations suggest that, in resting Escherichia coli cells, ethanol production and glucose uptake rates can be increased by 30% and 20%, respectively, by overexpression of a deregulated pyruvate kinase, while increase in phosphofructokinase expression levels has no effect on ethanol production and glucose uptake rates [8].
• Inorganic pyrophosphate: fructose-6-phosphate 1-phosphotransferase of the potato tuber is related to the major ATP-dependent phosphofructokinase of E. coli [9].

Biological context of PFK1

• The mutations are semidominant, do not complement one another, and define a gene PFK1 located 28-cm distal to rna1 on the extended right arm of chromosome XIII [10].
• Plasmids containing the information of one or the other gene were identified by back-transformation into pfk single mutants (pfk1 PFK2, PFK1 pfk2) [11].
• Single point mutations in either gene encoding the subunits of the heterooctameric yeast phosphofructokinase abolish allosteric inhibition by ATP [7].
• Phosphofructokinase mutants of yeast. Biochemistry and genetics [10].
• These data support the view that two gene duplication events occurred in the evolution of the yeast PFK genes [1].

Anatomical context of PFK1

• In contrast to the previously described lack of phosphofructokinase-1 activity in cell-free extracts of these mutants, we could measure a temporary enzyme activity immediately after lysis of protoplasts [12].
• The diminution or loss of the fructose 2,6-bisphosphate-dependent inhibition produced in aged cytosols was restored by addition of crystalline muscle phosphofructokinase, as well as by decreasing the amount of glucose-6-phosphate dehydrogenase in the assay [13].
• Our data are consistent with the concept that PFK1 protein is required for an event upstream of vacuole degradation (i.e. signaling, selection, or sequestration) [14].
• Activities of the glycolytic marker enzymes hexokinase, phosphofructokinase and pyruvate kinase were increased 1.7 to 3-fold in liver and/or adipose tissue by selenate treatment as compared to mice on selenium deficiency and mice with selenite administration [15].
• However, the degradation of peroxisomes does not require a catalytically active phosphofructokinase [14].

Associations of PFK1 with chemical compounds

• Other mutations that increase glucose-6-P, deletion of PFK1, which codes for the alpha-subunit of 6-phosphofructo-1-kinase, or of PGI1, the phosphoglucoisomerase gene, had similar effects on glycogen metabolism as did pfk2 mutants [16].
• Here we provide data demonstrating that an alanine residue at positions 874 (for the PFK1-encoded alpha-subunit) or 868 (for the PFK2-encoded beta-subunit) is crucial to achieve this structure [17].
• Physiological and metabolic analysis of the PFK1 PFK2 double mutant indicated that decreased Pf1k had no significant effect on growth, apparently due to compensatory increases in its positive effector, fructose 2,6-bisphosphate [18].
• One gene, PFK1, has already been cloned and sequenced and the other one is the probable yeast gene coding for the beta-subunit of the succinyl-CoA synthetase [19].
• All the glucose consumed by a double mutant lacking both P-fructokinase and 6-P-gluconate dehydrogenase ends up as 6-P-gluconate, yet the pfk1 mutants can glycolyze and grow on glucose in air [10].

Regulatory relationships of PFK1

• In the pdc2 pfk1 XSP18, strain, pfk1 suppresses the loss of induction of glucose-inducible enolase 2 brought about by XSP18 but fails to rescue temperature sensitivity [20].
• This has been achieved by overexpression of the latter in a PFK-deficient strain of Saccharomyces cerevisiae under the control of the PFK2 promoter [21].
• Phosphofructokinase is inhibited to a greater extent than hexokinase at acid pH [22].
• AMP deaminase reaction as a control system of glycolysis in yeast. Role of ammonium ion in the interaction of phosphofructokinase and pyruvate kinase activity with the adenylate energy charge [23].

Other interactions of PFK1

• Two metabolically antagonistic enzymes, FBPase and PFK, are present during the transition phase, but not during the exponential phase, of growth, and the decay or inactivation of these enzymes in vivo may be dependent upon a glucose-induced protease activity [24].
• Analysis of PFK3--a gene involved in particulate phosphofructokinase synthesis reveals additional functions of TPS2 in Saccharomyces cerevisiae [25].
• The dynamic and functional organization of the fructose-6-phosphate/fructose-1,6-bisphosphate cycle has been investigated in an open and homogeneous reconstituted enzyme system containing phosphofructokinase, fructose-1,6-biphosphatase, pyruvate kinase, adenylate kinase and glucose 6-phosphate isomerase [26].
• Apparently, during the start-up of fermentation hexokinase is more rate-limiting in the first section of glycolysis than phosphofructokinase [27].
• Detailed reexamination of the spectrophotometric assay resulted in the observation that the fructose 2,6-bisphosphate-dependent inhibition was a function of the cytosolic phosphoglucose isomerase and phosphofructokinase activities compared to the amount of glucose-6-phosphate dehydrogenase used as auxiliary enzyme [13].

Analytical, diagnostic and therapeutic context of PFK1

• Sequence analysis of the 43 kb CRM1-YLM9-PET54-DIE2-SMI1-PHO81-YHB4-PFK1 region from the right arm of Saccharomyces cerevisiae chromosome VII [28].
• Immunofluorescence microscopy displayed a conspicuously filamentous arrangement of the Pfk-1 mutant protein, exclusively in the pfk2 single deletion mutant [29].
• Thus subunits carrying substitutions by either aspartate or lysine of this residue cause a lack of phosphofructokinase activity in vitro and signals of the subunits are poorly detectable in Western blots [17].
• Changes in the quaternary structure of phosphofructokinase resulting from proteolysis were estimated by high performance size exclusion chromatography while changes in the primary sequence of the individual alpha and beta polypeptide chains were estimated by polyacrylamide-gel electrophoresis in sodium dodecylsulfate [30].
• Rapid purification and crystallization of yeast phosphofructokinase [31].

References