Disease relevance of PFKL

• The localization of PFKL to chromosome 21 and the chromatographic demonstration of a specific increase in the L subunit in red cells from trisomy 21 individuals has thus resolved the controversy about whether the previously observed elevation in PFK activity in Down syndrome represented a gene dosage effect [1].
• RESULTS: Combining the results from these eight individuals suggests the candidate region for DS-CHD is demarcated by D21S3 (defined by ventricular septal defect), through PFKL (defined by tetralogy of Fallot) [2].
• Significant allelic association (P = 0.02) between the disease mutation and PFKL was detected suggesting a founder effect in Mediterranean myoclonus [3].
• 3. Using three highly polymorphic DNA markers (D21S212, PFKL, and D21S171) which flank the EPM1 locus, we performed linkage analysis to investigate whether or not the EPM1 gene is also implicated in Lafora disease [4].
• The sequence/structure comparison of the protein with the crystal structure of a member of the PFK-B family, Escherichia coli ribokinase (EcRK), suggested that it might also form a stable and active dimer and revealed conservation of the ATP-binding site [5].

Psychiatry related information on PFKL

• In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22 [6].
• Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22 [7].

High impact information on PFKL

• Five of the other 46 families also show positive, but modest lod scores with PFKL [6].
• The EPM1 locus was mapped to within 0.3 cM from PFKL in chromosome 21q22 [8].
• Assignment of the human gene for liver-type 6-phosphofructokinase isozyme (PFKL) to chromosome 21 by using somatic cell hybrids and monoclonal anti-L antibody [9].
• We conclude from these data that PFKL is located on chromosome 21 and that the previously noted elevation of erythrocyte PFK activity in individuals with trisomy 21 is due to a gene-dosage effect [9].
• 3. No recombinations were observed between the disease phenotype and the PFKL marker and a maximum lod score of 5.63 was obtained [10].

Chemical compound and disease context of PFKL

• Exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis (phosphorylase and phosphofructokinase deficiency) and fatty acid oxidation (palmitoyl carnitine transferase deficiency) [11].

Biological context of PFKL

• Comparison to publicly available genomic sequence, and additional data, revealed that the gene is split into seven exons over 10.5 kb, further refining the mapping position to only 1.2 kb distal to PFKL with the direction of transcription toward the centromere [12].
• In addition, a cell line with a ring chromosome 21 containing a breakpoint which excluded the distal part of the q22.3 band was negative for expression of PFKL [13].
• These results demonstrated that the isolated clones contain sequences homologous to human PFKL mRNA [14].
• In vivo NMR measurements determined that cells overexpressing PFKL performed glycolysis 40% faster than controls [15].
• These facts, together with abnormalities which occur in DS glycolysis, make PFKL overexpression a candidate for causing some aspects of the DS phenotype [15].

Anatomical context of PFKL

• A cellular model for examining the consequences of PFKL overexpression in DS was constructed by transfecting rat PC12 cells with the human PFKL cDNA [15].
• It was found that while relative amount of PFKL mRNA in adult brain was one-fourth of that detected in fetal brain the level of PFKM mRNA in adult brain was slightly higher than in fetal tissue, suggesting that PFK expression might be controlled at the transcriptional level [16].
• The gene for the liver-type subunit of phosphofructokinase (PFKL), a key glycolytic enzyme, maps to this region and the product is overproduced in DS erythrocytes and fibroblasts [15].
• The localization of aldolase (ALD) was also shifted towards the plasma membrane (and colocalized with PFK) in CAV-1 over-expressing cells [17].
• We conclude that CAV-1 functions as a scaffolding protein for PFK, ALD and perhaps other glycolytic enzymes, either through direct interaction or accessory proteins, thus contributing to compartmented metabolism in vascular smooth muscle [17].

Associations of PFKL with chemical compounds

• Previous work has shown that GAPDH (glyceraldehyde-3-phosphate dehydrogenase), aldolase, PFK (phosphofructokinase), PK (pyruvate kinase) and LDH (lactate dehydrogenase) assemble into a GE (glycolytic enzyme) complex on the inner surface of the human erythrocyte membrane [18].
• Phosphofructokinase, malate dehydrogenase, creatine kinase, and glucose-6-phosphate dehydrogenase recovered only after cardioversion [19].
• As enzymatic assays confirmed the results of the structure/function analysis indicating a preferential specificity towards adenosine compounds, this new protein of the PFK-B family corresponds to an adenosine kinase from B. canis rossi [5].
• Activity, distribution and regulation of phosphofructokinase in salivary gland of rats with streptozotocin-induced diabetes [20].
• In conclusion, the increase in the activity of PFK-1 observed in the salivary glands of rats with streptozotocin-induced diabetes does not seem to be due to its modulator fructose-2,6-bisphosphate [20].

Other interactions of PFKL

• After excluding genetic linkage with 52 markers distributed evenly over the autosomes, significant linkage was present with the 21q22.3 locus PFKL (two-point lod score of Zmax = 6.86 at theta = 0.03) [21].
• The DS-CHD candidate region has been suggested to span between PFKL and D21S3, which is the STS marker near the ETS2 loci [22].
• A novel cDNA, termed SMT3A, was isolated and mapped between the loci PFKL and D21S171, about 2.2 Mb proximal to the telomere [23].
• In addition to the expected elevation of SOD-1, significant elevations of erythrocyte glutathione peroxidase (GSHPxase) and phosphofructokinase activities were found in Down syndrome [24].
• This single-copy gene maps approximately 200 kb proximal to PFKL in chromosome 21q22.3 between markers EHOC-1 and D21S25 [25].

Analytical, diagnostic and therapeutic context of PFKL

• PCR amplification of DNA from somatic cell hybrids mapped D21S171 to human chromosome 21, and linkage analysis localized this marker close to the loci CD18, PFKL, D21S113 and D21S112 in chromosomal band 21q22 [26].
• With PCR amplification, Southern blot analysis, and FISH, we have mapped this presumed human pericentrin gene (PCNT) to the long arm of chromosome 21 between marker PFKL and 21qter [27].
• Confocal immunofluorescence microscopy was used to study the distribution of phosphofructokinase (PFK) and CAV-1 in the transfected cells [17].
• Compared to the control group, the mouse in the group treated with the PO extracts by 1 g/d had significantly higher activities of PF, PFK, LDH and higher levels of ATP in the cortices, especially under the hypoxic environment for 24 hours [28].

References