Disease relevance of PGK1

• Hypoxic treatment of various mouse and human hepatoma cell lines led to the expected increase in the amount of PGK1 and PKM2 mRNA, while HIF-1alpha mRNA levels were not significantly elevated [1].
• The human phosphoglycerate kinase (PGK1) gene is located within Xq11-Xq13, a region implicated in familial prostate carcinoma, androgen insensitivity, perineal hypospadias, and other genitourinary abnormalities [2].
• Phosphoglycerate kinase (PGK) deficiency is associated with hereditary haemolytic anaemia and often with central nervous system dysfunction and/or myopathy [3].
• Use of cultured lymphoblastoid cells for the study of abnormal enzymes: molecular abnormality of a phosphoglycerate kinase variant associated with hemolytic anemia [4].
• We have determined a single amino acid substitution in a new phosphoglycerate kinase (PGK) variant, PGK Shizuoka, associated with chronic hemolysis and myoglobinuria [5].

Psychiatry related information on PGK1

• In the other case, which is associated with chronic hemolytic anemia and mental retardation (PGK Amiens), an A-->T nucleotide interchange was found at position 571 in cDNA (exon 5); this leads to amino acid substitution 163 Asp-->Val in the N-terminal domain, which contains the catalytic site for phosphoglycerate binding [6].
• PGK activity in corresponding brain regions of patients with Alzheimer's disease was comparable with controls [7].

High impact information on PGK1

• In one, DNA from circulating mononuclear cells obtained 29 days after transplantation revealed a monoclonal pattern on analysis of a restriction-fragment-length polymorphism in the phosphoglycerate kinase gene [8].
• Both the unusual conservation of function in this processed PGK-2 gene and its tissue-specific expression in spermatogenesis are best explained as a compensatory response to the inactivation of the X-linked PGK-1 gene in spermatogenic cells before meiosis [9].
• For example, an X-linked processed pseudogene of PGK-1 (psi PGK-1) in humans has been identified and shown to contain premature termination codons in all reading frames [9].
• PGK-1 is an X-linked gene expressed constitutively in all somatic cells and premeitotic germ cells [9].
• Phosphoglycerate kinase (PGK) (ATP:3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.2.3) is a metabolic enzyme functioning in the Embden-Meyerhof pathway that converts glucose (or fructose) to pyruvate [9].

Chemical compound and disease context of PGK1

• We studied the role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the metabolism of l-nucleoside analogs, using small interfering RNAs to down-regulate the amount of this enzyme in HelaS3 and 2.2.15 cells, chosen as models for studying the impact of the enzyme on the anticancer and antihepatitis B virus activities of these analogs [10].
• We describe a new PGK variant, PGK Herlev (Asp 285-->Val), in a 69-year-old Danish patient with isolated chronic hemolysis but who had no neurological or muscular disorders [11].
• Hypoxia was the most potent stimulus, and the cell lines demonstrated a 1.4- to 6.9-fold range of VEGF induction, maintained when other hypoxically regulated genes (phosphoglycerate kinase 1 and glucose transporter 1) and a HIF-1-dependent reporter gene were examined [12].
• Using hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase probes, we have demonstrated monoclonality of peripheral blood leukocytes in three females with myeloproliferative disorders who had uninformative chromosomal analysis [13].
• Muscle PGK deficiency is now added to two other newly recognized glycolytic defects, phosphoglycerate mutase and lactate dehydrogenase deficiencies, as a cause of recurrent myoglobinuria [14].

Biological context of PGK1

• Two-point analysis demonstrated maximum lod scores of 5.45, 4.95, 4.28, and 5.99 for DXS106, DXS159, PGK1, and DXS72, respectively, at recombination fractions of zero (DXS106 and DXS159), .01 (PGK1), and .04 (DXS72) [15].
• In 19 XDP kindreds significant linkage disequilibrium was found for loci DXS72 (delta = .47), PGK1 (delta = .36), DXS95 (delta = .30), DXS106 (delta = .28), and DXS159 (delta = .26) [15].
• The binding site region of PAK2, which also binds Lys, resembles those of PGK1 and PGK4 [16].
• The first is around the centromere (DXZ1), and the second is in the region around PGK1 (DXS441 to DXS995) [17].
• Linkage analysis studies were conducted with two DNA probes, DXS1 and PGK1, localized to the Xq11-Xq13 region of the long arm of the X chromosome near the centromere [18].

Anatomical context of PGK1

• We report the prenatal diagnosis of a male fetus with a high probability of the disorder by a linkage analysis utilizing restriction fragment length polymorphisms at the DXS159, PGK1, and DXS72 loci, from a DNA sample obtained by a chorionic villus biopsy at 9 weeks gestation [19].
• Expression of the PGK-2 gene may function solely to compensate for repressed expression of the PGK-1 gene due to X-chromosome inactivation in spermatocytes [20].
• We have isolated a cDNA of the human PGK-2 gene and used this as probe to demonstrate that transcription of this gene in spermatocytes and spermatids coincides with a period of repressed transcription of the X-linked PGK-1 gene during spermatogenesis in the human testis [20].
• Other erythrocyte enzyme deficiencies associated with non-haematological symptoms: phosphoglycerate kinase and phosphofructokinase deficiency [3].
• Purified PRP from HeLa cells and human placenta are composed of two subunits of 36,000 (PRP 1) and 41,000 (PRP 2) daltons [21].

Associations of PGK1 with chemical compounds

• In addition, co-culture of PGK1 transfectants with verapamil only partially reverses the multidrug resistant phenotype [22].
• Retransfection of the PGK1 insert into U-20S confers a multidrug resistant phenotype, characterized by a 30-fold increase in paclitaxel resistance, and cross-resistance to vincristine; adriamycin and mitoxantrone, but not methotrexate or cisplatin [22].
• Methylation patterns in genomic DNA are readily detectable; for example, 17 CpG dinucleotides in the 5' region of human X-linked PGK-1 (phosphoglycerate kinase 1) were found to be methylated on an inactive human X chromosome, but unmethylated on an active X chromosome [23].
• The mutation should cause Cys----Arg substitution at the 315th position from the NH2-terminal Ser of PGK, and it created an additional Ava II (or isoschimatic) cleavage site in the variant gene [24].
• A single nucleotide substitution from guanine to thymine at position 473 of PGK messenger RNA was found [5].

Physical interactions of PGK1

• The mRNA coding for PGK was subjected to coupled reverse transcription followed by amplification by the polymerase chain reaction [24].
• This is accomplished by means of a reaction series in which the activity of G3PDH is coupled with that of phosphoglycerate kinase, the next enzyme in the glycolytic pathway [25].

Enzymatic interactions of PGK1

• This assay employs phosphoglycerate kinase to catalyse the formation 1,3- bisphosphoglycerate which is then used to oxidise NADH in the presence of glyceraldehyde 3-phosphate dehydrogenase [26].
• High-resolution polyacrylamide gel analysis of 25 Hpa II, Hha I, and Tha I sites revealed that all clones expressing PGK1 were unmethylated in a large region of the CpG island that includes the transcription start site and 400 base pairs upstream [27].
• Using ligation-mediated polymerase chain reaction to separately map the distribution of induced oxidized bases and strand breaks along the human PGK1 promoter at nucleotide resolution, we previously described the pattern of oxidative DNA damage induced in vitro by Cu(II)/ascorbate/H2O2 [J. Biol. Chem. 270, 17633-17640 (1995)] [28].

Regulatory relationships of PGK1

• These results demonstrate that PGK regulates uPAR expression at the post-transcriptional level [29].
• Overexpression of human phosphoglycerate kinase 1 (PGK1) induces a multidrug resistance phenotype [22].
• We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) [30].
• One of the 14 clones expressed human glucose-6-phosphate dehydrogenase and another expressed human phosphoglycerate kinase [31].
• In cultured cells, mammalian MIG-10 promotes lamellipodial growth and Ena/VASP proteins induce filopodia [32].

Other interactions of PGK1

• The human phosphoglycerate kinase (PGK1) gene is located within Xqll-Xql3 and is closely linked to the androgen receptor gene within a region implicated in a number of X-chromosome-linked urologic disorders [33].
• These Alu-PCR products were synthesized from radiation hybrids containing the loci DXS159, PGK1, and PGK1P1 [34].
• Concordant segregation of X-linked enzymes and segments of the X chromosome generated by the translocations indicated assignment of the PGK gene to a proximal long arm region (q12-q22) and the HPRT and G6PD genes to the distal half (q22-qter) of the X long arm [35].
• The rate of heterozygosity was 25% for the PGK gene and 45% for the FMR1 gene [36].
• Hexokinase plus glucose (agents that promote breakdown of ATP) prevent stimulation of Na transport by exogenous ATP but not by the substrates for GAPDH and PGK [37].

Analytical, diagnostic and therapeutic context of PGK1

• Allele sizes were measured with an automated DNA sequencer after polymerase chain reaction (PCR) based copying of the PGK1 STR region [2].
• Synthetic oligonucleotide mixtures encoding two different portions of PGK were used as direct in situ hybridization probes for the cDNA library [38].
• The Southern blot and PCR assay gave similar results with regards to the PGK gene [36].
• The structural abnormality of the phosphoglycerate kinase variant, PGK München, associated with red cell enzyme deficiency and heat instability, was elucidated by a microscale peptide-mapping method [39].
• This is further confirmed by observation of the presence of annexin II and PGK in isolated nuclear matrices by immunoelectron microscopy [40].

References