HGNC Approved Gene Symbol:PFKL
Cytogenetic location:21q22.3 Genomic coordinates(GRCh38) :21:44,300,053-44,327,373 (from NCBI)
The PFKL gene encodes the liver isoform of phosphofructokinase (PFK) (ATP:D-fructose-6-phosphate-1-phosphotransferase,EC 2.7.1.11). PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and is a key regulatory enzyme in glycolysis.
Mammalian PFK is a tetramer made up of various combinations of 3 subunits: muscle (PFKM;610681), liver (PFKL), and platelet (PFKP;171840), the genes for which are located on chromosomes 12q13, 21q22, and 10p, respectively. The composition of the tetramers differs according to the tissue type. Muscle and liver PFK are a homotetramers of 4M and 4L subunits, respectively. Erythrocytes contain both L and M subunits, which randomly tetramerize to form M4, L4, M3L, M2L2, and ML3 hybrid forms of the holoenzyme (Vora et al., 1980;Raben and Sherman, 1995).
Levanon et al. (1986) isolated partial cDNA clones corresponding to the human PFKL gene.Levanon et al. (1987) isolated overlapping cDNA clones corresponding to the full-length human PFKL gene from a human fibroblast cDNA library. The deduced protein has a molecular mass of 80 kD and the PFKL mRNA is approximately 3.5 kb.Levanon et al. (1987) noted that the L-type isoform predominates in organs with active gluconeogenesis, such as liver and kidney.Levanon et al. (1989) stated that the human PFKL protein contains 779 amino acids and shares approximately 90% and 68% homology with mouse Pfkl and human PFKM, respectively.
Gehnrich et al. (1988) described the isolation and nucleotide sequencing of mouse Pfkl cDNA and presented evidence of hormonal and nutritional regulation of its expression.
Elson et al. (1990) determined that the PFKL gene contains 22 exons and spans approximately 28 kb.
Yi et al. (2012) demonstrated that the dynamic posttranslational modification of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at ser529 of phosphofructokinase-1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo.
On the basis of apparent dosage effect in trisomy 21 (Down syndrome;190685),Baikie et al. (1965) concluded that a gene for so-called 'red cell' phosphofructokinase was on chromosome 21. In support of these findings,Pantelakis et al. (1970) reported a 74% and 41% increase of erythrocyte PFK activity in newborn and older children with Down syndrome, respectively, suggesting localization of a gene to chromosome 21.
By somatic cell hybridization,Vora and Francke (1981) mapped the PFKL gene to chromosome 21. The authors also found that the mean red cell PFK was elevated in persons with Down syndrome. By study of dosage effects in cases of partial monosomy or partial trisomy of chromosome 21,Chadefaux et al. (1984) concluded that the liver-type PFK is located at 21q21-qter. This mapping was consistent with the regional assignment to 21q22 byCox et al. (1984).
Van Keuren et al. (1986) mapped the PFKL gene to 21q22.3 by somatic cell hamster-human hybridization.Levanon et al. (1986) confirmed the assignment of PFKL to chromosome 21 by demonstrating hybridization of genomic clones to the DNA from mouse-human hybrid cells containing chromosome 21 as the only human chromosome. By linkage studies with RFLPs,Petersen et al. (1991) confirmed the location of the gene in band 21q22.3 and determined its location relative to 15 other genes and DNA markers.
Wang et al. (1992) found that NotI fragments occur preferentially in band 21q22.3, suggesting that this band is unusually rich in genes, since NotI sites occur almost exclusively in CpG islands. Furthermore, comparison of the physical map and genetic map of that region showed a 10-fold higher than average recombination frequency. Band q22.3 is the most telomeric band on chromosome 21. Mapping studies indicate a concentration of genes in the telomeric regions of chromosomes, e.g., Xq28 and 11p15.5.
AlthoughLayzer and Epstein (1972) found that patients with trisomy 21 (190685) had increased red blood cell PFK levels, they concluded that no genes encoding the PFK subunits were located on chromosome 21. Their conclusions were based on detailed immunostudies of the various PFK isoforms.
Baikie, A. G., Loder, P. B., de Grouchy, G. C., Pitt, D. B.Phosphohexokinase activity of erythrocytes in Mongolism: another possible marker for chromosome 21. Lancet 285: 412-414, 1965. Note: Originally Volume 1. [PubMed:14238096,related citations] [Full Text]
Chadefaux, B., Rethore, M. O., Allard, D.Regional mapping of liver type 6-phosphofructokinase isoenzyme on chromosome 21. Hum. Genet. 68: 136-137, 1984. [PubMed:6238898,related citations] [Full Text]
Cox, D. R., Kawashima, H., Vora, S., Epstein, C. J.Regional mapping of SOD-1, PRGS, and PFK-L on human chromosome 21. (Abstract) Cytogenet. Cell Genet. 37: 441-442, 1984.
Elson, A., Levanon, D., Brandeis, M., Dafni, N., Bernstein, Y., Danciger, E., Groner, Y.The structure of the human liver-type phosphofructokinase gene. Genomics 7: 47-56, 1990. [PubMed:2139864,related citations] [Full Text]
Gehnrich, S. C., Gekakis, N., Sul, H. S.Liver (B-type) phosphofructokinase mRNA: cloning, structure, and expression. J. Biol. Chem. 263: 11755-11759, 1988. [PubMed:2969893,related citations]
Layzer, R. B., Epstein, C. J.Phosphofructokinase and chromosome 21. Am. J. Hum. Genet. 24: 533-543, 1972. [PubMed:4262345,related citations]
Levanon, D., Danciger, E., Dafni, N., Bernstein, Y., Elson, A., Moens, W., Brandeis, M., Groner, Y.The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK. DNA 8: 733-743, 1989. [PubMed:2533063,related citations] [Full Text]
Levanon, D., Danciger, E., Dafni, N., Groner, Y.Construction of a cDNA clone containing the entire coding region of the human liver-type phosphofructokinase. Biochem. Biophys. Res. Commun. 147: 1182-1187, 1987. [PubMed:2822040,related citations] [Full Text]
Levanon, D., Danciger, E., Dafni, N., Groner, Y.Genomic clones of the human liver-type phosphofructokinase. Biochem. Biophys. Res. Commun. 141: 374-380, 1986. [PubMed:2948503,related citations] [Full Text]
Pantelakis, S. N., Karaklis, A. G., Alexiou, D., Vardas, E., Valaes, T.Red cell enzymes in trisomy 21. Am. J. Hum. Genet. 22: 184-193, 1970. [PubMed:4244917,related citations]
Petersen, M. B., Slaugenhaupt, S. A., Lewis, J. G., Warren, A. C., Chakravarti, A., Antonarakis, S. E.A genetic linkage map of 27 markers on human chromosome 21. Genomics 9: 407-419, 1991. [PubMed:1674496,related citations] [Full Text]
Raben, N., Sherman, J. B.Mutations in muscle phosphofructokinase gene. Hum. Mutat. 6: 1-6, 1995. [PubMed:7550225,related citations] [Full Text]
Van Keuren, M., Drabkin, H., Hart, I., Harker, D., Patterson, D., Vora, S.Regional assignment of human liver-type 6-phosphofructokinase to chromosome 21q22.3 by using somatic cell hybrids and a monoclonal anti-L antibody. Hum. Genet. 74: 34-40, 1986. [PubMed:2944814,related citations] [Full Text]
Vora, S., Durham, S., de Martinville, B., Francke, U.Assignment of the genes for liver type phosphofructokinase (PFKL) to chromosome 21 and for muscle type (PFKM) to region p32-q32 of chromosome 1. (Abstract) Cytogenet. Cell Genet. 32: 324 only, 1982.
Vora, S., Francke, U.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. Proc. Nat. Acad. Sci. 78: 3738-3742, 1981. [PubMed:6455664,related citations] [Full Text]
Vora, S., Seaman, C., Durham, S., Piomelli, S.Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. Proc. Nat. Acad. Sci. 77: 62-66, 1980. [PubMed:6444721,related citations] [Full Text]
Wang, D., Fang, H., Cantor, C. R., Smith, C. L.A contiguous NotI restriction map of band q22.3 of human chromosome 21. Proc. Nat. Acad. Sci. 89: 3222-3226, 1992. [PubMed:1565613,related citations] [Full Text]
Yi, W., Clark, P. M., Mason, D. E., Keenan, M. C., Hill, C., Goddard, W. A., III, Peters, E. C., Driggers, E. M., Hsieh-Wilson, L. C.Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337: 975-980, 2012. [PubMed:22923583,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: PFKL
Cytogenetic location: 21q22.3 Genomic coordinates(GRCh38) : 21:44,300,053-44,327,373(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Hemolytic anemia due to phosphofructokinase deficiency | 1 |
The PFKL gene encodes the liver isoform of phosphofructokinase (PFK) (ATP:D-fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11). PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and is a key regulatory enzyme in glycolysis.
Mammalian PFK is a tetramer made up of various combinations of 3 subunits: muscle (PFKM; 610681), liver (PFKL), and platelet (PFKP; 171840), the genes for which are located on chromosomes 12q13, 21q22, and 10p, respectively. The composition of the tetramers differs according to the tissue type. Muscle and liver PFK are a homotetramers of 4M and 4L subunits, respectively. Erythrocytes contain both L and M subunits, which randomly tetramerize to form M4, L4, M3L, M2L2, and ML3 hybrid forms of the holoenzyme (Vora et al., 1980; Raben and Sherman, 1995).
Levanon et al. (1986) isolated partial cDNA clones corresponding to the human PFKL gene. Levanon et al. (1987) isolated overlapping cDNA clones corresponding to the full-length human PFKL gene from a human fibroblast cDNA library. The deduced protein has a molecular mass of 80 kD and the PFKL mRNA is approximately 3.5 kb. Levanon et al. (1987) noted that the L-type isoform predominates in organs with active gluconeogenesis, such as liver and kidney. Levanon et al. (1989) stated that the human PFKL protein contains 779 amino acids and shares approximately 90% and 68% homology with mouse Pfkl and human PFKM, respectively.
Gehnrich et al. (1988) described the isolation and nucleotide sequencing of mouse Pfkl cDNA and presented evidence of hormonal and nutritional regulation of its expression.
Elson et al. (1990) determined that the PFKL gene contains 22 exons and spans approximately 28 kb.
Yi et al. (2012) demonstrated that the dynamic posttranslational modification of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at ser529 of phosphofructokinase-1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo.
On the basis of apparent dosage effect in trisomy 21 (Down syndrome; 190685), Baikie et al. (1965) concluded that a gene for so-called 'red cell' phosphofructokinase was on chromosome 21. In support of these findings, Pantelakis et al. (1970) reported a 74% and 41% increase of erythrocyte PFK activity in newborn and older children with Down syndrome, respectively, suggesting localization of a gene to chromosome 21.
By somatic cell hybridization, Vora and Francke (1981) mapped the PFKL gene to chromosome 21. The authors also found that the mean red cell PFK was elevated in persons with Down syndrome. By study of dosage effects in cases of partial monosomy or partial trisomy of chromosome 21, Chadefaux et al. (1984) concluded that the liver-type PFK is located at 21q21-qter. This mapping was consistent with the regional assignment to 21q22 by Cox et al. (1984).
Van Keuren et al. (1986) mapped the PFKL gene to 21q22.3 by somatic cell hamster-human hybridization. Levanon et al. (1986) confirmed the assignment of PFKL to chromosome 21 by demonstrating hybridization of genomic clones to the DNA from mouse-human hybrid cells containing chromosome 21 as the only human chromosome. By linkage studies with RFLPs, Petersen et al. (1991) confirmed the location of the gene in band 21q22.3 and determined its location relative to 15 other genes and DNA markers.
Wang et al. (1992) found that NotI fragments occur preferentially in band 21q22.3, suggesting that this band is unusually rich in genes, since NotI sites occur almost exclusively in CpG islands. Furthermore, comparison of the physical map and genetic map of that region showed a 10-fold higher than average recombination frequency. Band q22.3 is the most telomeric band on chromosome 21. Mapping studies indicate a concentration of genes in the telomeric regions of chromosomes, e.g., Xq28 and 11p15.5.
Although Layzer and Epstein (1972) found that patients with trisomy 21 (190685) had increased red blood cell PFK levels, they concluded that no genes encoding the PFK subunits were located on chromosome 21. Their conclusions were based on detailed immunostudies of the various PFK isoforms.
Baikie, A. G., Loder, P. B., de Grouchy, G. C., Pitt, D. B.Phosphohexokinase activity of erythrocytes in Mongolism: another possible marker for chromosome 21. Lancet 285: 412-414, 1965. Note: Originally Volume 1. [PubMed: 14238096] [Full Text: https://doi.org/10.1016/s0140-6736(65)90007-3]
Chadefaux, B., Rethore, M. O., Allard, D.Regional mapping of liver type 6-phosphofructokinase isoenzyme on chromosome 21. Hum. Genet. 68: 136-137, 1984. [PubMed: 6238898] [Full Text: https://doi.org/10.1007/BF00279302]
Cox, D. R., Kawashima, H., Vora, S., Epstein, C. J.Regional mapping of SOD-1, PRGS, and PFK-L on human chromosome 21. (Abstract) Cytogenet. Cell Genet. 37: 441-442, 1984.
Elson, A., Levanon, D., Brandeis, M., Dafni, N., Bernstein, Y., Danciger, E., Groner, Y.The structure of the human liver-type phosphofructokinase gene. Genomics 7: 47-56, 1990. [PubMed: 2139864] [Full Text: https://doi.org/10.1016/0888-7543(90)90517-x]
Gehnrich, S. C., Gekakis, N., Sul, H. S.Liver (B-type) phosphofructokinase mRNA: cloning, structure, and expression. J. Biol. Chem. 263: 11755-11759, 1988. [PubMed: 2969893]
Layzer, R. B., Epstein, C. J.Phosphofructokinase and chromosome 21. Am. J. Hum. Genet. 24: 533-543, 1972. [PubMed: 4262345]
Levanon, D., Danciger, E., Dafni, N., Bernstein, Y., Elson, A., Moens, W., Brandeis, M., Groner, Y.The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK. DNA 8: 733-743, 1989. [PubMed: 2533063] [Full Text: https://doi.org/10.1089/dna.1989.8.733]
Levanon, D., Danciger, E., Dafni, N., Groner, Y.Construction of a cDNA clone containing the entire coding region of the human liver-type phosphofructokinase. Biochem. Biophys. Res. Commun. 147: 1182-1187, 1987. [PubMed: 2822040] [Full Text: https://doi.org/10.1016/s0006-291x(87)80194-8]
Levanon, D., Danciger, E., Dafni, N., Groner, Y.Genomic clones of the human liver-type phosphofructokinase. Biochem. Biophys. Res. Commun. 141: 374-380, 1986. [PubMed: 2948503] [Full Text: https://doi.org/10.1016/s0006-291x(86)80379-5]
Pantelakis, S. N., Karaklis, A. G., Alexiou, D., Vardas, E., Valaes, T.Red cell enzymes in trisomy 21. Am. J. Hum. Genet. 22: 184-193, 1970. [PubMed: 4244917]
Petersen, M. B., Slaugenhaupt, S. A., Lewis, J. G., Warren, A. C., Chakravarti, A., Antonarakis, S. E.A genetic linkage map of 27 markers on human chromosome 21. Genomics 9: 407-419, 1991. [PubMed: 1674496] [Full Text: https://doi.org/10.1016/0888-7543(91)90406-5]
Raben, N., Sherman, J. B.Mutations in muscle phosphofructokinase gene. Hum. Mutat. 6: 1-6, 1995. [PubMed: 7550225] [Full Text: https://doi.org/10.1002/humu.1380060102]
Van Keuren, M., Drabkin, H., Hart, I., Harker, D., Patterson, D., Vora, S.Regional assignment of human liver-type 6-phosphofructokinase to chromosome 21q22.3 by using somatic cell hybrids and a monoclonal anti-L antibody. Hum. Genet. 74: 34-40, 1986. [PubMed: 2944814] [Full Text: https://doi.org/10.1007/BF00278782]
Vora, S., Durham, S., de Martinville, B., Francke, U.Assignment of the genes for liver type phosphofructokinase (PFKL) to chromosome 21 and for muscle type (PFKM) to region p32-q32 of chromosome 1. (Abstract) Cytogenet. Cell Genet. 32: 324 only, 1982.
Vora, S., Francke, U.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. Proc. Nat. Acad. Sci. 78: 3738-3742, 1981. [PubMed: 6455664] [Full Text: https://doi.org/10.1073/pnas.78.6.3738]
Vora, S., Seaman, C., Durham, S., Piomelli, S.Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. Proc. Nat. Acad. Sci. 77: 62-66, 1980. [PubMed: 6444721] [Full Text: https://doi.org/10.1073/pnas.77.1.62]
Wang, D., Fang, H., Cantor, C. R., Smith, C. L.A contiguous NotI restriction map of band q22.3 of human chromosome 21. Proc. Nat. Acad. Sci. 89: 3222-3226, 1992. [PubMed: 1565613] [Full Text: https://doi.org/10.1073/pnas.89.8.3222]
Yi, W., Clark, P. M., Mason, D. E., Keenan, M. C., Hill, C., Goddard, W. A., III, Peters, E. C., Driggers, E. M., Hsieh-Wilson, L. C.Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337: 975-980, 2012. [PubMed: 22923583] [Full Text: https://doi.org/10.1126/science.1222278]
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