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PubMed1997

Molecular and cytological investigations of phosphoglucomutase (PGM1) in the K562 cell line.

Phosphoglucomutase 1 (PGM1) deficiency is a stable characteristic of the erythroleukaemic cell line, K562, whereas the activity of the isozymes of the other two PGM loci (PGM2 and PGM3) is slightly elevated. In this study the molecular basis of PGM1 deficiency was investigated by a combined approach utilising protein electrophoresis, immunodetection, cytogenetic techniques, and DNA and RNA analysis. Isoelectric focusing and activity staining confirmed that K562 has no detectable PGM1 activity. Immunoblot analysis of extracts, separated by isoelectric focusing, starch gel and SDS gel electrophoresis, using monospecific anti-PGM1 antibodies showed that K562 contained no detectable immunoreactive material. Karyotype analysis revealed the presence of two intact chromosomes 1 and a derivative chromosome 1, der(1)t(1;11), each of which carried a copy of the PGM1 gene as demonstrated by fluorescence in situ hybridization using a PGM1 cosmid as probe. Southern blot analysis using a PGM1 cDNA clone as probe suggested that the PGM1 genes had not been subject to any gross structural rearrangements. We were also able to determine that K562 is type PGM1 2+1+ by restriction endonuclease analysis of genomic DNA. Very low levels of PGM1 mRNA which appeared to be full length transcripts were detected in K562 using a reverse transcriptase PCR technique. We conclude that the most likely cause of PGM1 enzyme deficiency in K562 is abnormal regulation of transcription.

Blotting, Southern↗

PubMed1999

Identification and characterisation of polymorphisms in human phosphoglucomutase (PGM1).

This study is part of our effort to map recombination hotspots in two regions (site A, 18 kb; site B, 40 kb) of the human phosphoglucomutase PGM1 gene. Twenty-two PCR amplified fragments comprising six groups, covering about 5.2 kb, were screened for single nucleotide polymorphisms (SNPs) using non-isotopic single stranded conformation polymorphism (SSCP) analysis. Fourteen fragments were variable and seven of these showed common polymorphism. Our strategy for screening for polymorphic sites in the PGM1 gene was based on the results of allelic association analysis between each new marker and the sites of the classical isozyme polymorphism (2/1 in exon 4 and +/- in exon 8). Samples from four populations (Caucasian, Chinese, Vietnamese and New Guinean) were typed for each of the seven polymorphic markers. Between two and four common alleles were found in each case, together with a few rare alleles. Co-dominant inheritance patterns were demonstrated by family studies. The molecular basis of each new marker was determined by direct sequencing of the PCR products: most were SNPs except two that were small insertions/deletions. Direct sequence analysis of a 2.1 kb segment in sixteen individuals revealed no additional nucleotide variation indicating a very high level of efficiency of the SSCP screening method used in this study. The overall nucleotide diversity (theta) for PGM1 was estimated as 0.9 x 10(-3) based on 33 segregating sites in a sequence of 5187 nt and a sample size of 614 individuals.

Alleles↗

PubMed1996

Long-term alcohol intake enhances ADP-ribosylation of the multifunctional enzyme, phosphoglucomutase, in rat liver.

Adenosine diphosphate (ADP)-ribosylation is a posttranslational protein modification that, in turn, alters several regulatory proteins in mammalian cells. We demonstrated that long-term alcohol intake enhanced the ADP-ribosylation of a 58-kd protein in rat liver plasma membranes. To assess the biological significance of this phenomenon, we partially purified the 58-kd acceptor protein from solubilized rat liver homogenates by two sequential preparative high-pressure liquid chromatographies. Microsequencing revealed that it was phosphoglucomutase (PGM) (EC 5,4,2,2). This enzyme underwent negligible auto ADP-ribosylation, but the ADP-ribosylation was remarkably increased by adding rat liver plasma membranes. The extent of the increase was greater in alcohol-fed rats than in pair-fed controls, suggesting enhanced enzyme activities toward ADP-ribosylation of PGM after chronic alcohol consumption. Several important enzymes are ADP-ribosylated, after which their activities are modified. The results of this study showed that PGM is a novel substrate for ADP-ribosylation in the liver and that the ADP-ribosylation is increased after chronic alcohol consumption. In view of the variety of roles of PGM in the liver (carbohydrate metabolism and Ca2+ homeostasis), specific roles of this modification in terms of the effects of alcohol on hepatocytes may deserve further investigation.

Adenosine Diphosphate Ribose↗

PubMed1978

Homologous genes for enolase, phosphogluconate dehydrogenase, phosphoglucomutase, and adenylate kinase are syntenic on mouse chromosome 4 and human chromosome 1p.

It is possible to generate interspecific somatic cell hybrids that preferentially segregate mouse chromosomes, thus making possible mapping of mouse genes. Therefore, comparison of the linkage relationships of homologous genes in man and mouse is now possible. Chinese hamster x mouse somatic cell hybrids segregating mouse chromosomes were tested for the expression of mouse enolase (ENO-1; EC 4.2.1.11, McKusick no. 17245), 6-phosphogluconate dehydrogenase [PGD; EC 1.1.1.44, McKusick no. 17220], phosphoglucomutase-2 (PGM-2; EC 2.7.5.1, McKusick no. 17190), and adenylate kinase-2 (AK-2; EC 2.7.4.3, McKusick no. 10302). In man, genes coding for the homologous forms of these enzymes have been assigned to the short arm of human chromosome 1. Analysis of 41 primary, independent, hybrid clones indicated that, in the mouse, ENO-1 and AK-2 are syntenic with PGD and PGM-2 and therefore can be assigned to mouse chromosome 4. In contrast, they were asyntenic with 21 other enzymes including mouse dipeptidase-1 (DIP-1, human PEP-C; EC 3.4.11.(*), McKusick no. 17000) assigned to human chromosome arm 1q and mouse chromosome 1. Karyologic analysis confirmed this assignment. These data demonstrate that a large autosomal region (21 map units in the mouse and 51 map units in the human male) has been conserved in the evolution of mouse chromosome 4 and the short arm of human chromosome 1. Identification of such conserved regions will contribute to our understanding of the evolution of the mammalian genome and could suggest gene location by homology mapping.

Adenylate Kinase↗

PubMed1979

Evidence for a tyrosine residue at the active site of phosphoglucomutase and its interaction with vanadate.

The rate of transfer of [32P]phosphate from [32P]-labeled phosphoglucomutase (alpha-D-glucose-1,6-bisphosphate:alpha-D-glucose-1-phosphate phosphotransferase, EC 2.7.5.1) to glucose increases dramatically between pH 8.5 and 10.5 with a half maximal rate at pH 9.8. This suggests the participation of a residue containing an ionizable group with a pK close to 10. The inhibition of enzyme activity obtained with tyrosine-derivatizing reactions--iodination, nitration, acetylation, and diazo coupling--is strongly indicative of tyrosine participation. Thiol reagents, p-hydroxymercuribenzoate and ethyleneimine, were without effect. Vanadate and arsenate augmented the transfer reaction 200- and 2.5-fold, respectively, and lowered the pH optimum of the reaction.

Animals↗

PubMed1982

A phylogeny for the principal alleles of the human phosphoglucomutase-1 locus.

The results of phosphoglucomutase-1 (PGM1) typings by starch gel electrophoresis and subtypings by isoelectric focusing are presented for a sample of Japanese. A distinction made on the basis of isoelectric focusing (termed "+" and "-") is nonrandomly associated with each of the products of the four most common electrophoretic alleles (PGM1(1), PGM1(2), PGM1(3), and PGM1(7). The isoelectric trait cosegregates with the allele; the degree of nonrandomness of the association varies from allele to allele. Thus, the four alleles become eight. On the basis of these facts plus the additive nature of the pI differences between allele products and the geographical distribution of the alleles, an allele phylogeny can be constructed. This postulates that the eight alleles may be explained by three nucleotide substitutions involving the stem allele plus four intragenic recombinations between these substitutions. The potential of intragenic recombination as a cause of mutation has been insufficiently appreciated.

Alleles↗

PubMed1983

Adaptive significance of differences in the tissue-specific expression of a phosphoglucomutase gene in rainbow trout.

We have investigated the phenotypic effects of a mutant allele that results in the expression of a phosphoglucomutase locus (Pgm1) in the liver of rainbow trout. Embryos with liver Pgm1 expression hatch earlier than embryos without liver Pgm1 expression. These differences apparently result from increased flux through glycolysis in embryos with liver PGM1 activity while they are dependent on the yolk for energy. Fish with liver PGM1 activity are also more developmentally buffered, as indicated by less fluctuating asymmetry of five bilateral meristic traits. The more rapidly developing individuals begin exogenous feeding earlier and achieve a size advantage that is maintained until sexual maturity. This size advantage produces a significant tendency for earlier age of sexual maturity. These results show that different genotypes at this regulatory gene result in important phenotypic differences that are likely to be of important adaptive significance.

Age Factors↗

PubMed1992

Phosphoglucomutase 1: complete human and rabbit mRNA sequences and direct mapping of this highly polymorphic marker on human chromosome 1.

A cDNA clone encoding the mRNA for the highly polymorphic human enzyme phosphoglucomutase 1 (PGM1; EC 5.4.2.2) has been isolated and characterized. This was achieved indirectly by first isolating a rabbit cDNA from an expression library using anti-rabbit PGM antibodies. A comparison of the nucleotide sequences shows that the homologies between human and rabbit PGM1 mRNAs are 92% and 97% for the coding nucleotide sequence and the amino acid sequence, respectively. The derived rabbit amino acid sequence is in complete agreement with the published protein sequence for rabbit muscle PGM. A physical localization of the human PGM1 gene to chromosome 1p31 has been determined by in situ hybridization. Analysis of DNA from a wide variety of vertebrates indicates a high level of PGM1 sequence conservation during evolution.

Animals↗

PubMed1993

Intragenic recombination at the human phosphoglucomutase 1 locus: predictions fulfilled.

In 1982, we advanced a phylogeny that attributed eight alleles of the phosphoglucomutase 1 locus (PGM1) to three independent mutations in a primal allele, followed by four intragenic recombination events involving these mutants [Takahashi, N., Neel, J. V., Satoh, C., Nishizaki, J. & Masunari, N. (1982) Proc. Natl. Acad. Sci. USA 79, 6636-6640]. The recent description of a cDNA probe for this locus [Whitehouse, D. B., Putt, W., Lovegrove, J. U., Morrison, K., Hollyoake, M., Fox, M. F., Hopkinson, D. A. & Edwards, Y. H. (1992) Proc. Natl. Acad. Sci. USA 89, 411-415] now renders it possible to test the validity of this phylogeny. cDNAs of PGM1 reverse-transcribed from mRNAs obtained from Japanese individuals possessing eight different electrophoretically defined alleles (PGM1*1+, PGM1*1-, PGM1*2+, PGM1*2-, PGM1*3+, PGM1*3-, PGM1*7+, PGM1*7-) were amplified by PCR and the sequences were determined. Only three different base substitutions were identified when PGM1*1+ was taken as the reference allele, as follows: an A to T transversion at residue 265, a C to T transition at residue 723, and a T to C transition at residue 1320. The second of these substitutions creates a Bgl II restriction enzyme site and the third creates a Nla III site. At the amino acid level, these substitutions alter amino acid 67 from Lys to Met, amino acid 220 from Arg to Cys, and amino acid 419 from Tyr to His, respectively. These mutations resulted in the electrophoretic properties defining PGM1*7+, the PGM1*2+, and the PGM1*1- alleles, respectively. Subsequent intragenic recombinational events resulted in the remaining four alleles. For two of these latter alleles (PGM1*7- and PGM1*3-), more than one type of intragenic crossover can produce the allele. These findings verify the predicted phylogeny and provide a case study in the evolution of complexity at a genetic locus.

Alleles↗

PubMed1993

The classical human phosphoglucomutase (PGM1) isozyme polymorphism is generated by intragenic recombination.

The molecular basis of the classical human phosphoglucomutase 1 (PGM1) isozyme polymorphism has been established. In 1964, when this genetic polymorphism was first described, two common allelozymes PGM1 and PGM1 2 were identified by starch gel electrophoresis. The PGM1 2 isozyme showed a greater anodal electrophoretic mobility than PGM1 1. Subsequently, it was found that each of these allelozymes could be split, by isoelectric focusing, into two subtypes; the acidic isozymes were given the suffix + and the basic isozymes were given the suffix -. Hence, four genetically distinct isozymes 1+, 1-, 2+, and 2- were identified. We have now analyzed the whole of the coding region of the human PGM1 gene by DNA sequencing in individuals of known PGM1 protein phenotype. Only two mutations have been found, both C to T transitions, at nt 723 and 1320. The mutation at position 723, which changes the amino acid sequence from Arg to Cys at residue 220, showed complete association with the PGM1 2/1 protein polymorphism: DNA from individuals showing the PGM1 1 isozyme carried the Arg codon CGT, whereas individuals showing the PGM1 2 isozyme carried the Cys codon TGT. Similarly, the mutation at position 1320, which leads to a Tyr to His substitution at residue 419, showed complete association with the PGM1+/- protein polymorphism: individuals with the + isozyme carried the Tyr codon TAT, whereas individuals with the - isozyme carried the His codon CAT. The charge changes predicted by these amino acid substitutions are entirely consistent with the charge intervals calculated from the isoelectric profiles of these four PGM1 isozymes. We therefore conclude that the mutations are solely responsible for the classical PGM1 protein polymorphism. Thus, our findings strongly support the view that only two point mutations are involved in the generation of the four common alleles and that one allele must have arisen by homologous intragenic recombination between these mutation sites.

Alleles↗

PubMed2000

Loss of the major isoform of phosphoglucomutase results in altered calcium homeostasis in Saccharomyces cerevisiae.

Phosphoglucomutase (PGM) is a key enzyme in glucose metabolism, where it catalyzes the interconversion of glucose 1-phosphate (Glc-1-P) and glucose 6-phosphate (Glc-6-P). In this study, we make the novel observation that PGM is also involved in the regulation of cellular Ca(2+) homeostasis in Saccharomyces cerevisiae. When a strain lacking the major isoform of PGM (pgm2Delta) was grown on media containing galactose as sole carbon source, its rate of Ca(2+) uptake was 5-fold higher than an isogenic wild-type strain. This increased rate of Ca(2+) uptake resulted in a 9-fold increase in the steady-state total cellular Ca(2+) level. The fraction of cellular Ca(2+) located in the exchangeable pool in the pgm2Delta strain was found to be as large as the exchangeable fraction observed in wild-type cells, suggesting that the depletion of Golgi Ca(2+) stores is not responsible for the increased rate of Ca(2+) uptake. We also found that growth of the pgm2Delta strain on galactose media is inhibited by 10 microM cyclosporin A, suggesting that activation of the calmodulin/calcineurin signaling pathway is required to activate the Ca(2+) transporters that sequester the increased cytosolic Ca(2+) load caused by this high rate of Ca(2+) uptake. We propose that these Ca(2+)-related alterations are attributable to a reduced metabolic flux between Glc-1-P and Glc-6-P due to a limitation of PGM enzymatic activity in the pgm2Delta strain. Consistent with this hypothesis, we found that this "metabolic bottleneck" resulted in an 8-fold increase in the Glc-1-P level compared with the wild-type strain, while the Glc-6-P and ATP levels were normal. These results suggest that Glc-1-P (or a related metabolite) may participate in the control of Ca(2+) uptake from the environment.

Calcium↗

PubMed2006

The alpha-phosphoglucomutase of Lactococcus lactis is unrelated to the alpha-D-phosphohexomutase superfamily and is encoded by the essential gene pgmH.

alpha-Phosphoglucomutase (alpha-PGM) plays an important role in carbohydrate metabolism by catalyzing the reversible conversion of alpha-glucose 1-phosphate to glucose 6-phosphate. Isolation of alpha-PGM activity from cell extracts of Lactococcus lactis strain MG1363 led to the conclusion that this activity is encoded by yfgH, herein renamed pgmH. Its gene product has no sequence homology to proteins in the alpha-d-phosphohexomutase superfamily and is instead related to the eukaryotic phosphomannomutases within the haloacid dehalogenase superfamily. In contrast to known bacterial alpha-PGMs, this 28-kDa enzyme is highly specific for alpha-glucose 1-phosphate and glucose 6-phosphate and showed no activity for mannose phosphate. To elucidate the function of pgmH, the metabolism of glucose and galactose was characterized in mutants overproducing or with a deficiency of alpha-PGM activity. Overproduction of alpha-PGM led to increased glycolytic flux and growth rate on galactose. Despite several attempts, we failed to obtain a deletion mutant of pgmH. The essentiality of this gene was proven by using a conditional knock-out strain in which a native copy of the gene was provided in trans under the control of the nisin promoter. Growth of this strain was severely impaired when alpha-PGM activity was below the control level. We show that the novel L. lactis alpha-PGM is the only enzyme that mediates the interconversion of alpha-glucose 1-phosphate to glucose 6-phosphate and is essential for growth.

Amino Acid Sequence↗

PubMed1990

Purification and partial characterization of the phosphoglucomutase isozymes from human placenta.

We have developed a simple procedure for the purification of phosphoglucomutase (PGM) isozymes from human placenta of healthy women. The technique involves the ammonium sulfate fractionation, ion-exchange and dye-ligand chromatographies. By this method we obtained homogeneous isozyme preparations of the products ("primary" and "secondary") of the two PGM1 and PGM2 loci. The final specific activities were 1134.6-1441.8 units/mg for PGM1 forms and 40.2-46.5 units/mg for PGM2 forms. On SDS-polyacrylamide gel electrophoresis analysis, the final preparations gave a single protein band of 58,500 and 69,000 Mr for PGM1 and PGM2 isozymes, respectively. These forms have the same kinetic properties, but from the substrate specificity experiments we have found that PGM2 forms are more effective for catalyzing the phosphoribomutase and glucose 1,6-bisphosphate synthase reaction than PGM1 forms. All these properties are shared by the same isozymes previously isolated from human erythrocytes but in this procedure the use of human placenta for the PGM isozymes purification takes advantage of high specific activity of PGM in the extracts of this tissue as well as obtaining highly homogeneous protein suitable for studies at molecular level.

Adult↗

PubMedDate not supplied

Phosphoglucomutase polymorphism detected by isoelectric focusing: gene frequencies, evolution and linkage.

Four alleles at the phosphoglucomutase (PGM1) locus in man have been recently demonstrated by isoelectric focusing, and in this study gene frequencies have been estimated for four populations, and significant differences have been indicated between the results. Pedigree analysis of the PGM1 and rhesus loci confirm a weak linkage in males, but none in females. An examination of PGM1 phenotypes in a range of primates shows that a proportion possess a band focusing at the same isoelectric point as human PGM1+1. We propose that all the human and primate alleles may have evolved from a common ancestral PGM1+1 locus.

Animals↗

PubMedDate not supplied

Phosphoglucomutase (PGM) and group-specific component (Gc), isoelectric focusing sub-types among Zoroastrians of Iran.

A total of 243 and 236 red cell and serum samples from the Zoroastrians of Iran were sub-typed by isoelectric focusing for the red cell enzyme phosphoglucomutase locus 1 and the group-specific component respectively and the phenotype and gene frequency values were calculated. Comparison of the results with those of examinations performed on African, Asian and European population shows that for both the PGM and Gc systems Zoroastrians show similarity to western populations and differ from middle-eastern populations.

Carrier Proteins↗

PubMed1998

Purification, separation and characterization of phosphoglucomutase and phosphomannomutase from maize leaves.

Different phosphomutases-phosphoglucomutase (EC 2.7.5.1; PGM) and phosphomannomutase (EC 2.7.5.7; PMM) from maize (Zea mays L.) leaves have been purified. PGM and PMM were completely separated from each other. The purified PGM was shown to be electrophoretically homogeneous. The PGM from maize leaves was found to be a homodimer with an apparent molecular mass of 132 kDa, the size of the subunits was 66 kDa. The PGM is a bifunctional enzyme, which can use both glucose-1-phosphate and mannose-1-phosphate as substrates. In contrast, the PMM appears to be monospecific for mannose-1-phosphate. Evidence is presented that PMM differs from PGM. Some properties of the maize leaves PGM and PMM differ in many respects (K(m) for substrates, pH optimum). However, some properties of PGM and PMM were similar (influence of Mg2+ and Mn2+ ions).

Chromatography↗

PubMed1996

A phosphoglucomutase-like gene essential for the optimal expression of methicillin resistance in Staphylococcus aureus: molecular cloning and DNA sequencing.

We describe here the cloning and sequencing of a new auxiliary gene identified by Tn551 insertional mutagenesis of the highly and homogeneously methicillin-resistant Staphylococcus aureus strain COL. The insertionally inactivated mutant RUSA315 had intact mecA and normal amounts of PBP2A, but drastically reduced antibiotic resistance (drop in methicillin MIC from 1600 to 1.5 micrograms ml-1), a unique heterogeneous phenotype, and a compositional change in the cell wall characterized by the complete disappearance of the unsubstituted disaccharide pentapeptide from the peptidoglycan. Cloning in E. coli followed by sequencing located the Tn551 insert omega 720 in an open reading frame of 451 codons, provisionally called femR315, defining a polypeptide with a deduced amino acid sequence that showed over 26% sequence identity and 57% overall sequence similarity with the phosphoglucomutase (PGM) gene of E. coli. The Tn551 insertion site of a previously described mutant 12F (femD) also lies in the same gene as femR315. The wild-type form of femR315 subcloned in a shuttle vector fully restored expression of high level (parental) methicillin resistance in mutant RUSA315. The exact biochemical function of femR315 is not known. However, enzymes similar to PGM catalyze the isomerization of hexose and hexosamine phosphates leading to the formation of glucosamine-1-P, which is an obligate precursor in the biosynthesis of UDP-N-acetylglucosamine (UDP-NAGA). We propose that the suppression of methicillin resistance in RUSA315 is related to some functional or quantitative abnormality of UDP-NAGA metabolism.

Amino Acid Sequence↗

PubMed1982

Identification of a gene regulating the tissue expression of a phosphoglucomutase locus in rainbow trout.

Nine percent of the rainbow trout (Salmo gairdneri) from a hatchery source have a greater than 100-fold increase in expression of a phosphoglucomutase (PGM) locus, Pgm1, in the liver but have normal expression of this locus in other tissues. The results of genetic crosses are consistent with a single regulatory gene with additive inheritance being responsible for the differences in the amount of PGM activity in the liver.--The allele responsible for the expression of Pgm1 in the liver is apparently a recent mutation. This is supported by its restricted distribution in rainbow trout and the absence of liver Pgm1 expression in closely related species. This genetic system is valuable for future analysis of the control of gene expression and in determining the relative evolutionary importance of genetic variation at structural and regulatory genes.

Animals↗