Disease relevance of GPI

• We evaluated GPI as a target of autoantibodies in juvenile idiopathic arthritis (JIA) [1].
• Glucosephosphate isomerase (GPI) deficiency in humans is an autosomal recessive disorder, which results in nonspherocytic hemolytic anemia of variable clinical expression [2].
• A 4-year-old female with severe congenital hemolytic anemia had low red cell GPI activity of 15.5 IU/g Hb (50% of normal mean) indicating GPI deficiency [2].
• Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice [3].
• The observations are consistent with a downstream mediation role of MMP-3 in PGI/AMF-stimulated tumor cell metastasis [4].

Psychiatry related information on GPI

• A new variant of glucosephosphate isomerase (GPI) associated with hemolytic anemia, mental retardation, and muscular hypotonia is described [5].
• Data from these enzymes and glucose phosphate isomerase will separate L. townsendi (Ortiz) from the others and from L. longiflocosa Osorno, Morales, Osorno, and Hoyos, L. quasitownsendi Morales, Osorno, Osorno, and Hoyos, and L. sauroida Osorno, Morales, and Osorno (three species that are inseparable using enzyme data) [6].
• Regions of sequence homology between gp120 and NLK may account for this inhibitory property of gp120 and functional interactions between gp120 and NLK may be important in the pathogenesis of the AIDS dementia complex [7].
• Recent information from positron emission tomography studies in DS patients and our finding of downregulated phosphoglucose isomerase (PGI) in fetal brain with DS by gene hunting using subtractive hybridization, made us investigate PGI, a key enzyme of glucose metabolism, in brain of patients with DS, Alzheimer's disease (AD) and controls [8].
• For other enzymes (aldolase, phosphoglucose isomerase, triosephosphate isomerase and lactate dehydrogenase) no changes in enzyme activities corresponding to those found in dementia are observed in the normal ageing process [9].

High impact information on GPI

• Glucose phosphate isomerase deficiency as a cause of hydrops fetalis [10].
• Here we show linkage between MHS and DNA markers from the GPI region of human chromosome 19 with a maximum log likelihood ratio (lod score) of 5.65 at the CYP2A locus [11].
• In man, GPI has been mapped to the q12-13.2 region of chromosome 19 (refs 10-12) [11].
• The genetics of the porcine syndrome have been extensively studied; the locus controlling expression of porcine MH is genetically linked to the glucose phosphate isomerase locus (GPI) [11].
• Neuroleukin is also a lymphokine product of lectin-stimulated T cells and induces immunoglobulin secretion by cultured human peripheral blood mononuclear cells [12].

Chemical compound and disease context of GPI

• Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) catalyzes the isomerization between glucose-6-phosphate and fructose-6-phosphate, and is involved in cytokine activity, mitogenesis, differentiation, oncogenesis, and tumor metastasis [4].
• In hepatocellular carcinoma (HCC) tissues, hepatoma cells produce AMF/PHI and its receptor, Mr 78,000 glycoprotein (gp78), is strongly detected in hepatoma cells invading into the stroma and tumor thrombi in the portal vein [13].
• Since it can consume mannose and glucose equivalently in the hereditary deficiencies of hexokinase and phosphoglucose isomerase and since erythrocyte defense against oxidants is impaired in a variety of hereditary hemolytic anemias, we tested the hypothesis that mannose may be a significant alternative to glucose as a fuel for this defense system [14].
• Since PARP inhibitors sensitize tumor cells also to the methylating agent temozolomide (TMZ) and clinical trials are evaluating CPT-11 in combination with TMZ, we tested whether the PARP inhibitor GPI 15427 (10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one) increases the efficacy of CPT-11 + TMZ against colon cancer [15].
• We determined the enzyme activities of glucose-6-phosphate isomerase, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in serum from 23 normal controls, 27 anti-HIV seropositive individuals confirmed by Western blot, and 53 patients with acquired immunodeficiency syndrome (AIDS) [16].

Biological context of GPI

• We propose that GPI-anti-GPI complexes on articular surfaces initiate an inflammatory cascade via the alternative complement pathway, which is unbridled because the cartilage surface lacks the usual cellular inhibitors [17].
• Strikingly, the red cell GPI activity in this patient was higher than that found in a second patient expressing the same GPI variant, with a more severe clinical phenotype [2].
• Subsequent DNA sequence analysis revealed a novel homozygous 921C to G mutation in the GPI gene sequence, predicting a Phe307 to Leu replacement [2].
• G6PI-induced arthritis demonstrates for the first time the induction of organ-specific disease by systemic autoimmunity in genetically unaltered mice [3].
• MMP-3 inhibition abolished the PGI/AMF-induced cell motility [4].

Anatomical context of GPI

• In genetically unaltered mice, T cells are indispensable for both the induction and the effector phase of G6PI-induced arthritis [3].
• Combined glucose phosphate isomerase and glucose-6-phosphate dehydrogenase deficiency of erythrocytes [18].
• Here we show that 64% of humans with RA, but not controls, had increased concentrations of anti-GPI immunoglobulin G (IgG) in serum and synovial fluid [19].
• Immunohistochemistry of RA synovium showed high concentrations of GPI on the surface of the synovial lining and on the endothelial cell surface of arterioles; this indicated a mechanism by which antibodies to GPI may precipitate joint disease [19].
• IgG fractions were separated from the sera of anti-GPI Abs-positive RA patients and healthy subjects, and injected into the metacarpophalangeal joints of 4 cynomolgus monkeys [20].

Associations of GPI with chemical compounds

• In arthritic mice, these GPI deposits were amplified and localized with IgG and C3 complement [17].
• Additionally, we show here that human PHI is phosphorylated at serine 185 by casein kinase II (CK II) and we provide experimental evidence suggesting that this phosphorylation is associated with secretion, thus providing insights for elucidating the intracellular signal transmission of cell response to stimulation by AMF/NLK/MF [21].
• Four enzymes (phosphoglycerate kinase, M2 type pyruvate kinase, glucose phosphate isomerase and glucose-6-phosphate dehydrogenase) have been studied by immunological and enzymatic titration and electrofocusing [22].
• The remaining loci (serum albumin, lactate dehydrogenase, malate dehydrogenase and glucose-6-phosphate dehydrogenase, phosphohexose isomerase and superoxide dismutase) were monomorphic [23].
• Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased [24].
• Signaling analysis revealed that the senescence pathway involving p21 cyclin-dependent kinase inhibitor was up-regulated in PGI/AMF knockdown cells and that superoxide dismutase is the upstream regulator protein of p21-mediated cellular senescence [25].
• The raft-dependent endocytosis of AMF therefore follows a distinct phosphatidylinositol 3-kinase-dependent pathway that is up-regulated in more aggressive tumor cells [26].

Physical interactions of GPI

• Synovial fluid samples from RA patients showed a significantly higher level of binding to recombinant GPI proteins than samples from OA patients [27].
• Peptide T analogs or synthetic cogeners of Neuroleukin proposed to bind the CD4 determinant involved in gp120 binding had no competitive displacement of native gp120 binding as assessed by two independent methods that measure gp120 interaction with CD4 [28].

Regulatory relationships of GPI

• METHODS: Using an enzyme-linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI [29].
• LPS and interferon-alpha (IFN-alpha) both up-regulated neuroleukin mRNA, but only LPS-induced neuroleukin mRNA was suppressed by SB202190 [30].
• We also report that PGI/AMF degradation is mainly regulated by the ubiquitin-lysosome system and RNA interference experiments revealed that PARP-14 inhibits PGI/AMF ubiquitination, thus contributing to its stabilization and secretion [31].

Other interactions of GPI

• CONCLUSION: Our findings suggest that GPI is not a specific autoantigen in RA [32].
• Induction of hepatoma cells migration by phosphoglucose isomerase/autocrine motility factor through the upregulation of matrix metalloproteinase-3 [4].
• This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation [2].
• There was father-to-son transmission of PGI, PGM-1, peptidase C, 6PGD, 2,3-DPGAM, NADP-ICD, and acid phosphatase variants, suggesting that these loci are autosomal as in man [33].
• The elevated titers of anti-GRP78 and anti-PGI IgG observed at the beginning of treatment decreased significantly during therapy, whereas those of anti-LDH, anti-FN, and anti-actin IgG remained unchanged [34].

Analytical, diagnostic and therapeutic context of GPI

• By immunoblotting, antibodies binding to the GPI polypeptide were present in 70-80% of all groups tested [32].
• Anti-GPI antibodies were assessed by densitometrically evaluating immunoblots and ELISA using native and recombinant GPI [1].
• By using PET (positron emission tomography), we show here that purified anti-GPI IgG localizes specifically to distal joints in the front and rear limbs within minutes of intravenous injection, reaches saturation by 20 min and remains localized for at least 24 h [35].
• Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease [19].
• GPI-binding activity was measured in the synovial fluid using a surface plasmon resonance (SPR) biosensor [36].

References