Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleotide pyrophosphatase (NPPase) activity is markedly elevated in cultured skin fibroblasts from patients of Lowe's syndrome. cDNA clones encoding the NPPase were isolated using synthetic oligonucleotide probes designed on the basis of partial amino acid sequence of the enzyme purified from human placenta. The complete sequences of these clones yielded a merged sequence of 3508 bases. The polypeptide chain of the enzyme was deduced to comprise 873 amino acids with a calculated molecular weight of 99,703 and had the characteristics of a class II transmembrane protein. Ten potential N-glycosylation sites were detected in the protein. RNA blot analysis showed that human fibroblasts contain two minor mRNAs of 7.0 and 8.2 kb, respectively, in addition to a major 3.6-kb species that coincides with the merged cDNA in size. A computer search of a nucleotide sequence data-base revealed that plasma cell membrane glycoprotein PC-1, whose function was unknown at the time, is identical with the NPPase. Comparison of the amino acid sequence of the NPPase with the active site sequence of bovine 5'-nucleotide phosphodiesterase allowed the assignment of a putative active site domain to the central region of the COOH-terminal extracellular domain of the NPPase. The gene for human NPPase was localized to chromosome 6 at q22-q23 by in situ hybridization with a fragment of the NPPase cDNA.
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PMID:Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase. 131 2

A 32P-labeled protein that co-purified with acidic fibroblast growth factor (aFGF) receptor from bovine liver proved to be a distinct membrane protein, which itself has kinase activity that is stimulated by aFGF. The protein was designated MAFP for major aFGF-stimulated phosphoprotein. MAFP was purified from bovine liver using immunoaffinity chromatography with monoclonal antibody to MAFP following Triton X-100 extraction of plasma membranes and wheat germ lectin-Sepharose 4B column chromatography. The purified MAFP showed molecular masses of 130 kDa and 260 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing and nonreducing conditions, respectively. Purified MAFP elicited aFGF-stimulated Thr-specific autophosphorylation activity and phosphorylation activity toward protein substrates (myelin basic protein and histone). Amino acid sequence analyses of 16 peptide fragments of MAFP, produced by endoproteinase Lys-C digestion followed by reduction and S-pyridylethylation, showed approximately 80-100% homology with the cDNA-deduced amino acid sequences of human and mouse plasma cell membrane glycoprotein, PC-1 (Buckley, M. F., Loveland, K. A., McKinstry, W. J., Garson, O. M., and Goding, J. W. (1990) J. Biol. Chem. 265, 17506-17511), suggesting that MAFP is the bovine version of PC-1. The amino acid sequences of bovine MAFP, human and mouse PC-1 reveal a putative ATP binding site in their extracellular domains. These results suggest that MAFP(PC-1) is an ectoprotein kinase. In addition to the kinase activity, MAFP(PC-1) was also found to possess alkaline nucleotide phosphodiesterase activity. It is now clear that several of the unique properties previously attributed to the aFGF receptor kinase are actually properties of this novel Thr-specific ectoprotein kinase, which co-purifies with the aFGF receptor and is responsive to stimulation by aFGF.
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PMID:The plasma cell membrane glycoprotein, PC-1, is a threonine-specific protein kinase stimulated by acidic fibroblast growth factor. 171 69

A bone and cartilage enzyme with both 5'-nucleotide phosphodiesterase I and nucleotide pyrophosphohydrolase (NTPPPH) activity modulates physiologic mineralization and pathologic chondrocalcinosis by generating inorganic pyrophosphate. We hypothesized that, as for alkaline phosphatase, expression of an NTPPPH gene can be shared by cells from bone, cartilage, and liver and by certain leukocytes. Recently, we demonstrated the hepatocyte and murine plasma cell membrane glycoprotein PC-1 to have both 5'-nucleotide phosphodiesterase I and NTPPPH activity. We detected polypeptides cross-reactive with PC-1 in human U20S osteosarcoma cells, articular chondrocytes, homogenized human knee cartilages, human knee synovial fluids, hepatoma cells, and murine plasmacytoma cells. Constitutive low abundance PC-1 mRNA expression was detected in U20S cells and chondrocytes by a nested RNA-PCR assay and by Northern blotting. TGF beta is known to substantially increase NTPPPH activity in primary osteoblast cultures. We demonstrated that TGF beta 1 increased NTPPPH activity and the level of PC-1 mRNA and immunoprecipitable [35S]-methionine-labeled PC-1 polypeptides in U20S cells. The identification of PC-1 as an NTPPPH expressed in cells derived from bone and cartilage may prove useful in furthering the understanding of the role of NTPPPH i n physiologic and pathologic mineralization.
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PMID:Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells. Regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta. 804 Mar 11

Inorganic pyrophosphate (PP(i)) regulates certain intracellular functions and extracellular crystal deposition. PP(i) is produced, degraded, and transported by specialized mechanisms. Moreover, dysregulated cellular PP(i) production, degradation, and transport all have been associated with disease, and PP(i) appears to directly mediate specific disease manifestations. In addition, natural and synthetic analogs of PP(i) are in use or currently under evaluation as prophylactic agents or therapies for disease. This review summarizes recent developments in the understanding of how PP(i) is made and disposed of by cells and assesses the body of evidence for potentially significant physiological functions of intracellular PP(i) in higher organisms. Major topics addressed are recent lines of molecular evidence that directly link decreased and increased extracellular PP(i) levels with diseases in which connective tissue matrix calcification is disordered. To illustrate in depth the effects of disordered PP(i) metabolism, this review weighs the roles in matrix calcification of the transmembrane protein ANK, which regulates intracellular to extracellular movement of PP(i), and the PP(i)-generating phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1).
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PMID:Inorganic pyrophosphate generation and disposition in pathophysiology. 1140 20

In obese humans, insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein (PC-1) and decreased insulin receptor (IR) tyrosine kinase activity in skeletal muscle. PC-1 overexpression inhibits IR tyrosine kinase and possibly other downstream signaling events. The rhesus monkey in captivity is susceptible to obesity with concomitant insulin resistance. In the present study we analyzed obese (n = 10, 29.4% +/- 1.2% body fat) and non-obese (n = 12, 19.4% +/- 1.9% body fat) rhesus monkeys. Glucose clearance during an euglycemic hyperinsulinemic (400 mU/m(2) body surface area/min) clamp was lower for the obese group (non-obese, 9.7 +/- 0.9; obese, 3.2 +/- 0.7 mg/kg fat-free mass [FFM]/min; P <.01). We performed vastus lateralis muscle biopsies prior to and during the clamp. We measured PC-1 levels in these muscle samples to determine whether PC-1 content is elevated in this primate model of insulin resistance. PC-1 levels were determined by assay of phosphodiesterase activity and specific PC-1 enzyme-linked immunosorbent assay (ELISA). In the obese group, both PC-1 content and activity were 2-fold higher than in the non-obese group (P <.05). In order to investigate the ability of insulin to stimulate IR signaling in vivo in these 2 groups of monkeys, we then measured tyrosine autophosphorylation of the IR by specific ELISA. The increase in IR autophosphorylation in the non-obese group was twice that of the obese group (fold increase over basal: non-obese, 3.7 +/- 0.3; obese, 1.9 +/- 0.6; P <.05). We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle.
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PMID:Elevated plasma cell membrane glycoprotein levels and diminished insulin receptor autophosphorylation in obese, insulin-resistant rhesus monkeys. 1191 55

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.
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PMID:Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. 1288 24

Generalized arterial calcification of infancy (GACI), is characterized by calcification of the internal elastic lamina of large and medium-sized arteries and stenosis due to myointimal proliferation. Although survival to adulthood has been reported, most patients die within the first six months of life. Recently, we found mutations of ENPP1 coding for ecto-nucleotide pyrophosphatase/phosphodiesterase 1 to be associated with GACI in 8 of 11 families. In this study, we analyzed ENPP1 in affected individuals of another 12 unrelated families. We identified 11 novel homozygous or compound heterozygous mutations in 10 of the 12 new families. The mutations (1 nonsense, 7 missense, 1 single amino acid deletion, and 2 frame shift mutations) were scattered over the whole coding region with a slightly more condensed distribution within the catalytic and nuclease-like domain as compared to the first survey. In this study, three mutations were found repeatedly in apparently unrelated patients, 7 x c.913C>A (p.Pro305Thr) and c.2662C [corrected]>T (p.Arg888Trp) as well as c.2320C>T (p.Arg774Cys) each twice. However, haplotype analysis suggested a founder effect of British extraction for mutation c.913C>A (p.Pro305Thr). The fact that the two other mutations c.2662C [corrected]>T (p.Arg888Trp) and c.2320C>T (p.Arg774Cys) occurred twice within a single allele also suggests a single founder. This study confirms the role of ENPP1 mutations as the main cause of GACI and adds considerably to the mutational spectrum of ENPP1.
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PMID:The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). 1560 15

Inorganic pyrophosphate is a potent inhibitor of bone mineralization by preventing the seeding of calcium-phosphate complexes. Plasma cell membrane glycoprotein-1 and tissue nonspecific alkaline phosphatase were reported to be antagonistic regulators of mineralization toward inorganic pyrophosphate formation (by plasma cell membrane glycoprotein-1) and degradation (by tissue nonspecific alkaline phosphatase) under physiological conditions. In addition, they possess broad overlapping enzymatic functions. Therefore, we examined the roles of tissue nonspecific alkaline phosphatase within matrix vesicles isolated from femurs of 17-day-old chick embryos, under conditions where these both antagonistic and overlapping functions could be evidenced. Addition of 25 microM ATP significantly increased duration of mineralization process mediated by matrix vesicles, while supplementation of mineralization medium with levamisole, an alkaline phosphatase inhibitor, reduces the ATP-induced retardation of mineral formation. Phosphodiesterase activity of tissue nonspecific alkaline phosphatase for bis-p-nitrophenyl phosphate was confirmed, the rate of this phosphodiesterase activity is in the same range as that of phosphomonoesterase activity for p-nitrophenyl phosphate under physiological pH. In addition, tissue nonspecific alkaline phosphatase at pH 7.4 can hydrolyze ADPR. On the basis of these observations, it can be concluded that tissue nonspecific alkaline phosphatase, acting as a phosphomonoesterase, could hydrolyze free phosphate esters such as pyrophosphate and ATP, while as phosphodiesterase could contribute, together with plasma cell membrane glycoprotein-1, in the production of pyrophosphate from ATP.
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PMID:Phosphodiesterase activity of alkaline phosphatase in ATP-initiated Ca(2+) and phosphate deposition in isolated chicken matrix vesicles. 1614 95

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, also known as PC-1) inhibits insulin signal transduction pathway(s). Previous studies have demonstrated the K121Q variant of the ENPP1 gene to have a significant functional role in determining susceptibility to insulin resistance and type 2 diabetes (T2D). To assess whether the K121Q variant has any impact on T2D in Japanese, we undertook an extensive case-control association study using a total of 911 unrelated Japanese T2D patients and 876 control subjects. No significant difference was observed in either genotype distribution (P=0.95) or allele frequency (P=0.83) between T2D and control groups. Notably, the frequency of the ancestral Q121 allele, which is also present in other primates, was quite high in African-Americans, and showed a marked ethnic variation (77.3% in African-Americans, 16.7% in European Americans, 10.5% in Japanese and 4.2% in Han Chinese). Consequently, the pairwise F(ST )value (a classic measure of genetic distance between pairs of population) showed highly significant differentiations between African-American and non-African-American populations (F(ST)>0.3). Our results indicated that the K121Q variant of the ENPP1 gene has very little, if any, impact on T2D susceptibility in Japanese, but may play a role in the inter-ethnic variability in insulin resistance and T2D.
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PMID:No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population. 1660 60

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.
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PMID:Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity. 1706 59


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