Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The N-terminal sequences of the E1 alpha, E1 beta and E2 subunits of the human branched-chain alpha-keto acid dehydrogenase complex have been determined by microsequencing. The N-terminal of human E1 beta and E2 subunits (Val and Gly, respectively) are identical to those of the corresponding rat and bovine subunits. However, the N-terminus of the human E1 alpha subunit (Ser) is identical to bovine, but differs from the rat E1 alpha (Phe) subunit. Comparison of the N-terminal sequences of human and rat E1 alpha subunits shows that the serine residue at the +1 position in the human sequence is replaced by a proline residue in the rat sequence. The presence of the proline residue apparently causes a 5'-shift by one residue in the cleavage site by the mitochondrial processing peptidase in the rat sequence, when compared to the human sequence. The results provide evidence that the mitochondrial processing peptidase cannot cleave an X-Pro bond, similar to trypsin, chymotrypsin and microsomal signal peptidases.
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PMID:Differential processing of human and rat E1 alpha precursors of the branched-chain alpha-keto acid dehydrogenase complex caused by an N-terminal proline in the rat sequence. 791 75

Two isoforms of protein serine/threonine phosphatase were isolated and sequenced from mouse testis. A deletion of 48 nucleotides of PP2C beta 4 cDNA in comparison with PP2C beta 3 cDNA resulted in different COOH-terminal sequences of 12 and 15 amino acids, respectively. These COOH-terminal sequences of PP2C beta 3 and PP2C beta 4 were further found to be different from those of isoforms MPP beta 1 and MPP beta 2 of mouse PP2C beta reported (Terasawa, et al. Arch. Biochem. Biophys. 307: 342-349, 1993). The common sequence of 378 amino acids from these four isoforms of mouse PP2C beta exhibited 95% identity with the corresponding sequence of rat PP2C beta. The mRNAs of approximately 2.0 Kb for PP2C beta 3 and PP2C beta 4 were expressed only in testis, while the mRNAs of 3.3 Kb and 8.5 Kb for MPP beta 1 and MPP beta 2, respectively, were found in somatic tissues.
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PMID:Molecular cloning and expression of cDNAs encoding two isoforms of protein phosphatase 2C beta from mouse testis. 803 26

In this study we show that rat Mg(2+)-dependent protein phosphatase alpha (MPP alpha) expressed in Saccharomyces cerevisiae cells was phosphorylated on serine residues in vivo. The recombinant rat MPP alpha purified from Escherichia coli cells harboring an expression vector was phosphorylated in vitro by casein kinase II, but not by casein kinase I, to 1.5 mol phosphate per mol enzyme protein. Analysis by phosphopeptide mapping and amino acid analysis suggested that the sites of both in vivo and in vitro phosphorylation were the same and involved only serine residues. These results suggest that the rat MPP alpha expressed in yeast cells is phosphorylated by yeast casein kinase II in vivo. It is further proposed that the phosphorylation sites are located in the carboxyl terminal region of the enzyme molecule.
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PMID:Phosphorylation of Mg(2+)-dependent protein phosphatase alpha (type 2C alpha) by casein kinase II. 839 36

The iron-sulfur proteins of the cytochrome bc1 complexes of Schizosaccharomyces pombe and Saccharomyces cerevisiae contain the three amino acid motif RX( downward arrow)(F/L/I)XX(T/S/G)XXXX (downward arrow) that is typical for proteins that are cleaved sequentially in two steps by matrix processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP). Despite the presence of this recognition sequence the S. pombe iron-sulfur protein is processed only once during import into mitochondria, whereas the S. cerevisiae protein is processed in two steps. Import of S. pombe iron-sulfur protein in which the putative MIP or MPP recognition sites are eliminated by site-directed mutagenesis and import of iron-sulfur protein into mitochondria from yeast mutants that lack MIP activity indicate that one step processing of the S. pombe iron-sulfur protein is independent of those sites and of MIP activity. Sequencing of the mature protein obtained after import in vitro and of the endogenous iron-sulfur protein isolated from mitochondrial membranes by preparative 2D-electrophoresis shows that MPP recognizes a second site in the presequence and processing occurs between residues 43 and 44. If proline-20 of the S. pombe presequence is changed into a serine, a second cleavage step is induced. Conversely, if serine-24 of the S. cerevisiae presequence is changed to a proline, the first cleavage step that is normally catalyzed by MPP is blocked, causing precursor iron-sulfur protein to accumulate. Together these results indicate that a single amino acid change in the presequence is responsible for one-step processing in S. pombe versus two-step processing in S. cerevisiae.
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PMID:Processing of the presequence of the Schizosaccharomyces pombe Rieske iron-sulfur protein occurs in a single step and can be converted to two-step processing by mutation of a single proline to serine in the presequence. 953 40

We previously identified distal and proximal arginine residues in the N-terminal portion and an aromatic amino acid at position 1 (P1' site3) relative to the cleavage site as important recognition signals in substrates of mitochondrial processing peptidase [Niidome, T., Kitada, S., Shimokata, K., Ogishima, T., and Ito, A. (1994) J. Biol. Chem. 269, 24714-24722; Ogishima, T., Niidome, T., Shimokata, K., Kitada, S., and Ito, A. (1995) ibid. 270, 30322-30326]. To further elucidate the elements required for the specific recognition and cleavage by the enzyme, we synthesized synthetic peptides that possessed only the distal and proximal arginine residues and phenylalanine at the P1' site in a poly alanine sequence, and analyzed the processing reaction toward them. They were not cleaved by the peptidase although they inhibited the peptidase activity. However, when serine was introduced into the C-terminal portions of the sequence, processing was observed. The efficiency of the resultant peptides improved as the number of serine residues was increased. A peptide with serine or histidine at P2' and threonine at P3' was processed most efficiently. These results indicate that the processing reaction catalyzed by the peptidase depends not only on the N-terminal portion but also on the C-terminal portion from the cleavage site in the substrates.
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PMID:Importance of residues carboxyl terminal relative to the cleavage site in substrates of mitochondrial processing peptidase for their specific recognition and cleavage. 979 32

A new specific endopeptidase that cleaves eukaryotic precursor proteins has been found in Escherichia coli K but not in E. coli B strains. After purification, protein sequencing and Western blotting, the endopeptidase was shown to be identical with E. coli outer membrane protein OmpP [Kaufmann, A., Stierhof, Y.-D. & Henning, U. (1994) J. Bacteriol. 176, 359-367]. Further characterization of enzymatic properties of the new peptidase was performed. Comparison of the cleavage specificities of the newly found endopeptidase and that of rat mitochondrial processing peptidase (MPP) showed that patterns of proteolytic cleavage on the investigated precursor proteins by both enzymes are similar. By using three mitochondrial precursor proteins, the specificity assigned to OmpP previously, a cleavage position between two basic amino-acid residues, was extended to a three amino-acid recognition sequence. Positions +1 to +3 of this extended recognition site consist of an amino-acid residue with a small aliphatic side chain such as alanine or serine, a large hydrophobic residue such as leucine or valine followed by an arginine residue. Additionally, structural motifs of the substrate seem to be required for OmpP cleavage.
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PMID:Eukaryotic precursor proteins are processed by Escherichia coli outer membrane protein OmpP. 1041 46

The aim of this study was to investigate the role of phosphorylation/dephosphorylation mechanisms at the blood-brain barrier (BBB) in the uptake of organic cations. The experiments were performed using RBE4 cells, an immortalized, rat brain microvessel endothelial cell line, an in vitro model of the BBB. The modulation of the uptake of 1-methyl-4-phenylpyridinium (MPP(+)), a model organic cation, at the apical membrane of RBE4 cells was studied. Agents that stimulate protein kinase A, but not protein kinase C, produced a moderate inhibition (approximately 18% reduction) of uptake of [(3)H]MPP(+) by RBE4 cells. Okadaic acid, an inhibitor of protein serine/threonine phosphatase, did not affect uptake of (3)H-MPP(+), but the alkaline phosphatase (ALP) inhibitor levamisole markedly reduced (3)H-MPP(+) uptake. The activity of membrane-bound ALP expressed on the apical surface of RBE4 cells was studied at pH 7.4 using p-nitrophenylphosphate as substrate. Kaempferol, progesterone, 3-isobutyl-1-methylxanthine, all- trans-retinoic acid and iron stimulated ecto-ALP activity and uptake of [(3)H]MPP(+) in RBE4. Orthovanadate (a protein tyrosine phosphatase inhibitor) markedly inhibited both ecto-ALP activity and uptake of [(3)H]MPP(+) by RBE4 cells. In conclusion, these results suggest that apical transporter(s) of MPP(+) in RBE4 cells may be under the control of phosphorylation/dephosphorylation mechanisms, being active in the dephosphorylated state. A physiological role for ALP in the modulation of organic cation transport in the BBB is suggested.
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PMID:Regulation of [(3)H]MPP(+) transport by phosphorylation/dephosphorylation pathways in RBE4 cells: role of ecto-alkaline phosphatase. 1201 20

We have examined mitochondrial membranes and molecular hallmarks of apoptosis in response to increasing concentrations of 1-Methyl, 4-phenyl, Pyridinium ion (MPP(+)) in SK-N-SH neurons and have evaluated the neuroprotective potential of Selegiline with a primary objective to explore its mechanism(s) of neuroprotection. MPP(+)-induced apoptosis was characterized by spherical appearance, suppressed neuritogenesis, phosphatidyl serine externalization, plasma membrane perforations, mitochondrial membrane potential (Delta Psi) collapse, mitochondrial aggregation, and nuclear DNA fragmentation and condensation. At lower concentrations, MPP(+) (10-100 microM) produced mitochondrial swelling and loss of cristae, and at higher concentrations (300-500 microM), degeneration and aggregation of mitochondrial membranes in the peri-nuclear region, which were attenuated by Selegiline (10-50 microM) pre-treatment. At still higher concentrations, MPP(+) (>500 microM) produced necrotic changes represented by mitochondrial and plasma membrane ballooning and perforations. Selegiline provided partial neuroprotection at higher concentrations of MPP(+). MPP(+)-induced increases in reactive oxygen species, lipid peroxidation, cytochrome-C release, necrosis factor kappa-B (NF-kappa-B) activation, 8-hydroxy, 2 deoxy guanosine synthesis, alpha-synuclein indices, and reductions in glutathione, ATP, and superoxide dismutase were attenuated by Selegiline. Selegiline also attenuated MPP(+)-induced transcriptional activation of c-fos, c-jun, GAPDH, and caspase-3, suggesting that it may provide neuroprotection by preserving mitochondrial membranes, by attenuating molecular markers of apoptosis, by scavenging free radicals, and by regulating immediate early genes involved in neurodegeneration.
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PMID:Neuroprotective actions of Selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons. 1472 76

There are many clinical and experimental reports demonstrating that estrogens and insulin interact when affecting their target organs. Estrogen receptors consist of two isoforms, estrogen receptors-alpha (ER-alpha) and -beta (ER-beta), but their roles in insulin-induced glucose uptake in mature adipose tissue have yet to be clarified. To evaluate the roles of ER-alpha, expressed predominantly in adipocytes, we have investigated the effects of estradiol (E2), an ER-alpha selective agonist (PPT), and its selective antagonist (MPP) on glucose uptake and insulin action in 3T3-L1 adipocytes. 3T3-L1 adipocytes were exposed to E2 or PPT and/or MPP at different concentrations. The cells were then subjected to 2-deoxy-D-glucose transport assay, western blot analysis, or RT-PCR analysis. Treatment of these cells with E2 or PPT resulted in biphasic effects on glucose transport, that is high (10(-5) M or 3 x 10(-6) M each) and low (10(-8) M) doses produced inhibition and stimulation, respectively. The favorable effect observed at 10(-8) M of E2 was diminished by treatment with MPP. Western bolt analysis revealed that these effects of E2, PPT and MPP paralleled the level of IRS-1 tyrosine phosphorylation. However, IRS-1 serine phosphorylation, suppressor of cytokine signaling (SOCS)-1,-2,-3 and protein tyrosine phosphatase 1B (PTP1B) expression did not change compared to control subjects. Our data clearly show that ER-alpha contributes to insulin stimulated glucose uptake through regulation of the tyrosine phosphorylation of IRS-1 protein.
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PMID:Estrogen receptor alpha regulates insulin sensitivity through IRS-1 tyrosine phosphorylation in mature 3T3-L1 adipocytes. 1700 Nov 8

The toxicity caused by cell exposure to 1-methyl-4-phenylpyridinium ion (MPP(+)) is a useful model in the study of Parkinson's disease (PD). However, the exact molecular mechanisms triggered by MPP(+) in cell death are currently unclear. In the present research, we show that exposure to MPP(+) induce the cell death of neuroblastoma-derived dopaminergic B65 cells, which is not reversed by the widely known caspase inhibitor Z-VAD fmk or by calpain inhibition. Likewise, when B65 cells were treated with MPP(+), the DNA damage pathway that involves p53 was activated, and cells were arrested in the G(2)/M phase of the cell cycle. Interestingly, MPP(+) has two effects on the expression of cell cycle-related proteins. It increases the content of cyclins A, E, cdk2 and the phosphorylated form of pRb (serine 780). However, MPP(+) 5mM decreased the expression of cyclin D1, B1 and cdk4. The decrease in the expression of cyclin B1 may be related to the arrest of cells observed in the G(2)/M phase of cell cycle. The increase in S phase cell cycle proteins and retinoblastoma protein phosphorylation was an unexpected result. As the antioxidant trolox attenuated the process of cell loss and changes in the cell cycle, as measured by flow cytometry, we concluded that oxidative stress was involved in the effects of MPP(+) in this cell line. In summary, the present work characterizes the molecular changes involved in damage caused by MPP(+) in B65 cells, and highlights the effects of MPP(+) on molecules involved in the control of cell cycle progression.
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PMID:Effects of MPP+ on the molecular pathways involved in cell cycle control in B65 neuroblastoma cells. 2008 Jan 85


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