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

Immunoassays sensitive to a broad range of compounds structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) and 1-methyl-4-phenylpyridine (MPP+) have been developed and used to test for the presence of possible chemically related neurotoxins in the brains of Parkinson's disease patients. The sensitivity and chemical reactivity of the polyclonal antibodies used in these assays have been characterized with a range of endogenous and chemically related materials. Two methods were developed and tested for extraction followed by chromatographic separation which would be applicable to stored or accumulated substances. The immunoassays were tested and applied to the assay of tissue extracts from MPTP or MPTP-analogue exposed animals, and indicated detectability of MPP(+)-immunoreactivity greater than 8 weeks after exposure to MPTP in monkey brain. No difference in immunoactivity was measured in extracts from human brains of Parkinson's disease patients or controls, and particularly low levels of immunoreactivity were found in the striatum relative to the levels measured in several cortical regions. From these studies, there is no evidence for the role of an environmental neurotoxin chemically related to MPTP in the pathogenesis of Parkinson's disease.
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PMID:Search for neurotoxins structurally related to 1-methyl-4-phenylpyridine (MPP+) in the pathogenesis of Parkinson's disease. 157 86

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), the active product of MPTP, caused Parkinson's disease-like symptoms. The mechanism of action of MPP+ is unknown, but analogues of MPTP lacking an N-methyl group were found to be essentially devoid of toxicity, which means that the methyl group of the pyridine ring plays a role in the toxicity. This is of interest because S-adenosylmethionine (SAM), which is the biologic methyl donor and requires a methyl group for its action, also caused MPP(+)-like motor deficits in rodents. Therefore, the requirement of a methyl group by MPTP and MPP+ for their actions suggests that, like SAM, MPP+ and MPTP may serve as methyl donors. This hypothesis was tested by reacting SAM, MPP+, or MPTP with dopamine in the presence of catechol-O-methyltransferase and measuring the methylated product of dopamine produced. Like SAM, MPP+, but not MPTP, methylated dopamine. The methylated product coeluted from chromatographic columns with standard 3-methoxytyramine. Concentrations of 15.6, 62.5, 250, and 1000 nmoles/tube increased the 3-methoxytyramine recovered above controls by 0.0, 6.88, 44.55, 129.47 and 5.8, 13.9, 50.58, 121.31 nmoles for SAM and MPP+, respectively. The dopamine that remained unreacted was dose-dependently decreased. MPTP had no significant effect. The ability of MPP+ to serve as a methyl donor may represent a mechanism for the toxicity of MPP+.
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PMID:1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) serves as methyl donor for dopamine: a possible mechanism of action. 159 Sep 12

The role of opioid receptors in long-term potentiation (LTP) of the medial (MPP) and lateral (LPP) divisions of the perforant path-granule cell projection was investigated in urethane anesthetized rats. A stimulating electrode was positioned in the dorsomedial or ventrolateral aspect of the angular bundle for selective activation of the MPP and LPP, respectively. A push-pull cannula served to focally perfuse artificial cerebrospinal fluid (ACSF) across the perforant path terminal zone, while perforant path evoked potentials were monitored in the dentate hilus. Robust LTP of the excitatory postsynaptic potential (EPSP) initial slope and population spike height was induced by high frequency stimulation (400 Hz, 8 bursts of 8 pulses) applied to the medial or lateral perforant path in rats perfused with standard medium. In the lateral perforant path, a putative proenkephalin system, LTP of the EPSP and population spike was blocked when ACSF containing 100 microM of the opioid receptor antagonist naloxone was present during the tetanus, while perfusion with 0.1 microM naloxone prevented EPSP potentiation but only reduced the magnitude of the population spike increase. Naloxone had no effect on LTP induction in the MPP. Importantly, 0.1 microM ICI 174,864, a selective antagonist of delta opioid receptors, blocked LTP of synaptic transmission in the LPP while leaving the population spike increase intact. The results indicate that LTP of synaptic transmission in the LPP requires activation of delta opioid receptors, while 'non-delta' opioid receptors may be involved in augmenting granule cell output. This opioid receptor-dependent LTP illustrates peptidergic regulation of synaptic plasticity in the hippocampus.
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PMID:Delta opioid receptor activation is required to induce LTP of synaptic transmission in the lateral perforant path in vivo. 166 45

Many precursors of mitochondrial proteins are processed in two successive steps by independent matrix peptidases (MPP and MIP), whereas others are cleaved in a single step by MPP alone. To explain this dichotomy, we have constructed deletions of all or part of the octapeptide characteristic of a twice cleaved precursor (human ornithine transcarbamylase [pOTC]), have exchanged leader peptide sequences between once-cleaved (human methylmalonyl-CoA mutase [pMUT]; yeast F1ATPase beta-subunit [pF1 beta]) and twice-cleaved (pOTC; rat malate dehydrogenase (pMDH); Neurospora ubiquinol-cytochrome c reductase iron-sulfur subunit [pFe/S]) precursors, and have incubated these proteins with purified MPP and MIP. When the octapeptide of pOTC was deleted, or when the entire leader peptide of a once-cleaved precursor (pMUT or pF1 beta) was joined to the mature amino terminus of a twice-cleaved precursor (pOTC or pFe/S), no cleavage was produced by either protease. Cleavage of these constructs by MPP was restored by re-inserting as few as two amino-terminal residues of the octapeptide or of the mature amino terminus of a once-cleaved precursor. We conclude that the mature amino terminus of a twice-cleaved precursor is structurally incompatible with cleavage by MPP; such proteins have evolved octapeptides cleaved by MIP to overcome this incompatibility.
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PMID:Cleavage of precursors by the mitochondrial processing peptidase requires a compatible mature protein or an intermediate octapeptide. 167 32

High concentrations of the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) are toxic to the catecholaminergic cell line PC12, derived from rat phenochromocytoma. Prolonged exposure of wild-type PC12 cells to 500 microM MPP+ yields toxin-resistant colonies at a frequency of 2 X 10(-4). These spontaneously arising MPP(+)-resistant cells are morphologically quite distinct from wild-type PC12 cells, and are lacking in most of their characteristic catecholaminergic properties. In contrast, among PC12 cells infected with the murine retrovirus ZIPNEOSV(X), 20% are resistant to the toxin MPP+, a resistance frequency approximately 1,000 times higher than for uninfected cells. The morphology and catecholaminergic phenotype of the virus-infected MPP+ resistant cells are quite similar to those of wild-type PC12 cells. The results presented in this study suggest a unique mechanism of MPP+ resistance in the infected PC12 cells which may be conferred by the presence and/or expression of the retrovirus ZIPNEOSV(X).
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PMID:Infection with murine retrovirus confers resistance to the neurotoxin 1-methyl-4-phenylpyridinium ion in PC 12 cells. 169 21

Core I and core II proteins are the largest nuclear-encoded subunits of the mitochondrial ubiquinol-cytochrome-c reductase (bc1 complex) lacking redox prosthetic groups. cDNA clones of the two bovine core proteins have been isolated by the screening of lambda ZAP cDNA libraries either with an oligonucleotide probe based on the sequence of an internal peptide or with a polymerase-chain-reaction-amplified fragment. The core I precursor protein consists of 362 amino acids with a 34-amino-acid presequence typical for mitochondrial targeting signals. The mature protein migrates in SDS/polyacrylamide gels with an apparent molecular mass of 47 kDa, which does not correspond to the actual molecular mass of the protein of 35.8 kDa deduced from the cDNA sequence. The core II precursor protein is composed of 453 amino acids having a 14-amino-acid presequence as a targeting sequence. Comparison of the core I amino acid sequence with sequences of the newly discovered protein family [Schulte, U., Arretz, M., Schneider, H., Tropschug, M., Wachter E., Neupert, W. & Weiss, H. (1989) Nature 339, 147 - 149] comprising the processing enhancing protein (PEP), matrix processing peptidase (MPP), and core I and II proteins from Neurospora crassa and Saccharomyces cerevisiae, revealed a remarkable identity of 39% and a high similarity of 49% to N. crassa PEP, which in this fungus is identical to core I. Core II protein is only a distant relative of this protein family. Based on these sequence comparisons and data obtained by genomic Southern blots, we anticipate that the bovine core I subunit, like the N. crassa core I protein, is bifunctional, being responsible for the maintenance of electron transport and processing of proteins during their import into the mitochondrial matrix. The analysis of the primary structure of the two core proteins completes the set of primary structures of all subunits of bovine ubiquinol-cytochrome-c reductase.
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PMID:Core I protein of bovine ubiquinol-cytochrome-c reductase; an additional member of the mitochondrial-protein-processing family. Cloning of bovine core I and core II cDNAs and primary structure of the proteins. 171 95

U-78518F, a 21-aminosteroid from the novel family of lipid peroxidation inhibitors (lazaroids), increased survival of dopamine (DA) neurons in mesencephalic cell cultures incubated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Protection against DA neuron death occurred with increasing concentrations of U-78518F up to 30 microM. Non-specific toxicity produced with higher concentrations of MPP+ was not affected by the lazaroid. U-78518F inhibited cellular uptake of [3H]MPP+ and [3H]DA, but not that of gamma-[3H]aminobutyric acid. In human striatal membrane preparations, U-78518F competed with [3H]mazindol for binding to the DA transporter, with a calculated Ki value of 10 microM. Two of four lazaroids tested inhibited [3H]DA uptake in the cell culture system. The protective effects of 21-aminosteroids in MPP(+)-induced neurotoxicity are, in part, a function of the interaction of these agents with the DA transporter.
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PMID:21-aminosteroids interact with the dopamine transporter to protect against 1-methyl-4-phenylpyridinium-induced neurotoxicity. 172 40

The gene encoding the yeast mitochondrial rotenone-insensitive internal NADH: ubiquinone-6 oxidoreductase has been sequenced. The DNA sequence indicates the presence of an open reading frame of 1539 bp predicted to encode a protein of 513 amino acid residues (57.2 kDa). The NADH dehydrogenase is synthesized as a precursor protein containing a signal sequence of 26 residues. In vitro import experiments show that the precursor NADH dehydrogenase is cleaved to the mature size by the matrix processing peptidase. Both cleavage and translocation across the mitochondrial membrane(s) are dependent on the membrane potential component of the proton-motive force. Comparison of the protein sequence of the yeast NADH dehydrogenase with the data bank indicates that the enzyme from yeast is homologous to the NADH dehydrogenase of Escherichia coli (22.2% identical residues). Both NADH dehydrogenases contain in the central part of the protein a sequence predicted to fold into a beta alpha beta structure involved in the binding of NADH or FAD(H2). Various aspects of the protein structure are discussed.
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PMID:Primary structure and import pathway of the rotenone-insensitive NADH-ubiquinone oxidoreductase of mitochondria from Saccharomyces cerevisiae. 173 44

Apoptosis is a prominent mechanism of programmed cell death in lymphocytes and in cancer cells not previously found in neurons. We have identified apoptosis and internucleosomal DNA degradation in cultures of cerebellar granule neurons. 1-methyl-4-phenylpyridinium, a selective neurotoxin that destroys the dopaminergic nigrostriatal pathway and results in a parkinsonian syndrome, increases the rate of apoptosis and kills cerebellar granule cells in culture via induction of programmed cell death. Inhibition of gene expression in granule cells with cycloheximide prevents the MPP(+)-induced apoptosis and the DNA fragmentation. Our findings demonstrate a new pathway of neuron death and suggest the possibility that neurodegenerative diseases may result from the inappropriate activation of programmed cell death by apoptosis.
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PMID:Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. 176 96

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its oxidized metabolite, and two recently synthesized 2'-alkyl derivatives of MPTP (methyl and ethyl), found to be more toxic in vivo in mice, have been compared in two neuroblastoma hybrid cell lines (NCB-20 and 140-3) that express the B form of monoamine oxidase (MAO), as tissue culture models for the mode of action of MPTP in the central nervous system. Unlike previously reported studies with cultured cells of neuronal origin expressing only MAO A, both of these cell lines were sensitive to MPTP. Consistent with the in vivo findings, the 2'-alkyl derivatives were much more toxic than MPTP and comparable to the oxidized metabolite MPP+ in their effects on cell survival and morphology. The cells could be protected against the reduced toxins, but not MPP+, by either the MAO A selective inhibitor, clorgyline or the MAO B selective inhibitor, deprenyl. The effectiveness of the MAO inhibitors in blocking the action of the reduced toxins was consistent with their ability to inhibit MAO activity in the cell cultures, but did not reflect MAO-substrate specificity of the toxins. Inhibitors of serotonin and dopamine uptake, which have been found to protect against MPTP toxicity in vivo, were generally ineffective in the cell cultures, with the exception of a marginal increase in survival of MPP(+)-treated 140-3 cells in the presence of the serotonin uptake inhibitor fluoxetine. These findings are discussed in relation to proposed in vivo mechanisms of MPTP cytotoxicity.
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PMID:Toxicity of MPTP and structural analogs in clonal cell lines of neuronal origin expressing B type monoamine oxidase activity. 177 93


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