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 in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.
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PMID:In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species. 237 49

The respiratory chain complexes of mitochondria consist of many different subunits, of which only a few partake directly in electron transport. The functions of the subunits that do not contain prosthetic groups are largely unknown. The cytochrome reductase complex of Neurospora crassa, for examine, consists of nine different subunits, of which the peripheral membrane proteins I and II (ref.3) that are located on the matrix side of the mitochondrial inner membrane are the largest subunits devoid of redox centres. Significantly, a cytochrome reductase fraction lacking these two subunits was inactive in electron transfer, and in yeast mutants with defective genes for either of the two subunits, assembly of the reductase is disrupted. Most mitochondrial proteins are imported into the mitochondrion as precursor proteins, and two proteins are necessary for cleaving their presequences, namely the matrix processing peptidase (MPP) and the processing enhancing protein (PEP), the latter strongly stimulating the activity of the former. Temperature-sensitive yeast mutants, which are affected in PEP or MPP, accumulate precursors at the nonpermissive temperature. We report here that subunit I of the cytochrome reductase can be grouped as members of the same protein family.
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PMID:A family of mitochondrial proteins involved in bioenergetICS and biogenesis. 252 7

Passage of precursor proteins through translocation contact sites of mitochondria was investigated by studying the import of a fusion protein consisting of the NH2-terminal 167 amino acids of yeast cytochrome b2 precursor and the complete mouse dihydrofolate reductase. Isolated mitochondria of Neurospora crassa readily imported the fusion protein. In the presence of methotrexate import was halted and a stable intermediate spanning both mitochondrial membranes at translocation contact sites accumulated. The complete dihydrofolate reductase moiety in this intermediate was external to the outer membrane, and the 136 amino acid residues of the cytochrome b2 moiety remaining after cleavage by the matrix processing peptidase spanned both outer and inner membranes. Removal of methotrexate led to import of the intermediate retained at the contact site into the matrix. Thus unfolding at the surface of the outer mitochondrial membrane is a prerequisite for passage through translocation contact sites. The membrane-spanning intermediate was used to estimate the number of translocation sites. Saturation was reached at 70 pmol intermediate per milligram of mitochondrial protein. This amount of translocation intermediates was calculated to occupy approximately 1% of the total surface of the outer membrane. The morphometrically determined area of close contact between outer and inner membranes corresponded to approximately 7% of the total outer membrane surface. Accumulation of the intermediate inhibited the import of other precursor proteins suggesting that different precursor proteins are using common translocation contact sites. We conclude that the machinery for protein translocation into mitochondria is present at contact sites in limited number.
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PMID:Translocation arrest by reversible folding of a precursor protein imported into mitochondria. A means to quantitate translocation contact sites. 252 62

Import of proteins into mitochondria can be subdivided into several distinct steps. (1) Mitochondrial proteins are synthesized on free ribosomes and are released into cytosolic pools. Nucleoside triphosphates are required to keep precursors in a conformation competent for import. (2) Precursors are directed to mitochondria by specific targeting signals (in most cases contained in N-terminal presequences) and by binding to receptors on the surface of the outer membrane. (3) Precursors interact with a component in the outer membrane which is believed to facilitate membrane insertion ('general insertion protein'). (4) Outer membrane proteins are then directly routed to their final location. Proteins of all other submitochondrial compartments are directed into translocation contact sites between outer and inner membranes. Transfer into contact sites is dependent on the membrane potential (delta psi) across the inner membrane. (5) Presequences of precursors are cleaved in the matrix by the mitochondrial processing peptidase in cooperation with the processing enhancing protein. (6) Precursors of the intermembrane space or the outer surface of the inner membrane have to be re-translocated back across the inner membrane ('conservative sorting').
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PMID:Import of proteins into the various submitochondrial compartments. 255 90

1. The calcium dependence of spontaneous transmitter release from nerve terminals of different lengths was examined at neuromuscular junctions in frog muscle. Miniature endplate potential (MEPP) frequency was positively correlated with the endplate potential (EPP) quantal content and was dependent on external Ca2+. The higher the resting MEPP frequency in a 0.25 mM-Ca2+ Ringer solution, the greater the dependence on external Ca2+. MEPP frequency in all terminals dropped to approximately the same low level in a Ca2(+)-free Ringer solution containing EGTA. This suggests that terminals with higher release levels have a larger Ca2+ influx at rest. 2. Several tests were done to try to characterize the mode of Ca2+ entry into resting terminals. omega-Conotoxin (omega-CgTx) blocked evoked release and reduced MEPP frequency, but not as effectively as zero Ca2(+)-EGTA Ringer solution. Some component of Ca2+ influx thus appears to enter through channels insensitive to omega-CgTx. Tetrodotoxin (TTX) did not affect MEPP frequency, indicating that the Ca2+ did not enter through TTX-sensitive Na+ channels that might be opening spontaneously at rest. Hyperpolarization of the terminal by reducing the K+ in the Ringer solution caused no consistent differences in MEPP frequency, suggesting that the Ca2+ influx is relatively insensitive to small changes in membrane potential around the resting level. Strong buffering of the Ringer solution with citrate, to overwhelm any differences in Ca2+ buffering within different junctional clefts, had no significant effect on the MEPP frequency. 3. Evidence that the Na(+)-Ca2+ exchanger helps set the internal Ca2+ level was obtained. Reduction of the Na+ concentration in the Ringer solution caused increases in MEPP frequency ranging from 6 to 440%. However, these changes were not correlated with resting MEPP frequency, hence differences in MEPP frequency probably are not the result of differences in Na(+)-Ca2+ exchanger function in terminals having a uniform Ca2+ leak. 4. Although MEPP frequency was generally correlated with quantal content, in subsets of junctions grouped according to their similar quantal contents, there was a positive correlation between MEPP frequency and terminal length. 5. In zero Ca2(+)-EGTA Ringer solution, the low residual MEPP frequency is independent of terminal length, even when MPP frequency is sharply increased by tetanic stimulation.
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PMID:Dependence of spontaneous release at frog junctions on synaptic strength, external calcium and terminal length. 257 68

The tissue distribution of interleukin-2 (IL-2) in normal and 1-methyl-4-phenyl-pyridinium (MPP+)-lesioned brains of rats was investigated. Intrastriatal administration of MPP+ caused visible damage in the vicinity of the injected region two weeks after injection. Autoradiography of the tissue section with anti-IL-2 antibodies plus trace amounts of radiolabeled IL-2 showed that the antibodies treatment elicited a selective radiolabeling of the brain tissues localized at the MPP(+)-lesioned region but not at normal cryo-sliced sections. Addition of radiolabeled IL-2 alone or normal rabbit immunoglobulins did not show any labeling effect. These autoradiographic imaging results suggest that there is an accumulation of cells bearing IL-2-like molecules at the MPP(+)-induced lesion sites.
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PMID:Visualization of interleukin-2-like molecules in MPP(+)-lesioned rat brain. 261 Jun 95

The kinetic mechanism of yeast inorganic pyrophosphatase (PPase) was examined by carrying out initial velocity studies. Ca2+ and Rh(H2O)4(methylenediphosphonate) (Rh(H2O)4PCP) were used as dead-end inhibitors to study the order of binding of Cr(H2O)4PP to the substrate site and Mg2+ to the "low affinity" activator site on the enzyme. Competitive inhibition was observed for Ca2+ vs Mg2+ (Kis = 0.93 +/- 0.03 mM), for Rh(H2O)4PCP vs Cr(H2O)4PP (Kis = 0.25 +/- 0.07 mM), and for RH(H2O)4PCP vs Mg2+ (Kis = 0.38 +/- 0.03 mM). Uncompetitive inhibition was observed for Ca2+ vs Cr(H2O)4PP (Kii = 0.49 +/- 0.01). On the basis of these results a rapid equilibrium ordered mechanism in which Cr(H2O)4PP binding precedes Mg2+ ion binding is proposed. The inert substrate analog, Mg(imidodiphosphate) (MgPNP) was shown to induce Mg2+ inhibition of the PPase-catalyzed hydrolysis of MgPP. The Mg2+ inhibition observed was competitive vs MgPP and partial. These results suggest that Mg2+/MgPNP release from the enzyme occurs in preferred rather than strict order and that the Mg2+/MgPP-binding steps are at steady state. Zn2+, Co2+, and Mn2+ (but not Mg2+) displayed activator inhibition of the PPase-catalyzed hydrolysis of PPi (this study) and of Cr(H2O)4PP (W.B. Knight, S. Fitts, and D. Dunaway-Mariano, (1981) Biochemistry 20, 4079). These findings suggest that cofactor release from the low affinity cofactor site on the enzyme must precede product release and that Zn2+, Mn2+, and Co2+ (but not Mg2+) have high affinities for the cofactor sites on both the PPase.M.MPP and PPase.M.M(P)2 complexes. The role of the metal cofactor in determining PPase substrate specificity was briefly explored by testing the ability of the Mg2+ complex of tripolyphosphate (PPPi) (a substrate for the Zn2+-activated enzyme but not the Mg2+-activated enzyme) to induce Mg2+ inhibition of PPase-catalyzed hydrolysis of MgPP. MgPPP was shown to be as effective as MgPNP in inducing competitive Mg2+ inhibition (vs MgPP). This result suggests that the low affinity Mg2+ cofactor-binding site present in the enzyme-MgPP complex is maintained in the enzyme-MgPPP complex. Thus, failure of Mg2+ to bind to the enzyme-MgPPP complex was ruled out as a possible explanation for the failure of the Mg2+-activated enzyme to catalyze the hydrolysis of MgPPP.
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PMID:The kinetic mechanism of yeast inorganic pyrophosphatase. 282 96

We investigated the import and sorting pathways of cytochrome b2 and cytochrome c1, which are functionally located in the intermembrane space of mitochondria. Both proteins are synthesized on cytoplasmic ribosomes as larger precursors and are processed in mitochondria in two steps upon import. The precursors are first translocated across both mitochondrial membranes via contact sites into the matrix. Processing by the matrix peptidase leads to intermediate-sized forms, which are subsequently redirected across the inner membrane. The second proteolytic processing occurs in the intermembrane space. We conclude that the hydrophobic stretches in the presequences of the intermediate-sized forms do not stop transfer across the inner membrane, but rather act as transport signals to direct export from the matrix into the intermembrane space.
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PMID:Successive translocation into and out of the mitochondrial matrix: targeting of proteins to the intermembrane space by a bipartite signal peptide. 282 12

The efficiency of various dust respirators for eliminating mouse allergens [mouse urine proteins (MUP), pelts proteins (MPP) and serum albumin (MSA)] were evaluated with use of low-volume air samplers and immunochemical methods. Three kinds of dust respirators from one manufacturer which have different efficacy in the exclusion of dust particles were put on the fiber glass filter in each air sampler. Then the air in a mouse housing room was sampled. The allergens passed through the respirators, were trapped in the fiber glass filters, and then extracted from the filters. The allergens of MUP and MPP in the extract were measured by an inhibition method of fluorometric enzyme-linked immunosorbent assay (ELISA) for IgE antibody and those of MSA measured by a fluorometric sandwich ELISA. The respirator with the lowest capability of exclusion was found to eliminate 65-86% of respective allergens. The other two respirators with higher powers eliminated 98% of MUP. MPP and MSA were eliminated to undetectable levels through these respirators. This study provided a means for the evaluation of dust respirators for animal aeroallergens.
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PMID:Evaluation of dust respirators for elimination of mouse aeroallergens. 291 88

Transport of nuclear-encoded precursor proteins into mitochondria includes proteolytic cleavage of amino-terminal targeting sequences in the mitochondrial matrix. We have isolated the processing activity from Neurospora crassa. The final preparation (enriched ca. 10,000-fold over cell extracts) consists of two proteins, the matrix processing peptidase (MPP, 57 kd) and a processing enhancing protein (PEP, 52 kd). The two components were isolated as monomers. PEP is about 15-fold more abundant in mitochondria than MPP. It is partly associated with the inner membrane, while MPP is soluble in the matrix. MPP alone has a low processing activity whereas PEP alone has no apparent activity. Upon recombining both, full processing activity is restored. Our data indicate that MPP contains the catalytic site and that PEP has an enhancing function. The mitochondrial processing enzyme appears to represent a new type of "signal peptidase," different from the bacterial leader peptidase and the signal peptidase of the endoplasmic reticulum.
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PMID:Mitochondrial protein import: identification of processing peptidase and of PEP, a processing enhancing protein. 296 9


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