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)

Mitochondrial cytochrome bc1 complex performs two functions: It is a respiratory multienzyme complex and it recognizes a mitochondrial targeting presequence. Refined crystal structures of the 11-subunit bc1 complex from bovine heart reveal full views of this bifunctional enzyme. The "Rieske" iron-sulfur protein subunit shows significant conformational changes in different crystal forms, suggesting a new electron transport mechanism of the enzyme. The mitochondrial targeting presequence of the "Rieske" protein (subunit 9) is lodged between the two "core" subunits at the matrix side of the complex. These "core" subunits are related to the matrix processing peptidase, and the structure unveils how mitochondrial targeting presequences are recognized.
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PMID:Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. 967 19

Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling. We identified the mitochondrial processing peptidase beta (MPPbeta) as a frataxin protein partner using the yeast two-hybrid assay. In in vitro assays, MPPbeta binds frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41-210) that is processed further to the mature form. In vitro and in vivo experiments suggest that two C-terminal missense mutations found in FRDA patients modulate interaction with MPPbeta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function.
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PMID:Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. 970 Feb 4

To investigate the relationship between post-translational processing of the Rieske iron-sulfur protein of Saccharomyces cerevisiae and its assembly into the mitochondrial cytochrome bc1 complex we used iron-sulfur proteins in which the presequences had been changed by site-directed mutagenesis of the cloned iron-sulfur protein gene, so that the recognition sites for the matrix processing peptidase or the mitochondrial intermediate peptidase (MIP) had been destroyed. When yeast strain JPJ1, in which the gene for the iron-sulfur protein is deleted, was transformed with these constructs on a single copy expression vector, mitochondrial membranes and bc1 complexes isolated from these strains accumulated intermediate length iron-sulfur proteins in vivo. The cytochrome bc1 complex activities of these membranes and bc1 complexes indicate that intermediate iron-sulfur protein (i-ISP) has full activity when compared with that of mature sized iron-sulfur protein (m-ISP). Therefore the iron-sulfur cluster must have been inserted before processing of i-ISP to m-ISP by MIP. When iron-sulfur protein is imported into mitochondria in vitro, i-ISP interacts with components of the bc1 complex before it is processed to m-ISP. These results establish that the iron-sulfur cluster is inserted into the apoprotein before MIP cleaves off the second part of the presequence and that this second processing step takes place after i-ISP has been assembled into the bc1 complex.
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PMID:Intermediate length Rieske iron-sulfur protein is present and functionally active in the cytochrome bc1 complex of Saccharomyces cerevisiae. 1009 99

Frataxin is a nuclear-encoded mitochondrial protein which is deficient in Friedreich's ataxia, a hereditary neurodegenerative disease. Yeast mutants lacking the yeast frataxin homologue (Yfh1p) show iron accumulation in mitochondria and increased sensitivity to oxidative stress, suggesting that frataxin plays a critical role in mitochondrial iron homeostasis and free radical toxicity. Both Yfh1p and frataxin are synthesized as larger precursor molecules that, upon import into mitochondria, are subject to two proteolytic cleavages, yielding an intermediate and a mature size form. A recent study found that recombinant rat mitochondrial processing peptidase (MPP) cleaves the mouse frataxin precursor to the intermediate but not the mature form (Koutnikova, H., Campuzano, V., and Koenig, M. (1998) Hum. Mol. Gen. 7, 1485-1489), suggesting that a different peptidase might be required for production of mature size frataxin. However, in the present study we show that MPP is solely responsible for maturation of yeast and human frataxin. MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. In this way, MPP could influence frataxin function and indirectly affect mitochondrial iron homeostasis.
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PMID:Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. 1042 60

The neurotoxic effect of dopamine (DA) and iron(III) on DAergic terminals in striatum has been studied by intracerebral microdialysis technique. Twenty-four hours after surgery (day 1), DA and/or iron(III) with and without DA reuptake inhibitor, nomifensine, were perfused for 1 h. Forty-eight hours after surgery (day 2), MPP(+) 1 mM was perfused for 15 min and the output of DA was measured, its amount being directly proportional to the remaining striatal DAergic terminals, supported by tyrosine hydroxylase immunohistochemistry technique. Perfusion of exogenous DA, as well as iron(III) 10 and 100 microM, did not produce any neurotoxic effect. However, perfusion of iron(III) (333 and 1000 microM) produced a concentration-dependent toxic effect. Co-perfusion of iron(III) at non-toxic concentration (100 microM) with DA (15 microM) produced a toxic effect. Elevation of the endogenous extracellular levels of DA by inhibiting its uptake with nomifensine increased the neurotoxic effect of iron(III) in a dose-dependent manner. The use of tetrodotoxin after elevation of DA with nomifensine partially prevented the neurotoxic effect of its co-perfusion with iron(III) (100 microM). These results suggest that DAergic system could be synergistically damaged by DA and iron(III). Thus, alterations in the clearance of DA from extracellular space along with an increase of iron may have significant consequences for DAergic system toxicity.
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PMID:Neurotoxic relationship between dopamine and iron in the striatal dopaminergic nerve terminals. 1070 May 92

MPP(+), an active metabolite of MPTP, causes a dopaminergic neuronal degeneration similar to that observed in Parkinson's disease. Current data suggest that MPP(+)-induced cytotoxicity may be mediated by oxygen free radicals. To evaluate this hypothesis, we first investigated whether MPP(+) could cause oxidative stress by producing oxygen free radicals in the SH-SY5Y, human neuroblastoma cell line. MPP(+) was toxic to the cells dose-dependently but did not increase the level of lipid peroxidation at toxic concentrations. Second, we examined the effects of various antioxidants and an inhibitor of nitric oxide synthase (NOS) on the development of MPP(+) cytotoxicity. Pretreatment with antioxidants such as ascorbic acid, Trolox, phenyl-tertiary-butyl-nitrone (PBN), which show protective effects on tert-butyl hydroperoxide (tBOOH) toxicity did not attenuate MPP(+) cytotoxicity. Similarly, the combination of antioxidant enzymes, SOD and catalase (50 U/ml, respectively), did not protect the cells from the toxic action of MPP(+). Also N-nitro-l-arginine methyl ester (NAME), a competitive inhibitor of NOS, and combined incubation with NAME and antioxidant enzymes failed to attenuate MPP(+) cytotoxicity. On the other hand, a sublethal dose of MPP(+) potentiated iron and H(2)O(2)-induced cytotoxicity. These results suggest that oxygen free radicals may not be a primary cause of MPP(+)-induced cell death but that MPP(+) increases the vulnerability of cells to oxidative stress.
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PMID:MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. 1096 95

We determined the methamphetamine (MA), a potent dopamine (DA) releaser, enhances 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (&z.rad;OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of .OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. After administration of MA (5 mg/kg i.v., every 2 h, four times), MA drastically increased DA release and the &z.rad;OH formation. When iron (II) was administered to the MA-treated animals, a marked elevation of DHBA was observed, compared with MPP(+)-only treated animals, that showed a positive linear correlation between DA and .OH formation trapped as DHBA (R(2)=0.985) in the dialysate. These results suggest that MA enhances the &z.rad;OH products of efflux/oxidation due to MPP(+).
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PMID:Methamphetamine enhances 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in the rat striatum. 1099 48

The yeast frataxin homolog (Yfh1p) participates in mitochondrial iron homeostasis. The phenotypic defects of the Delta yfh1 mutant include drastic accumulation of iron in mitochondria and slow growth. The Yfh1p precursor protein contains two N-terminal domains that are sequentially cleaved by the matrix processing peptidase on import into mitochondria, generating the mature protein. We have precisely mapped these two cleavage sites. Mutations blocking the first or the second cleavage of Yfh1p do not interfere with its in vitro import or with its ability to complement phenotypes of the Delta yfh1 mutant strain. Distinct roles have been ascertained for the two cleaved domains of Yfh1p. The first cleaved domain (domain I) is sufficient for in vitro mitochondrial import of a non-mitochondrial passenger protein. However, neither domain I nor other matrix-targeting signals alone can support efficient in vitro import of mature Yfh1p. The second cleaved domain (domain II) is required as a spacer between a targeting signal and mature Yfh1p. Likewise, when Yfh1p constructs lacking domain I or II are expressed in vivo, they fail to attain appreciable steady-state amounts in mitochondria and cannot complement phenotypes of the Delta yfh1 mutant.
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PMID:Distinct roles for two N-terminal cleaved domains in mitochondrial import of the yeast frataxin homolog, Yfh1p. 1115 45

Oxygen free radical formation has been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP+) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP+ is one of the most potent dopamine (DA)-releasing agents. Iron-catalyzed DA autoxidation and oxidative stress may be involved in the pathogenesis of Parkinson's disease. If indeed the effect of MPP+ on hydroxyl radical (.OH) formation is due to DA release, reserpine-induced DA depletion may reduce MPP(+)-induced .OH formation. Imidapril, an angiotensin converting enzyme (ACE) inhibitor, can resist MPP(+)-induced .OH formation via suppression of release of DA by angiotensin. Histidine, a singlet oxygen (1O2) scavenger, protects MPP(+)-induced .OH formation. Fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist MPP(+)-induced .OH formation. The inhibitory effect on the susceptibility of LDL oxidation can reduce .OH generation. These drugs may be applied as antiparkinsonian agents. Further clinical investigation is necessary in the future.
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PMID:[Parkinsonism induced by MPTP and free radical generation]. 1123 1

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30


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