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:3.4.24.59 (MIP)
4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of nuclearly encoded mitochondrial protein precursors that are transported into the matrix and inner membrane are cleaved in two sequential steps by two distinct matrix peptidases, mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP). We have isolated and purified MIP from rat liver mitochondrial matrix. The enzyme, purified 2250-fold, is a monomer of 75 kDa and cleaves all tested mitochondrial intermediate proteins to their mature forms. About 20% of the final MIP preparation consists of equimolar amounts of two peptides of 47 kDa and 28 kDa, which are apparently the products of a single cleavage of the 75 kDa protein. These peptides are not separable from the 75 kDa protein, nor from each other, under any conditions used in the purification. The peptidase has a broad pH optimum between pH 6.6 and 8.9 and is inactivated by N-ethylmaleimide (NEM) and other sulfhydryl group reagents. The processing activity is divalent cation-dependent; it is stimulated by manganese, magnesium or calcium ions and reversibly inhibited by EDTA. Zinc, cobalt and iron strongly inhibit MIP activity. This pattern of cation dependence and inhibition is not clearly consistent with that of any known family of proteases.
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PMID:Rat liver mitochondrial intermediate peptidase (MIP): purification and initial characterization. 132 90

A characteristic feature of malaria infection is the occurrence of periodic bouts of fever. Experimental and clinical studies have strongly implicated inflammatory cytokines, like tumour necrosis factor (TNF), in the induction of these intermittent fevers [Clark et al., Infect Immunol 32:1058-1066, 1981; Clark et al., Am J Pathol 129:192-199, 1987; Karunaweera et al., Proc Natl Acad Sci USA 89:3200-3203, 1992], but the malaria-specific metabolite(s) which induce the production of such endogenous pyrogens have not yet been fully characterized. It is well known that during the course of malaria infection, a unique schizont component, alternatively referred to as "malaria pigment" or hemozoin, is released along with merozoites as the host erythrocyte bursts [Urquhart, Clin Infect Dis 19:117-131, 1994]. We have recently determined that the core structure of hemozoin comprises a novel insoluble polymer of heme units linked by iron-carboxylate bonds [Slater et al., Proc Natl Acad Sci USA 88:325-329, 1991; Slater et al., Nature 355:167-169, 1992]. We now report that purified native, as well as chemically synthesized, hemozoin crystals potently induce the release of several pyrogenic cytokines, including TNF, MIP-1 alpha, and MIP-1 beta, from murine macrophages and human peripheral blood monocytes in vitro. Also, intravenous administration of chemically synthesized preparations of hemozoin to anaesthetized rats results in a marked drop in body temperature. A similar drop in body temperature is observed following the intravenous injection of other well-characterized pyrogenic cytokines (e.g., TNF) which are known to induce a fever response in awake animals, and is thought to reflect the inability of rats to appropriately regulate their body temperature while anaesthetized. As a consequence of its ability to induce pyrogenic cytokines in vitro, and thermal dysregulation in vivo, we propose that this unique parasite metabolite is an important pyrogen released by malaria parasites at schizogomy, which acts by eliciting the production of a group of potent endogenous pyrogens, which include MIP-1 alpha and MIP-1 beta, as well as TNF, in macrophages.
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PMID:Malaria-specific metabolite hemozoin mediates the release of several potent endogenous pyrogens (TNF, MIP-1 alpha, and MIP-1 beta) in vitro, and altered thermoregulation in vivo. 758 61

Cleavage of amino-terminal octapeptides, F/L/IXXS/T/GXXXX, by mitochondrial intermediate peptidase (MIP) is typical of many mitochondrial precursor proteins imported to the matrix and the inner membrane. We previously described the molecular characterization of rat liver MIP (RMIP) and indicated a putative homolog in the sequence predicted from gene YCL57w of yeast chromosome III. A new yeast gene, MIP1, has now been isolated by screening a Saccharomyces cerevisiae genomic library with an RMIP cDNA probe. MIP1 predicts a protein of 772 amino acids (YMIP), which is 54% similar and 31% identical to RMIP and includes a putative 37-residue mitochondrial leader peptide. RMIP and YMIP contain the sequence LFHEMGHAM HSMLGRT, which includes a zinc-binding motif, HEXXH, while the predicted YCL57w protein contains a comparable sequence with a lower degree of homology. No obvious biochemical phenotype was observed in a chromosomally disrupted ycl57w mutant. In contrast, a mip1 mutant was unable to grow on nonfermentable substrates, while a mip1 ycl57w double disruption did not result in a more severe phenotype. The mip1 mutant exhibited defects of complexes III and IV of the respiratory chain, caused by failure to carry out the second MIP-catalyzed cleavage of the nuclear-encoded precursors for cytochrome oxidase subunit IV (CoxIV) and the iron-sulfur protein (Fe-S) of the bc1 complex to mature proteins. In vivo, intermediate-size CoxIV was accumulated in the mitochondrial matrix, while intermediate-size Fe-S was targeted to the inner membrane. Moreover, mip1 mitochondrial fractions failed to carry out maturation of the human ornithine transcarbamylase intermediate (iOTC), specifically cleaved by RMIP. A CEN plasmid-encoded YMIP protein restored normal MIP activity along with respiratory competence. Thus, YMIP is a functional homolog of RMIP and represents a new component of the yeast mitochondrial import machinery.
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PMID:MIP1, a new yeast gene homologous to the rat mitochondrial intermediate peptidase gene, is required for oxidative metabolism in Saccharomyces cerevisiae. 803 33

The iron-sulfur protein of the cytochrome bc1 complex is one of a small number of proteins that are processed in two sequential steps by matrix processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP) during import into Saccharomyces cerevisiae mitochondria. To test whether two-step processing is necessary for import and assembly of the iron-sulfur protein into the cytochrome bc1 complex, we mutagenized the presequence of the iron-sulfur protein to eliminate the original MPP site and replace the MIP site with a new MPP site. The mutated presequence is cleaved and forms mature-sized protein in a single step, and the mature-sized iron-sulfur protein is correctly targeted to the outer side of the inner mitochondrial membrane in vitro. Mutant iron-sulfur protein which is processed to mature size in one step complements the respiratory deficient phenotype of a yeast strain in which the endogenous gene for the iron-sulfur protein is deleted. These results establish that mature-sized iron-sulfur protein can be formed by single-step processing and assembled into a functionally active form in the cytochrome bc1 complex in S. cerevisiae.
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PMID:Two-step processing is not essential for the import and assembly of functionally active iron-sulfur protein into the cytochrome bc1 complex in Saccharomyces cerevisiae. 899 25

A new component, which substitutes cytochrome P-450 as an acceptor of reducing equivalents from NADPH-cytochrome P-450 reductase, was identified in the bovine retina microsomal monooxigenase system, which does not contain cytochrome P-450. This component is a non-heme iron-containing protein with molecular mass of 66 kDa. The properties of the protein from the bovine retina are similar to those of MIP, a non-heme iron-containing protein from the heart microsomal monooxigenase system, in which cytochrome P-450 was not identified, either. Activation of the microsomal monooxigenase system (an increase in the NADPH-cytochrome P-450 reductase activity, an increased rate of microsomal NADPH oxidation) was shown in the retina upon long-term intensive illumination. It was shown also that the development of hereditary degeneration of the retina in rats was accompanied by activation of the specific microsomal monooxigenase system in the target tissues (retina, brain cortex) irrespective of its composition (cytochrome P-450 or non-heme iron-containing protein).
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PMID:Membranes of retinal microsomes: a new protein of the microsomal monooxigenase system. 935 97

The purpose of this study was to evaluate the contribution of an ultrasmall superparamagnetic iron oxide particles (USPIOs) based contrast agent (AMI 227), in a transverse three-dimensional time-of-flight TONE MR angiography sequence of abdominal aorta in rabbits. The main goal was to assess improvement in the visualization of small arteries such as renal arteries, when using such a sequence. Imaging experiments were performed on a 1.5 T magnet, using a transverse 3D time-of-flight (TOF) tilted optimized nonsaturating excitation (TONE) sequence with magnetization transfer suppression. The contrast media used were composed of a USPIO core surrounded by a dextran-surfactant (AMI 227). Different concentrations of AMI 227 were evaluated in 12 rabbits. Concentrations varied within the range 8.5-34 micromol Fe/kg - bw: 8.5 micromol Fe/kg (three rabbits); 17 micromol Fe/kg (three rabbits); 25.5 micromol Fe/kg (three rabbits); 34 micromol Fe/kg (three rabbits). A visual analysis based on the improvement of visualization of small arteries (renal arteries) on MIP images and a quantitative analysis based on the percentage of contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained. A signal-to-noise ratio enhancement of the distal part of the aorta and only improvement in the delineation of the renal arteries were noted when using low concentrations of the contrast media. A loss of signal-to-noise ratio of the aorta and a decrease in arterial visualization were respectively noted with higher concentration of contrast media. In this experimental study, using a transverse three-dimensional TOF TONE MR angiography sequence of renal arteries, in which sequence the saturation effect is minimized, the use of AMI 227 allows only improvement in the delineation of small arteries when using low concentrations of contrast media.
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PMID:Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool contrast agent for MR angiography: experimental study in rabbits. 940 Aug 37

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

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

Friedreich's ataxia (FRDA) is a neurodegenerative disease typically caused by a deficiency of frataxin, a mitochondrial protein of unknown function. In Saccharomyces cerevisiae, lack of the yeast frataxin homolog ( YFH1 gene, Yfh1p polypeptide) results in mitochondrial iron accumulation, suggesting that frataxin is required for mitochondrial iron homeostasis and that FRDA results from oxidative damage secondary to mitochondrial iron overload. This hypothesis implies that the effects of frataxin deficiency could be influenced by other proteins involved in mitochondrial iron usage. We show that Yfh1p interacts functionally with yeast mitochondrial intermediate peptidase ( OCT1 gene, YMIP polypeptide), a metalloprotease required for maturation of ferrochelatase and other iron-utilizing proteins. YMIP is activated by ferrous iron in vitro and loss of YMIP activity leads to mitochondrial iron depletion, suggesting that YMIP is part of a feedback loop in which iron stimulates maturation of YMIP substrates and this in turn promotes mitochondrial iron uptake. Accordingly, YMIP is active and promotes mitochondrial iron accumulation in a mutant lacking Yfh1p ( yfh1 [Delta]), while genetic inactivation of YMIP in this mutant ( yfh1 [Delta] oct1 [Delta]) leads to a 2-fold reduction in mitochondrial iron levels. Moreover, overexpression of Yfh1p restores mitochondrial iron homeostasis and YMIP activity in a conditional oct1 ts mutant, but does not affect iron levels in a mutant completely lacking YMIP ( oct1 [Delta]). Thus, we propose that Yfh1p maintains mitochondrial iron homeostasis both directly, by promoting iron export, and indirectly, by regulating iron levels and therefore YMIP activity, which promotes mitochondrial iron uptake. This suggests that human MIP may contribute to the functional effects of frataxin deficiency and the clinical manifestations of FRDA.
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PMID:Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae. 1033 43

The determination methods of germanium (Ge) in biological specimens such as blood plasma, erythrocytes, urine, hair, nail, and other organs were established using graphite furnace atomic absorption spectrometry (GFAAS) and microwave-induced plasma mass spectrometry (MIP-MS). The detection limits of Ge standard solution were 3 ng/mL with GFAAS and 0.05 ng/mL with MIP-MS. The detection limits in organ samples depended on the type of samples and sampling amounts: 3-30 ng/g by GFAAS and 0.05-0.5 ng/g by MIP-MS. The sensitivity of GFAAS was lower than that of MIP-MS; however, it was adequate for determining Ge concentrations in specimens from patients who had ingested Ge. Samples were digested by a simple wet-ashing procedure using nitric acid and perchloric acid. To avoid the interfering effects of coexisting elements and perchloric acid residue, an extraction method using organic solvent was tried. When using MIP-MS, extraction was not necessary; however, both dilution and addition of an internal standard were needed. Special attention was required for iron-rich samples because a molecular ion of 56Fe16O was observed at nm/z72 where 2Ge was monitored. The results of Ge concentrations in human samples obtained by these methods agreed well. Interfering effects of perchloric acid, which was used for digestion and which remained in samples, were observed in both methods. Hair and nail samples from people who had ingested Ge were useful for monitoring Ge in the body. Hair samples were useful for determining past exposure to Ge when the distribution patterns from the scalp to the end of the strand were analyzed. In control subjects, Ge concentrations in the listed specimens and organs were lower than 0.1 microg/g or mL, and these low levels of Ge were able to be determined by MIP-MS in combination with the extraction method.
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PMID:Determination of germanium in human specimens: comparative study of atomic absorption spectrometry and microwave-induced plasma mass spectrometry. 1059 51


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