Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Many mitochondrial proteins are encoded by nuclear genes and after translation in the cytoplasm are imported via translocases in the outer and inner membranes, the TOM and TIM complexes, respectively. Here, we report the characterization of the mitochondrial protein, Mmp37p (YGR046w) and demonstrate its involvement in the process of protein import into mitochondria. Haploid cells deleted of MMP37 are viable but display a temperature-sensitive growth phenotype and are inviable in the absence of mitochondrial DNA. Mmp37p is located in the mitochondrial matrix where it is peripherally associated with the inner membrane. We show that Mmp37p has a role in the translocation of proteins across the mitochondrial inner membrane via the TIM23-PAM complex and further demonstrate that substrates containing a tightly folded domain in close proximity to their mitochondrial targeting sequences display a particular dependency on Mmp37p for mitochondrial import. Prior unfolding of the preprotein, or extension of the region between the targeting signal and the tightly folded domain, relieves their dependency for Mmp37p. Furthermore, evidence is presented to show that Mmp37 may affect the assembly state of the TIM23 complex. On the basis of these findings, we hypothesize that the presence of Mmp37p enhances the early stages of the TIM23 matrix import pathway to ensure engagement of incoming preproteins with the mtHsp70p/PAM complex, a step that is necessary to drive the unfolding and complete translocation of the preprotein into the matrix.
Mol Biol Cell 2006 Sep
PMID:Characterization of Mmp37p, a Saccharomyces cerevisiae mitochondrial matrix protein with a role in mitochondrial protein import. 1679 Apr 93

The strong fluorescence Tb/acetyl acetone (acac)/Poly (Acrylamide) (PAM) composite nanoparticles have been prepared under ultrasonic radiation. The nanoparticles were water-soluble, stable and have extremely narrow emission bands and high internal quantum efficiencies. Based on the fluorescence quenching of Tb/acac/PAM by Cr (VI), a method for the selective determination of Cr (VI), without separation of Cr (III) in water, was developed. The reaction condition between Cr (VI) and Tb/acac/PAM were investigated in detail. Under optimal experimental conditions, the linear calibration curve was obtained over the concentration range of 5-600 ng mL(-1) with a correlation coefficient of 0.9939. The corresponding detection limit is 0.8 ng mL(-1) and the relative standard deviation is 1.5% for 0.05 microg mL(-1) (n=7). The proposed method has been applied to the selective quantification of Cr (VI) in synthetic samples and waste-water samples with the satisfactory results. The assay is characterized by short reaction time, very few interference, stable fluorescence signals, simple instrument and simplicity.
Spectrochim Acta A Mol Biomol Spectrosc 2006 Sep
PMID:Selective fluorescence determination of chromium (VI) in water samples with terbium composite nanoparticles. 1687 37

Available evidence suggests that, in African populations, systemic blood-dwelling parasitoses of mothers are associated with enhanced susceptibility to infection of their offspring. Thus, children born to mothers with filariasis or schistosomiasis are infected earlier, and offspring of mothers with placental Plasmodium falciparum at delivery, commonly referred to as pregnancy-associated malaria or PAM, are themselves at higher risk of developing parasitaemia during infancy. Since foetal/neonatal antigen-presenting cells (APC) are either immature or provide insufficient costimulatory signals to T cells, thus favouring tolerance induction, it is commonly assumed that soluble parasite components [protein antigens], transferred transplacentally and inducing foetal immune tolerance, are largely, if not exclusively, responsible for these outcomes. Plasmodial asexual blood stage antigen-specific T cells are detectable in as many as two-thirds of all cord blood samples in malaria-endemic countries of sub-Saharan Africa, indicating that in utero sensitization may be a common phenomenon during pregnancy in these populations. Parasite antigen-specific T cell responses of neonates born to helminth-infected mothers display a highly skewed Th2-type cytokine pattern, with a prominent role for the regulatory cytokine interleukin (IL)-10. Similarly, the cord blood immune response of those born to mothers identified with on-going PAM is characterised by inducible parasite antigen-specific IL-10-producing regulatory T cells that can inhibit both APC HLA expression and Th1-type T cell responses. In contrast, plasmodial antigen-specific Th1-type responses, characterised by IFN-gamma production, predominate in cord blood of those born to mothers successfully treated for Pf malaria during gestation, suggesting that the duration and/or the nature of antigen exposure in utero governs the outcome with respect to neonatal immune responses. Aspects of APC function in the context of these differentially modulated responses, whether and how the latter translate into altered susceptibility to Pf infection during infancy, as well as the possible implications for vaccination in early life, are aspects that are discussed in this review.
Mol Biochem Parasitol 2007 Jan
PMID:Placental Plasmodium falciparum infection: causes and consequences of in utero sensitization to parasite antigens. 1708 34

Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for sustained porphyrin synthesis.
Mol Cancer Ther 2007 Mar
PMID:Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates. 1736 82

A novel luminescent and magnetic Fe(3)O(4)/pyrene/polyacrylamide (Fe(3)O(4)/Py/PAM) nanocomposite has been prepared under ultrasonic radiation. This magnetic nanocomposite combined with pyrene would lead to a special functional magnetic luminescent composite that enjoys both the advantages of magnetic nanoparticles of Fe(3)O(4) and fluorescence nanoparticles of pyrene. Taking advantage of the magnetic property of Fe(3)O(4) nanocomposites, we can separate Fe(3)O(4)/Py/PAM nanocomposites from solution easily just by using a permanent magnet. Based on the fluorescence quenching of Fe(3)O(4)/Py/PAM nanocomposites by Cr(VI), a method for the selective determination of Cr(VI), without separation of Cr(III) in water, was developed. Under optimal experimental conditions, a limit of detection of 0.01 microg mL(-1) was achieved. The calibration curve was linear over the concentration range of 0.1-14.0 microg mL(-1) with a correlation coefficient of 0.9975. The proposed method has been applied to the selective quantification of Cr(VI) in synthetic samples and wastewater samples with the satisfactory results.
Spectrochim Acta A Mol Biomol Spectrosc 2008 Jul
PMID:Luminescent and magnetic Fe3O4/Py/PAM nanocomposites for the chromium(VI) determination. 1832 70

High-resolution microwave spectra of the monohydrate and dihydrate of acetic acid were recorded using a pulsed nozzle Fourier transform microwave spectrometer. The rotational and centrifugal distortion constants of these species were determined, which confirms the structures predicted by ab initio calculations that the H(2)O molecules bind to the carboxylic group to form hydrogen-bonded ring complexes. The dependence of the intensity of the rotational transitions on the power of the microwave pulses suggests that both hydrates have small a-and b-dipole moments of less than 0.3 Debye. All rotational transitions were split into two by internal rotation of the methyl group. Analysis of the splitting using both the PAM and the CAM methods allows the orientation and the height of the three-fold barrier to internal rotation (V(3)) of the methyl group to be determined accurately. A consistently declining trend of V(3) from the acid monomer [168.16 cm(-1), B. P. van Eijck, J. van Opheusden, M. M. M. van Schaik and E. van Zoeren, J. Mol. Spectrosc., 1981, 86, 465] through the monohydrate (138.396 cm(-1)) and the dihydrate (118.482 cm(-1)) was observed, which suggests that the amount of decrease of V(3) may be correlated with the strength of hydrogen bonding in these complexes.
 ...
PMID:The monohydrate and dihydrate of acetic acid: a high-resolution microwave spectroscopic study. 1908 93

mTOR complex 1 (mTORC1) plays a central role in cell growth and cellular responses to metabolic stress. Although mTORC1 has been shown to be activated after Toll-like receptor (TLR)-4 engagement, there is little information concerning the role that mTORC1 may play in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury. To examine these issues, we determined the effects of rapamycin-induced inhibition of mTORC1 on TLR2- and TLR4-induced neutrophil activation. mTORC1 was dose- and time-dependently activated in murine bone marrow neutrophils cultured with the TLR4 ligand, LPS, or the TLR2 ligand, Pam(3) Cys-Ser-(Lys)(4) (PAM). Incubation of PAM- or LPS-stimulated neutrophils with rapamycin inhibited expression of TNF-alpha and IL-6, but not IkappaB-alpha degradation or nuclear translocation of NF-kappaB. Exposure of PAM or LPS-stimulated neutrophils to rapamycin inhibited phosphorylation of serine 276 in the NF-kappaB p65 subunit, a phosphorylation event required for optimal transcriptional activity of NF-kappaB. Rapamycin pretreatment inhibited PAM- or LPS-induced mTORC1 activation in the lungs. Administration of rapamycin also decreased the severity of lung injury after intratracheal LPS or PAM administration, as determined by diminished neutrophil accumulation in the lungs, reduced interstitial pulmonary edema, and diminished levels of TNF-alpha and IL-6 in bronchoalveolar lavage fluid. These results indicate that mTORC1 activation is essential in TLR2- and TLR4-induced neutrophil activation, as well as in the development and severity of acute lung injury.
Am J Respir Cell Mol Biol 2009 Aug
PMID:Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. 1913 41

Fbxo45 is an F-box protein that is restricted to the nervous system. Unlike other F-box proteins, Fbxo45 was found not to form an SCF complex as a result of an amino acid substitution in the consensus sequence for Cul1 binding. Proteomics analysis revealed that Fbxo45 specifically associates with PAM (protein associated with Myc), a RING finger-type ubiquitin ligase. Mice deficient in Fbxo45 were generated and found to die soon after birth as a result of respiratory distress. Fbxo45(-)(/)(-) embryos show abnormal innervation of the diaphragm, impaired synapse formation at neuromuscular junctions, and aberrant development of axon fiber tracts in the brain. Similar defects are also observed in mice lacking Phr1 (mouse ortholog of PAM), suggesting that Fbxo45 and Phr1 function in the same pathway. In addition, neuronal migration was impaired in Fbxo45(-)(/)(-) mice. These results suggest that Fbxo45 forms a novel Fbxo45-PAM ubiquitin ligase complex that plays an important role in neural development.
Mol Cell Biol 2009 Jul
PMID:Fbxo45 forms a novel ubiquitin ligase complex and is required for neuronal development. 1939 81

Mitochondrial import of cleavable preproteins occurs at translocation contact sites, where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport form containing the presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23(SORT)). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23(SORT) and TOM-TIM23-PAM. These two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import.
Mol Cell Biol 2010 Jan
PMID:Distinct forms of mitochondrial TOM-TIM supercomplexes define signal-dependent states of preprotein sorting. 1988 44

PHR [PAM (protein associated with Myc)-HIW (Highwire)-RPM-1 (regulator of presynaptic morphology 1)] proteins are conserved, large multi-domain E3 ubiquitin ligases with modular architecture. PHR proteins presynaptically control synaptic growth and axon guidance and postsynaptically regulate endocytosis of glutamate receptors. Dysfunction of neuronal ubiquitin-mediated proteasomal degradation is implicated in various neurodegenerative diseases. PHR proteins are characterized by the presence of two PHR domains near the N-terminus, which are essential for proper localization and function. Structures of both the first and second PHR domains of Mus musculus (mouse) Phr1 (MYC binding protein 2, Mycbp2) have been determined, revealing a novel beta sandwich fold composed of 11 antiparallel beta-strands. Conserved loops decorate the apical side of the first PHR domain (MmPHR1), yielding a distinct conserved surface feature. The surface of the second PHR domain (MmPHR2), in contrast, lacks significant conservation. Importantly, the structure of MmPHR1 provides insights into a loss-of-function mutation, Gly1092-->Glu, observed in the Caenorhabditis elegans ortholog RPM-1.
J Mol Biol 2010 Apr 09
PMID:Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092-->Glu) of the C. elegans ortholog RPM-1. 2015 52


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