Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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

Typically, pathogenesis of the hemibiotroph Colletotrichum graminicola and defense responses of its host, Zea mays, are studied on young leaves. Equivalent studies have not been performed with leaves undergoing senescence, a situation that is relevant in the field. We discovered that, in contrast to anthracnose symptoms formed on young and mature leaves, green islands reminiscent of those known from obligate biotrophs were formed on senescing leaves. Microscopy revealed that the fungus grew in both symptoms from the epidermis towards the bundle sheath. In green islands, tissues remained intact for an extended time period. Imaging PAM (pulse-amplitude-modulation) fluorescence analyses revealed that photosynthesis is transiently maintained at green islands but declined in tissue surrounding the infection. In younger leaves however, photosynthesis was reduced only at infection sites. Support for the local modification of host physiology came from quantitative reverse transcription-polymerase chain reaction analyzing gene expression at high spatial resolution. Decreased transcript levels of the senescence markers see1 and ccp1 corroborated a pathogen-induced delay of senescence. Expression of several genes encoding proteins involved in photosynthesis was strongly reduced by infection. In contrast, transcript levels of incw1, encoding a cell-wall invertase, were increased 70-fold at green islands, suggesting that C. graminicola induced carbon sinks in senescing tissue.
Mol Plant Microbe Interact 2010 Jul
PMID:The hemibiotroph Colletotrichum graminicola locally induces photosynthetically active green islands but globally accelerates senescence on aging maize leaves. 2052 51

Neurons and endocrine cells package peptides in secretory granules (large dense-core vesicles) for storage and stimulated release. Studies of peptidylglycine alpha-amidating monooxygenase (PAM), an essential secretory granule membrane enzyme, revealed a pathway that can relay information from secretory granules to the nucleus, resulting in alterations in gene expression. The cytosolic domain (CD) of PAM, a type 1 membrane enzyme essential for the production of amidated peptides, is basally phosphorylated by U2AF homology motif kinase 1 (Uhmk1) and other Ser/Thr kinases. Proopiomelanocortin processing in AtT-20 corticotrope tumor cells was increased when Uhmk1 expression was reduced. Uhmk1 was concentrated in the nucleus, but cycled rapidly between nucleus and cytosol. Endoproteolytic cleavage of PAM releases a soluble CD fragment that localizes to the nucleus. Localization of PAM-CD to the nucleus was decreased when PAM-CD with phosphomimetic mutations was examined and when active Uhmk1 was simultaneously overexpressed. Membrane-tethering Uhmk1 did not eliminate its ability to exclude PAM-CD from the nucleus, suggesting that cytosolic Uhmk1 could cause this response. Microarray analysis demonstrated the ability of PAM to increase expression of a small subset of genes, including aquaporin 1 (Aqp1) in AtT-20 cells. Aqp1 mRNA levels were higher in wild-type mice than in mice heterozygous for PAM, indicating that a similar relationship occurs in vivo. Expression of PAM-CD also increased Aqp1 levels whereas expression of Uhmk1 diminished Aqp1 expression. The outlines of a pathway that ties secretory granule metabolism to the transcriptome are thus apparent.
Mol Endocrinol 2010 Aug
PMID:Signaling from the secretory granule to the nucleus: Uhmk1 and PAM. 2057 87

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.
Mol Pharmacol 2010 Dec
PMID:Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. 2092 53


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