Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 have been proven to predict a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. There is evidence of in vivo therapeutic response to the cross-linking agents; such as mitomycin C (MMC) in BRCA2 mutated pancreatic cell lines. We present the 'first patient' who achieved a prolonged survival on irinotecan, a topoisomerase I poison, administered alone and then in combination with cetuximab. Our patient presented at the age of 71 years with a dual diagnosis of prostate carcinoma and pancreatic carcinoma on the background of a significant family history of cancer. On genetic testing, he was found to have the common Ashkenazi Jewish BRCA2 mutation, 6174delT. To date, he has received 22 cycles of docetaxel, capecitabine, and gemcitibine followed by single agent irinotecan every 3 weeks for 27 cycles, and then weekly cetuximab was added to the regimen at cycle 28. His disease then remained stable for an additional 13 months. He did not have mutated KRAS. MMC and oxaliplatin was then introduced upon progression. His current treatment is MMC plus irinotecan as oxaliplatin was removed because of a hypersensitivity reaction. This patient is stable with an Eastern Cooperative Oncology Group performance status of 0, four and a half years (56 months) after his initial diagnosis. DNA topoisomerases are nuclear enzymes responsible for the regulation of DNA topology. They are involved in basic DNA transactions during replication, transcription, and recombination. BRCA2-deficient human cells are deficient in the repair of double-strand breaks and DNA cross-links through homologous recombination. Active poisons of topoisomerase I include derivatives of camptothecin. Our case is the first clinical piece of evidence that demonstrates an increased sensitivity to camptothecin-11 and a reduced topoisomerase I relaxation activity in BRCA2 associated pancreatic cancer. This case shows that patients with metastatic pancreatic carcinoma and BRCA2 mutations may have disease that is biologically more chemosensitive and consequently prolong survival despite prognostically unfavorable disease.
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PMID:Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. 1943 78

We describe a previously healthy, non-leukaemic young male presenting with neurological deficit and a pathological dislocation of D8 over D9 vertebra. The magnetic resonance imaging showed an enhancing soft tissue tumour. His basic laboratory workup as well as a bone marrow biopsy was normal. Through a single midline posterior approach, he underwent a decompressive laminectomy of D8 and D9 vertebra, anterior column reconstruction with a meshed titanium cage and posterior pedicle screw instrumentation. The histological diagnosis of granulocytic sarcoma was confirmed by appropriate immuno-histochemical studies. He received postoperative radiotherapy following which his wound dehiscesed and the tumour fungated and spread to his left thigh. He declined chemotherapy and unfortunately expired 9 months later. This case is presented to draw attention to the unusual presentation and to stress that granulocytic sarcoma should be kept in mind when making the differential diagnosis in patients with signs of spinal cord compression even in non-leukaemic individuals.
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PMID:Pathological dislocation of the dorsal spine following granulocytic sarcoma in a non-leukaemic patient. 1968 54

A father and daughter both had multiple pathological fractures and nodal osteoarthropathy. The father, aged 50 years, had at least 20 healed fractures of the axial and appendicular skeleton, sustained by minor trauma over his 50-year lifespan, many of which had been surgically fixed prior to his first presentation to us. Fractures of the clavicles, thoracic cage and long bones of the arms and legs, had healed with malalignment and deformity. Healed fractures were complicated by ankylosis of the cervical vertebrae and both elbows. He also had osteoarthritis of the hands, with exuberant osteophytosis, and profound perceptive deafness. His general health was good, his intellect and facies were normal, and his sclerae were white. The daughter, aged 27 years, had sustained at least seven fractures of the axial and appendicular skeleton following trivial injuries, in distribution similar to those of the father.She had also experienced painful swelling of the fingers,which preceded progressive development of nodal osteoarthropathy.Her hearing was normal. In both individuals,biochemical and immunological investigations yielded normal results. It was not possible for molecular studies to be undertaken. Pedigree data were consistent with autosomal dominant transmission, and this disorder appeared to be a previously undocumented heritable skeletal dysplasia.
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PMID:Hereditary bone dysplasia with pathological fractures and nodal osteoarthropathy. 1975 88

Self-assembling protein cage structures have many potential applications in nanotechnology, one of which is therapeutic delivery. For intracellular targeting, pH-controlled disassembly of virus-like particles and release of their molecular cargo is particularly strategic. We investigated the potential of using histidines for introducing pH-dependent disassembly in the E2 subunit of pyruvate dehydrogenase. Two subunit interfaces likely to disrupt stability, an intratrimer interface (the N-terminus) and an intertrimer interface (methionine-425), were redesigned. Our results show that changing the identity of the putative anchor site 425 to histidine does not decrease stability. In contrast, engineering non-native pH-dependent behavior and modulating the transition pH at which disassembly occurs can be accomplished by mutagenesis of the N-terminus and by ionic strength changes. The observed pH-triggered disassembly is due to electrostatic repulsions generated by histidine protonation. These results suggest that altering the degree of electrostatic repulsion at subunit interfaces could be a generally applicable strategy for designing pH-triggered assembly in protein macromolecular structures.
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PMID:pH-triggered disassembly in a caged protein complex. 1987 26

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
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PMID:Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. 1993 46

This paper presents the results of the study of the effects of long-term low-level exposure of rats to microwaves. Rats were exposed in far field to 2450 MHz continuous wave fields providing an incident power density at the cages of 500 microW/cm2 for 7 hours daily for a total of 30 days resulting in a whole-body SAR of 0.16 +/- 0.04 W/kg. Three groups ("EMF-exposure", "sham-exposure" and cage-control) were formed, each consisting of 16 rats. Circulating antibodies (IgA, IgG and IgM) directed against 16 chemical substances were evaluated in coded serum from each group of rats by enzyme multiplied analysis (ELISA test). An increased amount of compounds resulting from interaction of amino acids with nitric oxide (NO) or its derivatives (NO2-Tyrosine, NO-Arginine, NO-Cysteine + NO-Bovine Serum Albumin, NJ-Methionine + NO-Asparagine + No-Histidine, NO-BTrypnohan + NJ-Tyrosin), fatty acids with small chains, hydroxylated fatty acids, palmitic/myristic/oleic acid, AZE (product of oxidation of fatty acids) was found in blood serum from EMF-exposed rats. As a rule, antibodies to conjugated antigens were seen for IgM, rarely seen for IgG and were completely absent for IgA. The levels of antibodies were higher on day 7 after the exposure compared to those on day 14 after the exposure.
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PMID:[Autoimmune processes after long-term low-level exposure to electromagnetic fields (the results of an experiment). Part 4. Manifestation of oxidative intracellular stress-reaction after long-term non-thermal EMF exposure of rats]. 2029 77

Covalent binding of nitric oxide to specific cysteine residues in proteins is a key event in cellular redox signal transduction. This modification influences both physiological and pathological processes, such as cardiovascular, neurological, and cancer-associated events. Even though, since its introduction, the biotin switch technique is the most used indirect method for the study of S-nitrosylation both in vivo and in vitro, during the last years modifications of this method have emerged, allowing more efficient sample enrichment and the precise identification of the modified aminoacidic sites. At the same time, to bypass the difficulties generated by the multiple chemical reaction steps required by these labeling methods, the direct identification of the SNO groups by mass spectrometry is emerging as a useful tool in this field, although, until now, it has been limited to the study of synthetic or purified recombinant proteins. Here we present two different techniques, developed in our laboratories, for detection of S-nitrosylation: the first is based on a modification of the biotin switch technique and is called His-tag switch, and the second is a direct mass spectrometry-based method used to detect in vivo generated SNO groups.
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PMID:Direct and indirect detection methods for the analysis of S-nitrosylated peptides and proteins. 2051 83

Hybridization of metal complexes and protein scaffolds is an important subject in bioinorganic chemistry and materials science. Efforts to provide non-natural functions to proteins will likely lead to advances in development of catalysts, sensors, and so on. Mechanistic investigations of the process of binding of metal complexes within protein scaffolds and characterization of the resulting coordination structures will help us to design and control coordination structures of metal complexes for construction of hybrid proteins containing metal complexes. In this work, the processes of accumulation and incorporation of organometallic palladium complexes within the cage of the iron storage protein apo-ferritin (apo-Fr) are elucidated by analysis of X-ray crystal structures of apo-Fr and selected mutants thereof, in the presence of the metal complexes. The crystal structure of apo-Fr containing Pd(allyl) (allyl = eta(3)-C(3)H(5)) complexes shows that thiolato-bridged dinuclear Pd(allyl) complexes are formed at two binding sites within the cage of apo-Fr. The crystal structures of apo-Fr and its Cys- and His-deletion mutants containing Pd(allyl) complexes indicate that Cys126 accelerates the incorporation of Pd(allyl) complexes into the cage. In addition, Cys48 and Cys126 are essential for accumulation of Pd(allyl) complexes and stabilizing the square planar coordination structure.
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PMID:Mechanism of accumulation and incorporation of organometallic Pd complexes into the protein nanocage of apo-ferritin. 2058 8

Apo-ferritin (apo-Fr) mutants are used as scaffolds to accommodate palladium (allyl) complexes. Various coordination arrangements of the Pd complexes are achieved by adjusting the positions of cysteine and histidine residues on the interior surface of the apo-Fr cage.
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PMID:Definite coordination arrangement of organometallic palladium complexes accumulated on the designed interior surface of apo-ferritin. 2073 Feb 33

Spherical protein cages such as an iron storage protein, ferritin, have great potential as nanometer-scale capsules to assemble and store metal ions and complexes. We report herein the synthesis of a composite of an apo-ferritin cage and Ru(p-cymene) complexes. Ru complexes were efficiently incorporated into the ferritin cavity without degradation of its cage structure. X-Ray crystallography revealed that the Ru complexes were immobilized on the interior surface of the cage mainly by the coordination of histidine residues.
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PMID:Incorporation of organometallic Ru complexes into apo-ferritin cage. 2111 34


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