19 research outputs found
Mechanism of substrate specificity and insights into activation of phosphatidylinositol phosphate kinases
No full textThe phosphatidylinositol phosphate kinase family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and Type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the Type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish Type I kinase PIP5Kα, we identified a subdomain unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas motifs flanking the phosphate binding Arg-244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how phosphatidylinositol phosphate kinases achieve their exquisite substrate specificity. In addition, the data presented here offers insights into activation of the Type I kinase, PIP5K, opening up a number of additional research questions yet to be addressed in this field
Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis
Get PDFAbstract Background The present study compares antiepileptic drugs and aromatase (CYP19) inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs) are needed, especially since every individual responds differently to given treatment options. Methods Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. Results The pharmacophore model returned 73% (19 out of 26) of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62) of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. Conclusions This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity, and the similarity analyses performed propose a number of antiepileptic compounds with high potential for aromatase inhibition.</p
Erratum to “Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19)” [Bioorg. Med. Chem. Lett. 20 (2010) 3050]
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Targeting Glioma Stem Cells
Get PDFOnly a small fraction of the tumor cell population, glioma-initiating cells (GICs) help glioblastoma propagate, invade, evade immune recognition, repair DNA in response to radiation more efficiently, remodel the microenvironment for optimal growth, and actively pump out chemotherapies. Recent data hint that efforts toward GIC characterization and quantification can help predict patient outcomes, and yet the different subpopulations of GICs remain incompletely understood. A better understanding of GIC subtypes and functions proves critical for engineering targeted therapies. Challenges for doing so are discussed, and dopamine receptor antagonists are introduced as new means to enhance the efficacy of the current standard-of-care against GICs
Non-muscle invasive bladder cancer tissues have increased base excision repair capacity
No full textThe molecular mechanisms underlying the development and progression of bladder cancer (BC) are complex and have not been fully elucidated. Alterations in base excision repair (BER) capacity, one of several DNA repair mechanisms assigned to preserving genome integrity, have been reported to influence cancer susceptibility, recurrence, and progression, as well as responses to chemotherapy and radiotherapy. We report herein that non-muscle invasive BC (NMIBC) tissues exhibit increased uracil incision, abasic endonuclease and gap-filling activities, as well as total BER capacity in comparison to normal bladder tissue from the same patient (p<0.05). No significant difference was detected in 8-oxoG incision activity between cancer and normal tissues. NMIBC tissues have elevated protein levels of uracil DNA glycosylase, 8-oxoguanine DNA glycosylase, AP endonuclease 1 and DNA polymerase beta protein. Moreover, the fold increase in total BER and the individual BER enzyme activities were greater in high-grade tissues than in low-grade NMIBC tissues. These findings suggest that enhanced BER activity may play a role in the etiology of NMIBC and that BER proteins could serve as biomarkers in disease prognosis, progression or response to genotoxic therapeutics, such as Bacillus Calmette-Guerin.Muftuoglu, M (corresponding author), Acibadem Mehmet Ali Aydinlar Univ, Dept Med Biotechnol, TR-34752 Istanbul, Turkey ; Acibadem Mehmet Ali Aydinlar Univ, Dept Mol Biol & Genet, TR-34752 Istanbul, Turkey.
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A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases
No full textEvaluation of anterior and posterior corneal aberrations in patients with keratoconus
No full textEvaluation of anterior and posterior corneal aberrations in patients with keratoconusPoster DetailsFirst Author: E.AltinkurtTURKEYCo Author(s): O. Muftuoglu S. Karaman Erdur Abstract DetailsPurpose:To evaluate the anterior and posterior corneal aberrations in patients with keratoconus.Setting:The study is made in a tertiary referral center.Methods:100 eyes of 57 patients with clinical keratoconus and 100 eyes of 50 control patients who were refractive surgery candidates were included in this study. All eyes were evaluated before and 6-months after surgery using Placido-Scheimpflug combined topo/tomographer. Visual acuity, keratometry, anterior, posterior, and total corneal aberrations were analyzed.Results:The mean Ksteep was 48.6 ± 4.8 D in keratoconus group, and 43.2 ±2.1 D in control group. The mean anterior corneal total higher order aberration, coma, and spherical aberration were 1.83±1.39 µm, 1.44 ± 0.92 µm, 0.31 ± 0.29 µm, respectively. The mean posterior corneal total higher order aberration, coma, and spherical aberration were 1.04 ± 1.63 µm, 0.36 ± 0.32 µm, 0.16 ± 0.21 µm, respectively. The mean anterior and posterior corneal total higher order aberration, coma, and spherical aberration were significantly higher than those of control groups (p˂0.05). The differences were more prominent in posterior corneal aberrations.Conclusions:Corneal higher order aberrations, particularly posterior corneal aberrations are significantly higher in eyes with keratoconus compared to normal controls
WITHDRAWN: The effect of coenzyme q10 on a rat model of oleic acid-induced acute lung injury
No full textThis article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy
