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Natalia Mast Casey Charvet Irina A. Pikuleva C. David Stout 《The Journal of biological chemistry》2010,285(41):31783-31795
Cytochrome P450 46A1 (CYP46A1) initiates the major pathway of cholesterol elimination from the brain and thereby controls cholesterol turnover in this organ. We determined x-ray crystal structures of CYP46A1 in complex with four structurally distinct pharmaceuticals; antidepressant tranylcypromine (2.15 Å), anticonvulsant thioperamide (1.65 Å), antifungal voriconazole (2.35 Å), and antifungal clotrimazole (2.50 Å). All four drugs are nitrogen-containing compounds that have nanomolar affinity for CYP46A1 in vitro yet differ in size, shape, hydrophobicity, and type of the nitrogen ligand. Structures of the co-complexes demonstrate that each drug binds in a single orientation to the active site with tranylcypromine, thioperamide, and voriconazole coordinating the heme iron via their nitrogen atoms and clotrimazole being at a 4 Å distance from the heme iron. We show here that clotrimazole is also a substrate for CYP46A1. High affinity for CYP46A1 is determined by a set of specific interactions, some of which were further investigated by solution studies using structural analogs of the drugs and the T306A CYP46A1 mutant. Collectively, our results reveal how diverse inhibitors can be accommodated in the CYP46A1 active site and provide an explanation for the observed differences in the drug-induced spectral response. Co-complexes with tranylcypromine, thioperamide, and voriconazole represent the first structural characterization of the drug binding to a P450 enzyme. 相似文献
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Natalia Mast Yong Li Marlin Linger Matthew Clark Jeffrey Wiseman Irina A. Pikuleva 《The Journal of biological chemistry》2014,289(6):3529-3538
Cytochrome P450 46A1 (CYP46A1) is a brain-specific cholesterol 24-hydroxylase responsible for the majority of cholesterol elimination from the brain. Genetically increased CYP46A1 expression in mice leads to improved cognition and decreases manifestations of Alzheimer disease. We found that four pharmaceuticals (efavirenz (EFV), acetaminophen, mirtazapine, and galantamine) prescribed for indications unrelated to cholesterol maintenance increased CYP46A1 activity in vitro. We then evaluated the anti-HIV medication EFV for the mode of interaction with CYP46A1 and the effect on mice. We propose a model for CYP46A1 activation by EFV and show that EFV enhanced CYP46A1 activity and cerebral cholesterol turnover in animals with no effect on the levels of brain cholesterol. The doses of EFV administered to mice and required for the stimulation of their cerebral cholesterol turnover are a hundred times lower than those prescribed to HIV patients. At such small doses, EFV may be devoid of adverse effects elicited by high drug concentrations. CYP46A1 could be a novel therapeutic target and a tool to further investigate the physiological and medical significance of cerebral cholesterol turnover. 相似文献
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Tajvur P Saber CT Ng Guillaume Renard Bernadette M Lynch Eliza Pontifex Ceara AE Walsh Alexia Grier Marian Molloy Barry Bresnihan Oliver FitzGerald Ursula Fearon Douglas J Veale 《Arthritis research & therapy》2010,12(3):1-6
Introduction
Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFα) therapy and to examine possible predictors of response.Methods
Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected.Results
A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P < 0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P < 0.001).Conclusions
DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ. 相似文献87.
Primula (c. 430 species) and relatives (Primulaceae) are paradigmatic to our understanding of distyly. However, the common co-occurrence of distyly and monomorphy in closely related groups within the family has made the interpretation of its evolution difficult.Here, we infer a chloroplast DNA (cpDNA) phylogeny for 207 accessions, including 51% of the species and 95% of the sections of Primula with monomorphic populations, using Bayesian methods. With this tree, we infer the distribution of ancestral states on critical nodes using parsimony and likelihood methods.The inferred cpDNA phylogeny is consistent with prior estimates. The most recent common ancestor (MRCA) of Primula is resolved as distylous using both methods of inference. However, whether the distyly in Primula, Hottonia, and Vitaliana arose once or three independent times is not clear.We conclude that monomorphism in descendants of the MRCA of Primula is derived from distyly in all cases. Thus, scenarios for the evolution of distyly that rely on the persistence of primitive monomorphy (such as in Primula section Sphondylia) require re-evaluation. 相似文献
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A 64-year-old male, with a history of a lateral myocardial infarction, presented with haemodynamically well-tolerated incessant therapy-resistant slow monomorphic ventricular tachycardia (mVT), despite implantable cardioverter defibrillator and antiarrhythmic drugs. 相似文献
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Rudi Wisaksana Quirijn de Mast Bachti Alisjahbana Hadi Jusuf Primal Sudjana Agnes R. Indrati Rachmat Sumantri Dorine Swinkels Reinout van Crevel Andre van der Ven 《PloS one》2013,8(11)