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[PMID]:28642370
[Au] Autor:Mast N; Anderson KW; Johnson KM; Phan TTN; Guengerich FP; Pikuleva IA
[Ad] Endereço:From the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106.
[Ti] Título: cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds.
[So] Source:J Biol Chem;292(31):12934-12946, 2017 Aug 04.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, γ-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 , the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH-cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our data, along with those from previous cell culture and studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance.
[Mh] Termos MeSH primário: Acetilcolina/metabolismo
Ácido Aspártico/metabolismo
Colesterol 24-Hidroxilase/metabolismo
Ácido Glutâmico/metabolismo
Modelos Moleculares
Proteínas do Tecido Nervoso/agonistas
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Acetilcolina/química
Regulação Alostérica/efeitos dos fármacos
Substituição de Aminoácidos
Fármacos Anti-HIV/química
Fármacos Anti-HIV/metabolismo
Fármacos Anti-HIV/farmacologia
Ácido Aspártico/química
Benzoxazinas/química
Benzoxazinas/metabolismo
Benzoxazinas/farmacologia
Sítios de Ligação
Biocatálise/efeitos dos fármacos
Colesterol 24-Hidroxilase/química
Colesterol 24-Hidroxilase/genética
Medição da Troca de Deutério
Ativação Enzimática/efeitos dos fármacos
Ácido Glutâmico/química
Ligantes
Simulação de Acoplamento Molecular
Mutagênese Sítio-Dirigida
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Conformação Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Ácido gama-Aminobutírico/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Benzoxazines); 0 (Ligands); 0 (Nerve Tissue Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 30KYC7MIAI (Aspartic Acid); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); EC 1.14.14.25 (Cholesterol 24-Hydroxylase); JE6H2O27P8 (efavirenz); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.794909


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[PMID]:28190002
[Au] Autor:Mast N; Anderson KW; Lin JB; Li Y; Turko IV; Tatsuoka C; Bjorkhem I; Pikuleva IA
[Ad] Endereço:From the Departments of Ophthalmology and Visual Sciences and.
[Ti] Título:Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum.
[So] Source:J Biol Chem;292(12):4913-4924, 2017 Mar 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and cholestanol, the 5α-saturated analog of cholesterol. In mice, xanthomas are not formed, despite a significant cholestanol increase in the brain and cerebellum. The mechanism behind cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize cholestanol. It also is unclear why CYP27A1 deficiency results in preferential cholestanol accumulation in the cerebellum. We hypothesized that cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models ( , , , and two wild type strains) and human brain specimens. experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in cholestanol removal from the brain and that several factors contribute to the preferential increase in cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, the lack of which probably selectively increases the cerebellar cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/cholestanol-metabolizing P450s from a pool of metabolically available cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Colestanotriol 26-Mono-Oxigenase/metabolismo
Colestanol/metabolismo
Colesterol/metabolismo
[Mh] Termos MeSH secundário: Animais
Cerebelo/metabolismo
Colestanotriol 26-Mono-Oxigenase/genética
Colestenonas/metabolismo
Colesterol 24-Hidroxilase/metabolismo
Feminino
Técnicas de Inativação de Genes
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholestenones); 3862-25-7 (7 alpha-hydroxy-4-cholesten-3-one); 8M308U816E (Cholestanol); 97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase); EC 1.14.15.15 (CYP27A1 protein, human); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.15 (Cyp27a1 protein, mouse)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170213
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.774760


  3 / 136 MEDLINE  
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[PMID]:27789278
[Au] Autor:Lopez AM; Chuang JC; Posey KS; Turley SD
[Ad] Endereço:Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: adam.lopez@utsouthwestern.edu.
[Ti] Título:Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis.
[So] Source:Brain Res;1654(Pt A):77-84, 2017 Jan 01.
[Is] ISSN:1872-6240
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2 and their Mecp2 littermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2 mice than in their Mecp2 controls except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2 mice than in age-matched Mecp2 littermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2 mice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Encéfalo/metabolismo
Colesterol/biossíntese
Ácidos Graxos/biossíntese
Proteína 2 de Ligação a Metil-CpG/deficiência
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas E/metabolismo
Encéfalo/crescimento & desenvolvimento
Encéfalo/patologia
Colesterol 24-Hidroxilase/metabolismo
Fígado/crescimento & desenvolvimento
Fígado/metabolismo
Pulmão/crescimento & desenvolvimento
Pulmão/metabolismo
Masculino
Proteína 2 de Ligação a Metil-CpG/genética
Camundongos da Linhagem 129
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Tamanho do Órgão
RNA Mensageiro
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Fatty Acids); 0 (Mecp2 protein, mouse); 0 (Methyl-CpG-Binding Protein 2); 0 (RNA, Messenger); 97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


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[PMID]:27663182
[Au] Autor:Moutinho M; Nunes MJ; Rodrigues E
[Ad] Endereço:Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
[Ti] Título:Cholesterol 24-hydroxylase: Brain cholesterol metabolism and beyond.
[So] Source:Biochim Biophys Acta;1861(12 Pt A):1911-1920, 2016 12.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The major elimination pathway of brain cholesterol is its hydroxylation into 24 (S)-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1). Interestingly, there seems to be an association between CYP46A1 and high-order brain functions, in a sense that increased expression of this hydroxylase improves cognition, while a reduction leads to a poor cognitive performance. Moreover, increasing amount of epidemiological, biochemical and molecular evidence, suggests that CYP46A1 has a role in the pathogenesis or progression of neurodegenerative disorders, in which up-regulation of this enzyme is clearly beneficial. However, the mechanisms underlying these effects are poorly understood, which highlights the importance of studies that further explore the role of CYP46A1 in the central nervous system. In this review we summarize the major findings regarding CYP46A1, and highlight the several recently described pathways modulated by this enzyme from a physiological and pathological perspective, which might account for novel therapeutic strategies for neurodegenerative disorders.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Colesterol 24-Hidroxilase/metabolismo
Colesterol/metabolismo
[Mh] Termos MeSH secundário: Animais
Sistema Nervoso Central/metabolismo
Seres Humanos
Doenças Neurodegenerativas/metabolismo
Regulação para Cima/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160925
[St] Status:MEDLINE


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[PMID]:27622776
[Au] Autor:Pérez-Cañamás A; Sarroca S; Melero-Jerez C; Porquet D; Sansa J; Knafo S; Esteban JA; Sanfeliu C; Ledesma MD
[Ad] Endereço:Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
[Ti] Título:A diet enriched with plant sterols prevents the memory impairment induced by cholesterol loss in senescence-accelerated mice.
[So] Source:Neurobiol Aging;48:1-12, 2016 Dec.
[Is] ISSN:1558-1497
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholesterol reduction at the neuronal plasma membrane has been related to age-dependent cognitive decline. We have used senescent-accelerated mice strain 8 (SAMP8), an animal model for aging, to examine the association between cholesterol loss and cognitive impairment and to test strategies to revert this process. We show that the hippocampus of SAMP8 mice presents reduced cholesterol levels and enhanced amount of its degrading enzyme Cyp46A1 (Cyp46) already at 6 months of age. Cholesterol loss accounts for the impaired long-term potentiation in these mice. Plant sterol (PSE)-enriched diet prevents long-term potentiation impairment and cognitive deficits in SAMP8 mice without altering cholesterol levels. PSE diet also reduces the abnormally high amyloid peptide levels in SAMP8 mice brains and restores membrane compartmentalization of presenilin1, the catalytic component of the amyloidogenic γ-secretase. These results highlight the influence of cholesterol loss in age-related cognitive decline and provide with a noninvasive strategy to counteract it. Our results suggest that PSE overtake cholesterol functions in the brain contributing to reduce deleterious consequences of cholesterol loss during aging.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Envelhecimento/psicologia
Colesterol/deficiência
Disfunção Cognitiva/etiologia
Disfunção Cognitiva/prevenção & controle
Suplementos Nutricionais
Fitosteróis/administração & dosagem
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/metabolismo
Animais
Colesterol/metabolismo
Colesterol 24-Hidroxilase/metabolismo
Hipocampo/enzimologia
Hipocampo/metabolismo
Potenciação de Longa Duração
Masculino
Camundongos Endogâmicos
Modelos Animais
Presenilina-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Phytosterols); 0 (Presenilin-1); 97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160914
[St] Status:MEDLINE


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[PMID]:27514747
[Au] Autor:Saadane A; Mast N; Dao T; Ahmad B; Pikuleva IA
[Ad] Endereço:From the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio and.
[Ti] Título:Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells.
[So] Source:J Biol Chem;291(39):20427-39, 2016 Sep 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1(-/-)Cyp46a1(-/-) mice. These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1(-/-)Cyp46a1(-/-) retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content. Mouse OS were also found to express the cholesterol-esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT1), but not lecithin-cholesterol acyltransferase (LCAT), and to differ from humans in retinal expression of ACAT1. Nevertheless, cholesterol esters were discovered to be abundant in human OS. We suggest a mechanism for cholesterol ester accumulation in the OS and that activity impairment of ACAT1 in humans may underlie the development of subretinal drusenoid deposits, a hallmark of age-related macular degeneration, which is a common blinding disease. We generated Cyp27a1(-/-)Cyp46a1(-/-)Acat1(-/-) mice, characterized their retina by different imaging modalities, and confirmed that unesterified cholesterol does accumulate in their OS and that there is photoreceptor apoptosis and OS degeneration in this line. Our results provide insights into the retinal response to local hypercholesterolemia and the retinal significance of cholesterol esterification, which could be cell-specific and both beneficial and detrimental for retinal structure and function.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Hipercolesterolemia/metabolismo
Células Fotorreceptoras de Vertebrados/metabolismo
Doenças Retinianas/metabolismo
[Mh] Termos MeSH secundário: Acetil-CoA C-Acetiltransferase/genética
Acetil-CoA C-Acetiltransferase/metabolismo
Animais
Colestanotriol 26-Mono-Oxigenase/genética
Colestanotriol 26-Mono-Oxigenase/metabolismo
Colesterol/genética
Colesterol 24-Hidroxilase/genética
Colesterol 24-Hidroxilase/metabolismo
Esterificação
Seres Humanos
Hipercolesterolemia/complicações
Hipercolesterolemia/genética
Hipercolesterolemia/patologia
Camundongos
Camundongos Knockout
Células Fotorreceptoras de Vertebrados/patologia
Doenças Retinianas/etiologia
Doenças Retinianas/genética
Doenças Retinianas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.15 (Cyp27a1 protein, mouse); EC 2.3.1.9 (Acat1 protein, mouse); EC 2.3.1.9 (Acetyl-CoA C-Acetyltransferase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170923
[Lr] Data última revisão:
170923
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160813
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.744656


  7 / 136 MEDLINE  
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[PMID]:27162448
[Au] Autor:Chandra A; Abbas S; Raza ST; Singh L; Rizvi S; Mahdi F
[Ad] Endereço:Department of Biochemistry, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India.
[Ti] Título:Polymorphism of CYP46A1 and PPARγ2 Genes in Risk Prediction of Primary Open Angle Glaucoma Among North Indian Population.
[So] Source:Middle East Afr J Ophthalmol;23(2):172-6, 2016 Apr-Jun.
[Is] ISSN:0975-1599
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Glaucoma is the leading cause of irreversible blindness and the second most common cause of all blindness after cataracts. This study investigates the association of polymorphism in the CYP46A1 and PPARγ2 genes and primary open angle glaucoma (POAG). MATERIALS AND METHODS: This study evaluated 122 POAG cases (POAG group) and 112 cases of nonglaucomatous patients (control group). Polymorphisms of the CYP46A1 gene and PPARγ2 gene were evaluated with the polymerase chain reaction-restriction fragment length polymorphism method in both groups. RESULTS: The mean ages were 49.88 ± 12.34 years and 53.74 ± 11.87 years for the POAG group and control group, respectively. The CYP46A1 gene CC, CT, TT genotype frequencies were 13.93%, 58.2%, 27.87% in the POAG group and 19.6%, 40.19%, 40.19% in the control group, respectively. The PPARγ2 gene CC, CG, GG genotype frequencies were 16.83%, 54.45%, 28.71% in cases and 3.92%, 28.43%, 67.64% in the control group, respectively. Statistically, significant differences in the frequencies of CYP46A1 CC, CT, TT and PPARγ2 CC, CG, GG (P < 0.05) genotype were found between groups (P < 0.05, all comparisons). CONCLUSION: Findings of this study suggest that CYP46A1 gene and PPARγ2 gene polymorphisms can be a predictive marker for early identification of population at risk of POAG, although a larger sample size is required to determine the role of these polymorphisms in the pathogenesis and course of POAG.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética
Colesterol 24-Hidroxilase/genética
Glaucoma de Ângulo Aberto/genética
PPAR gama/genética
Polimorfismo Genético
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Casos e Controles
Feminino
Marcadores Genéticos
Técnicas de Genotipagem
Seres Humanos
Índia
Masculino
Meia-Idade
Reação em Cadeia da Polimerase
Polimorfismo de Fragmento de Restrição
Medição de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Genetic Markers); 0 (PPAR gamma); EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160511
[St] Status:MEDLINE
[do] DOI:10.4103/0974-9233.171772


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[PMID]:27056331
[Au] Autor:Anderson KW; Mast N; Hudgens JW; Lin JB; Turko IV; Pikuleva IA
[Ad] Endereço:From the Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, the Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, and.
[Ti] Título:Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity.
[So] Source:J Biol Chem;291(22):11876-86, 2016 May 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 46A1 (CYP46A1) is a microsomal enzyme and cholesterol 24-hydroxylase that controls cholesterol elimination from the brain. This P450 is also a potential target for Alzheimer disease because it can be activated pharmacologically by some marketed drugs, as exemplified by efavirenz, the anti-HIV medication. Previously, we suggested that pharmaceuticals activate CYP46A1 allosterically through binding to a site on the cytosolic protein surface, which is different from the enzyme active site facing the membrane. Here we identified this allosteric site for efavirenz on CYP46A1 by using a combination of hydrogen-deuterium exchange coupled to MS, computational modeling, site-directed mutagenesis, and analysis of the CYP46A1 crystal structure. We also mapped the binding region for the CYP46A1 redox partner oxidoreductase and found that the allosteric and redox partner binding sites share a common border. On the basis of the data obtained, we propose the mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site.
[Mh] Termos MeSH primário: Benzoxazinas/farmacologia
Colesterol 24-Hidroxilase/metabolismo
Colesterol/metabolismo
Inibidores da Transcriptase Reversa/farmacologia
[Mh] Termos MeSH secundário: Sítio Alostérico
Sequência de Aminoácidos
Sítios de Ligação
Domínio Catalítico
Colesterol 24-Hidroxilase/química
Colesterol 24-Hidroxilase/genética
Cristalografia por Raios X
Seres Humanos
Dados de Sequência Molecular
Mutagênese Sítio-Dirigida
Mutação/genética
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Benzoxazines); 0 (Reverse Transcriptase Inhibitors); 97C5T2UQ7J (Cholesterol); EC 1.14.14.25 (Cholesterol 24-Hydroxylase); JE6H2O27P8 (efavirenz)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170527
[Lr] Data última revisão:
170527
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160409
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.723577


  9 / 136 MEDLINE  
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[PMID]:27026489
[Au] Autor:Jia F; Liu Z; Song N; Du X; Xie J; Jiang H
[Ad] Endereço:Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
[Ti] Título:The association between CYP46A1 rs4900442 polymorphism and the risk of Alzheimer's disease: A meta-analysis.
[So] Source:Neurosci Lett;620:83-7, 2016 May 04.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Polymorphisms in the CYP46A1 rs4900442 have been controversially associated with increased risk of developing Alzheimer's disease (AD). Therefore, a meta-analysis was performed to assess the possible association between CYP46A1 gene rs4900442 polymorphism and AD. A comprehensive search was conducted to identify all case-control or cohort design studies of the associations between CYP46A1 rs4900442 and AD. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed-effects models. Heterogeneity among studies was evaluated using the I(2) and funnel plot and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. Six case-control studies corresponded to the inclusion criteria including 1555 AD cases and 1347 controls for the present meta-analysis. Our results showed that no significant associations between CYP46A1 rs4900442 genetic polymorphism and risk of AD in allele model T vs. C (OR=0.947, 95%CI=0.853-1.051), dominant model CC+TC vs. TT (OR=0.878, 95%CI=0.734-1.049) and recessive model CC vs. TC+TT (OR=0.974, 95%CI=0.826-1.149). Moreover, in the subgroup analysis based on location (Chinese and Caucasian), there was significant association in Chinese population in allele model T vs. C (OR=0.780, 95%CI=0.628-0.968), although no obvious associations were found in Caucasian. The meta-analysis suggested that CYP46A1 rs4900442 genetic polymorphism was associated with increased risk of AD in the Chinese population, but no evidences were detected in Caucasian population.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Colesterol 24-Hidroxilase/genética
[Mh] Termos MeSH secundário: Doença de Alzheimer/etnologia
Grupo com Ancestrais do Continente Asiático
Estudos de Casos e Controles
Grupo com Ancestrais do Continente Europeu
Seres Humanos
Polimorfismo de Nucleotídeo Único
Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160331
[St] Status:MEDLINE


  10 / 136 MEDLINE  
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[PMID]:26912634
[Au] Autor:Boussicault L; Alves S; Lamazière A; Planques A; Heck N; Moumné L; Despres G; Bolte S; Hu A; Pagès C; Galvan L; Piguet F; Aubourg P; Cartier N; Caboche J; Betuing S
[Ad] Endereço:1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France.
[Ti] Título:CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease.
[So] Source:Brain;139(Pt 3):953-70, 2016 Mar.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington's disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington's disease.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Doença de Huntington/enzimologia
Doença de Huntington/prevenção & controle
Esteroide Hidroxilases/biossíntese
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Células Cultivadas
Córtex Cerebral/metabolismo
Córtex Cerebral/patologia
Colesterol 24-Hidroxilase
Feminino
Seres Humanos
Doença de Huntington/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos CBA
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160226
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awv384



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