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Pesquisa : D04.210.500.247.222.222.347.200 [Categoria DeCS]
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[PMID]:28746983
[Au] Autor:Kurogi K; Sakakibara Y; Suiko M; Liu MC
[Ad] Endereço:Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, OH, USA.
[Ti] Título:Sulfation of vitamin D -related compounds-identification and characterization of the responsible human cytosolic sulfotransferases.
[So] Source:FEBS Lett;591(16):2417-2425, 2017 08.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While 25-hydroxyvitamin D 3-O-sulfate is known to be present in circulation, how it is generated in the body remains unclear. This study aimed to investigate its sulfation in major human organs and to unveil the responsible cytosolic sulfotransferases (SULTs). Of the vitamin D -related compounds tested, 25-hydroxyvitamin D and 7-dehydrocholesterol are preferentially sulfated by human organ cytosols. Among the 13 human SULTs, SULT2A1 shows sulfating activity toward all vitamin D -related compounds, whereas SULT1A1 and SULT2B1a/SULT2B1b show sulfating activity exclusively for, respectively, calcitriol and 7-dehydrocholesterol. These findings suggest that the metabolic pathway leading to the formation of 25-hydroxyvitamin D 3-O-sulfate may be mediated by the sulfation of 25-hydroxyvitamin D or by the conversion of 7-dehydrocholesterol-3-O-sulfate in the skin.
[Mh] Termos MeSH primário: Calcifediol/metabolismo
Citosol/enzimologia
Desidrocolesteróis/metabolismo
Sulfatos/metabolismo
Sulfotransferases/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Concentração de Íons de Hidrogênio
Cinética
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Sulfates); BK1IU07GKF (7-dehydrocholesterol); EC 2.8.2.- (Sulfotransferases); P6YZ13C99Q (Calcifediol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12767


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[PMID]:28736297
[Au] Autor:Endo-Umeda K; Aoyama A; Shimizu M; Ishikawa M; Hashimoto Y; Yamada S; Makishima M
[Ad] Endereço:Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
[Ti] Título:1α-Hydroxy derivatives of 7-dehydrocholesterol are selective liver X receptor modulators.
[So] Source:J Steroid Biochem Mol Biol;172:136-148, 2017 Sep.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The nuclear receptors liver X receptor (LXR) α and LXRß are involved in the regulation of lipid metabolism, inflammation, immunity, cellular proliferation, and apoptosis. Oxysterols are endogenous LXR ligands, and also interact with other nuclear and membrane receptors. We previously reported that a phytosterol derivative with a 1α-hydroxy group acts as a potent LXR agonist with intestine-selective action and that 25-hydroxy and 26/27-hydroxy metabolites of 7-dehydrocholesterol (7-DHC) exhibit partial LXR agonism. In this study, we report that 1α-hydroxy derivatives of 7-DHC, 1α-OH-7-DHC and 1,25-(OH) -7-DHC, act as LXR modulators. Luciferase reporter gene assays showed that 1α-OH-7-DHC activates LXRα and LXRß and that 1,25-(OH) -7-DHC activates both LXRs and vitamin D receptor. Examination of cofactor peptide association showed that the 1α-hydroxy derivatives, specifically 1,25-(OH) -7-DHC, induce association of coactivator/corepressor peptide in a different manner from the agonist T0901317. Docking modeling and alanine mutational analysis of LXRα demonstrated that 1,25-(OH) -7-DHC interacts with LXRα residues in a manner distinct from potent agonists, such as T0901317 and 24(S),25-epoxycholesterol. 1α-OH-7-DHC and 1,25-(OH) -7-DHC induced expression of LXR target genes in a cell type- and gene-selective manner. 1,25-(OH) -7-DHC effectively suppressed lipopolysaccharide-stimulated proinflammatory gene expression in an LXR-dependent manner. Therefore, 1α-hydroxy derivatives, such as 1,25-(OH) -7-DHC, are unique LXR modulators with selective agonistic activity and potent transrepression function. These oxysterols have potential as LXR-targeted therapeutics for inflammatory disease.
[Mh] Termos MeSH primário: Calcitriol/farmacologia
Colesterol/análogos & derivados
Desidrocolesteróis/farmacologia
Hidrocarbonetos Fluorados/farmacologia
Receptores X do Fígado/genética
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Células CACO-2
Calcitriol/química
Linhagem Celular Tumoral
Colesterol/química
Colesterol/farmacologia
Desidrocolesteróis/química
Regulação da Expressão Gênica
Genes Reporter
Células HEK293
Células Hep G2
Seres Humanos
Hidrocarbonetos Fluorados/química
Queratinócitos/citologia
Queratinócitos/efeitos dos fármacos
Queratinócitos/metabolismo
Receptores X do Fígado/agonistas
Receptores X do Fígado/química
Receptores X do Fígado/metabolismo
Luciferases/genética
Luciferases/metabolismo
Células MCF-7
Simulação de Acoplamento Molecular
Especificidade de Órgãos
Receptores de Calcitriol/genética
Receptores de Calcitriol/metabolismo
Transdução de Sinais
Relação Estrutura-Atividade
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Hydrocarbons, Fluorinated); 0 (Liver X Receptors); 0 (Receptors, Calcitriol); 0 (Sulfonamides); 0 (TO-901317); 0 (VDR protein, human); 68138-65-8 (24,25-epoxycholesterol); 97C5T2UQ7J (Cholesterol); BK1IU07GKF (7-dehydrocholesterol); EC 1.13.12.- (Luciferases); FXC9231JVH (Calcitriol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


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[PMID]:28330720
[Au] Autor:Makarova AM; Pasta S; Watson G; Shackleton C; Epstein EH
[Ad] Endereço:UCSF Benioff Children's Hospital Oakland Research Institute (CHORI), Oakland, CA, USA.
[Ti] Título:Attenuation of UVR-induced vitamin D synthesis in a mouse model deleted for keratinocyte lathosterol 5-desaturase.
[So] Source:J Steroid Biochem Mol Biol;171:187-194, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The lower risk of some internal cancers at lower latitudes has been linked to greater sun exposure and consequent higher levels of ultraviolet radiation (UVR)-produced vitamin D (D ). To separate the experimental effects of sunlight and of all forms of D , a mouse in which UVR does not produce D would be useful. To this end we have generated mice carrying a modified allele of sterol C5-desaturase (Sc5d), the gene encoding the enzyme that converts lathosterol to 7-dehydrocholesterol (7-DHC), such that Sc5d expression can be inactivated using the Cre/lox site-specific recombination system. By crossing to mice with tissue-specific expression of Cre or CreER (Cre/estrogen receptor), we generated two lines of transgenic mice. One line has constitutive keratinocyte-specific inactivation of Sc5d (Sc5d ). The other line (Sc5d ) has tamoxifen-inducible keratinocyte-specific inactivation of Sc5d. Mice deleted for keratinocyte Sc5d lose the ability to increase circulating D following UVR exposure of the skin. Thus, unlike in control mice, acute UVR exposure did not affect circulating D level in inducible Sc5d mice. Keratinocyte-specific inactivation of Sc5d was proven by sterol measurement in hair - in control animals lathosterol and cholesta-7,24-dien-3ß-ol, the target molecules of SC5D in the sterol biosynthetic pathways, together constituted a mean of 10% of total sterols; in the conditional knockout mice these sterols constituted a mean of 56% of total sterols. The constitutive knockout mice had an even greater increase, with lathosterol and cholesta-7,24-dien-3ß-ol accounting for 80% of total sterols. In conclusion, the dominant presence of the 7-DHC precursors in hair of conditional animals and the lack of increased circulating D following exposure to UVR reflect attenuated production of the D photochemical precursor 7-DHC and, consequently, of D itself. These animals provide a useful new tool for investigating the role of D in UVR-induced physiological effects and, more broadly, for investigations of the cholesterol synthetic pathway in the skin and other targeted tissues.
[Mh] Termos MeSH primário: Colecalciferol/sangue
Modelos Animais de Doenças
Queratinócitos/metabolismo
Erros Inatos do Metabolismo/metabolismo
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência
Pele/metabolismo
[Mh] Termos MeSH secundário: Animais
Colecalciferol/biossíntese
Colesterol/metabolismo
Cruzamentos Genéticos
Desidrocolesteróis/metabolismo
Feminino
Cabelo/metabolismo
Heterozigoto
Estimativa de Kaplan-Meier
Queratinócitos/patologia
Queratinócitos/efeitos da radiação
Masculino
Erros Inatos do Metabolismo/sangue
Erros Inatos do Metabolismo/genética
Erros Inatos do Metabolismo/patologia
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
Gravidez
Distribuição Aleatória
Pele/patologia
Pele/efeitos da radiação
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dehydrocholesterols); 1C6V77QF41 (Cholecalciferol); 566-96-1 (cholesta-7,9-dien-3-beta-ol); 80-99-9 (lathosterol); 97C5T2UQ7J (Cholesterol); EC 1.14.21.6 (lathosterol delta-5-dehydrogenase); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE


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[PMID]:28220990
[Au] Autor:Sharif NF; Korade Z; Porter NA; Harrison FE
[Ad] Endereço:Neuroscience Program, Vanderbilt University, Nashville, TN, USA.
[Ti] Título:Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome.
[So] Source:Genes Brain Behav;16(6):619-626, 2017 Jul.
[Is] ISSN:1601-183X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Smith-Lemli-Opitz syndrome is an inherited monogenic disorder in which mutations to the 7-dehydrocholesterol (7-DHC) reductase (Dhcr7) gene lead to deficits in cholesterol synthesis. As a result, many patients suffer from gross physiological and neurological deficits. The purpose of this study was to identify a potential abnormal behavioral phenotype in a compound mutant mouse model for Smith-Lemli-Opitz disease (Dhcr7 ) to further validate the model and to provide potential targets for future therapeutic interventions. We also sought to identify some of the underlying changes in brain function that may be responsible for behavioral differences among groups. The Dhcr7 compound mutant mice were smaller than their single mutant littermates. Both single and compound heterozygous mice made fewer ultrasonic vocalizations when separated from the dam, which may suggest a communication deficit in these animals. Striking increases of the highly oxidizable 7-DHC were observed in the compound mutant mice. 7-Dehydrocholesterol is the precursor to cholesterol and builds up because of decreased function of the mutated Dhcr7 enzyme. Additionally, several differences were noted in the serotonergic system including increased expression of the serotonin transporter and increased uptake of serotonin by isolated synaptosomes. We propose that changes to the oxidative environment during development can have a significant impact on the development of serotonergic function and that this contributes to behavioral differences observed in the mutant mice.
[Mh] Termos MeSH primário: Estresse Oxidativo
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética
Serotonina/metabolismo
Síndrome de Smith-Lemli-Opitz/genética
Vocalização Animal
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/fisiopatologia
Desidrocolesteróis/metabolismo
Feminino
Heterozigoto
Masculino
Camundongos
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Síndrome de Smith-Lemli-Opitz/metabolismo
Síndrome de Smith-Lemli-Opitz/fisiopatologia
Ondas Ultrassônicas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Serotonin Plasma Membrane Transport Proteins); 333DO1RDJY (Serotonin); BK1IU07GKF (7-dehydrocholesterol); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.21 (7-dehydrocholesterol reductase)
[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:170222
[St] Status:MEDLINE
[do] DOI:10.1111/gbb.12376


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[PMID]:27289046
[Au] Autor:Vasilevskaya AV; Yantsevich AV; Sergeev GV; Lemish AP; Usanov SA; Gilep AA
[Ad] Endereço:Institute of Bioorganic Chemistry, National Academy of Sciences, 220141, Minsk, Kuprevicha 5/2, Belarus.
[Ti] Título:Identification of Mycobacterium tuberculosis enzyme involved in vitamin D and 7-dehydrocholesterol metabolism.
[So] Source:J Steroid Biochem Mol Biol;169:202-209, 2017 May.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Problems arising during treatment of tuberculosis are well known, therefore studies of Mycobacterium drug molecular targets are an area of particular importance. Members of the cytochrome P450 family (CYP) may belong to potential candidates for drug targets being involved in metabolism of biologically important molecules in the host organism. CYP124 of Mycobacterium tuberculosis (MTCYP124) catalyzes ω-hydroxylation of methyl-branched lipids. The data obtained in the present study indicate that this enzyme can also oxidize provitamin D3 (7-dehydrocholesterol) and vitamin D3. We found that the final product is different from 1α- and 25-hydroxyvitamin D3, so we propose that MTCYP124 is involved in alternative pathway for metabolism of vitamin D3.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Colecalciferol/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Desidrocolesteróis/metabolismo
Mycobacterium tuberculosis/enzimologia
[Mh] Termos MeSH secundário: Catálise
Domínio Catalítico
Cromatografia Líquida de Alta Pressão
Clonagem Molecular
Cristalografia por Raios X
Ligantes
Espectrometria de Massas
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Dehydrocholesterols); 0 (Ligands); 1C6V77QF41 (Cholecalciferol); 9035-51-2 (Cytochrome P-450 Enzyme System); BK1IU07GKF (7-dehydrocholesterol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160612
[St] Status:MEDLINE


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[PMID]:27060335
[Au] Autor:Miller WL
[Ad] Endereço:Center for Reproductive Sciences and Department of Pediatrics, HSE 1634, University of California San Francisco, San Francisco, CA 94143-0556, USA. Electronic address: wlmlab@ucsf.edu.
[Ti] Título:Genetic disorders of Vitamin D biosynthesis and degradation.
[So] Source:J Steroid Biochem Mol Biol;165(Pt A):101-108, 2017 Jan.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Vitamin D, an inactive secosteroid pro-hormone, is produced by the action of ultraviolet light on 7-dehydrocholesterol in the skin. The active hormone, 1,25(OH) D is produced by sequential 25-hydroxylation in the liver, principally by CYP2R1, and 1α-hydroxylation in the kidney by CYP27B1. Mutations in CYP27B1 cause 1α-hydroxylase deficiency, also known as vitamin D dependent rickets type I or hereditary pseudo-vitamin D deficient rickets; very rare mutations in CYP2R1 can cause 25-hydroxylase deficiency. Both deficiencies cause hypocalcemia, secondary hyperparathyroidism, severe rickets in infancy, and low serum concentrations of 1,25(OH) D; both disorders respond to hormonal replacement therapy with calcitriol. The inactivation of vitamin D is principally initiated by its 23- and 24-hydroxylation by CYP24A1. Mutations in CYP24A1 can cause both severe neonatal hypercalcemia and a less severe adult hypercalcemic syndrome. Other pathways of vitamin D metabolism are under investigation, notably its 20-hydroxylation by the cholesterol side-chain cleavage enzyme, CYP11A1.
[Mh] Termos MeSH primário: 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética
Colestanotriol 26-Mono-Oxigenase/genética
Família 2 do Citocromo P450/genética
Vitamina D3 24-Hidroxilase/genética
Vitamina D/biossíntese
Vitamina D/metabolismo
[Mh] Termos MeSH secundário: Animais
Calcitriol/química
Proliferação Celular
Colesterol/metabolismo
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética
Análise Mutacional de DNA
Desidrocolesteróis/metabolismo
Seres Humanos
Hipercalcemia/genética
Camundongos
Mutação
Ratos
Raquitismo/diagnóstico
Raquitismo/genética
Esteroides/metabolismo
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Steroids); 1406-16-2 (Vitamin D); 97C5T2UQ7J (Cholesterol); BK1IU07GKF (7-dehydrocholesterol); EC 1.14.13.13 (25-Hydroxyvitamin D3 1-alpha-Hydroxylase); EC 1.14.13.13 (CYP27B1 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.24 (CYP2R1 protein, human); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.16 (CYP24A1 protein, human); EC 1.14.15.16 (Vitamin D3 24-Hydroxylase); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme); FXC9231JVH (Calcitriol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160410
[St] Status:MEDLINE


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[PMID]:26976653
[Au] Autor:Griffiths WJ; Abdel-Khalik J; Crick PJ; Ogundare M; Shackleton CH; Tuschl K; Kwok MK; Bigger BW; Morris AA; Honda A; Xu L; Porter NA; Björkhem I; Clayton PT; Wang Y
[Ad] Endereço:College of Medicine, Grove Building, Swansea University, Singleton Park, Swansea SA2 8PP, UK. Electronic address: w.j.griffiths@swansea.ac.uk.
[Ti] Título:Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients.
[So] Source:J Steroid Biochem Mol Biol;169:77-87, 2017 May.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Smith-Lemli-Opitz syndrome (SLOS) is a severe autosomal recessive disorder resulting from defects in the cholesterol synthesising enzyme 7-dehydrocholesterol reductase (Δ -sterol reductase, DHCR7, EC 1.3.1.21) leading to a build-up of the cholesterol precursor 7-dehydrocholesterol (7-DHC) in tissues and blood plasma. Although the underling enzyme deficiency associated with SLOS is clear there are likely to be multiple mechanisms responsible for SLOS pathology. In an effort to learn more of the aetiology of SLOS we have analysed plasma from SLOS patients to search for metabolites derived from 7-DHC which may be responsible for some of the pathology. We have identified a novel hydroxy-8-dehydrocholesterol, which is either 24- or 25-hydroxy-8-dehydrocholesterol and also the known metabolites 26-hydroxy-8-dehydrocholesterol, 4-hydroxy-7-dehydrocholesterol, 3ß,5α-dihydroxycholest-7-en-6-one and 7α,8α-epoxycholesterol. None of these metabolites are detected in control plasma at quantifiable levels (0.5ng/mL).
[Mh] Termos MeSH primário: Oxisteróis/sangue
Síndrome de Smith-Lemli-Opitz/sangue
Esteróis/sangue
[Mh] Termos MeSH secundário: Colestadienóis/sangue
Desidrocolesteróis/sangue
Radicais Livres/química
Seres Humanos
Mutação
Oxirredutases atuantes sobre Doadores de Grupo CH-CH
Plasma/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholestadienols); 0 (Dehydrocholesterols); 0 (Free Radicals); 0 (Oxysterols); 0 (Sterols); 70741-38-7 (cholesta-5,8-dien-3 beta-ol); BK1IU07GKF (7-dehydrocholesterol); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.21 (7-dehydrocholesterol reductase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160316
[St] Status:MEDLINE


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[PMID]:27697512
[Au] Autor:Prabhu AV; Luu W; Li D; Sharpe LJ; Brown AJ
[Ad] Endereço:School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
[Ti] Título:DHCR7: A vital enzyme switch between cholesterol and vitamin D production.
[So] Source:Prog Lipid Res;64:138-151, 2016 10.
[Is] ISSN:1873-2194
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The conversion of 7-dehydrocholesterol to cholesterol, the final step of cholesterol synthesis in the Kandutsch-Russell pathway, is catalyzed by the enzyme 7-dehydrocholesterol reductase (DHCR7). Homozygous or compound heterozygous mutations in DHCR7 lead to the developmental disease Smith-Lemli-Opitz syndrome, which can also result in fetal mortality, highlighting the importance of this enzyme in human development and survival. Besides serving as a substrate for DHCR7, 7-dehydrocholesterol is also a precursor of vitamin D via the action of ultraviolet light on the skin. Thus, DHCR7 exerts complex biological effects, involved in both cholesterol and vitamin D production. Indeed, we argue that DHCR7 can act as a switch between cholesterol and vitamin D synthesis. This review summarizes current knowledge about the critical enzyme DHCR7, highlighting recent findings regarding its structure, transcriptional and post-transcriptional regulation, and its links to vitamin D synthesis. Greater understanding about DHCR7 function, regulation and its place within cellular metabolism will provide important insights into its biological roles.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
Vitamina D/metabolismo
[Mh] Termos MeSH secundário: Animais
Desidrocolesteróis/metabolismo
Embrião não Mamífero/metabolismo
Seres Humanos
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética
Domínios Proteicos
Síndrome de Smith-Lemli-Opitz/metabolismo
Síndrome de Smith-Lemli-Opitz/patologia
Xenopus/crescimento & desenvolvimento
Xenopus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Dehydrocholesterols); 1406-16-2 (Vitamin D); 97C5T2UQ7J (Cholesterol); BK1IU07GKF (7-dehydrocholesterol); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.21 (7-dehydrocholesterol reductase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


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[PMID]:27315086
[Au] Autor:Balajthy A; Somodi S; Petho Z; Péter M; Varga Z; Szabó GP; Paragh G; Vígh L; Panyi G; Hajdu P
[Ad] Endereço:Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
[Ti] Título:7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome.
[So] Source:Pflugers Arch;468(8):1403-18, 2016 Aug.
[Is] ISSN:1432-2013
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.
[Mh] Termos MeSH primário: Canal de Potássio Kv1.3/metabolismo
Síndrome de Smith-Lemli-Opitz/metabolismo
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Criança
Desidrocolesteróis/metabolismo
Seres Humanos
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Kv1.3 Potassium Channel); BK1IU07GKF (7-dehydrocholesterol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160618
[St] Status:MEDLINE
[do] DOI:10.1007/s00424-016-1851-4


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[PMID]:27162362
[Au] Autor:Sever N; Mann RK; Xu L; Snell WJ; Hernandez-Lara CI; Porter NA; Beachy PA
[Ad] Endereço:Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305; Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Howa
[Ti] Título:Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols.
[So] Source:Proc Natl Acad Sci U S A;113(21), 2016 May 24.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith-Lemli-Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-ß-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3ß,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith-Lemli-Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.
[Mh] Termos MeSH primário: Desidrocolesteróis/metabolismo
Proteínas Hedgehog/metabolismo
Transdução de Sinais
Receptor Smoothened/metabolismo
[Mh] Termos MeSH secundário: Animais
Chlamydomonas reinhardtii/química
Desidrocolesteróis/química
Desidrocolesteróis/farmacologia
Flagelos/química
Células HEK293
Proteínas Hedgehog/genética
Seres Humanos
Camundongos
Células NIH 3T3
Síndrome de Smith-Lemli-Opitz/genética
Síndrome de Smith-Lemli-Opitz/metabolismo
Receptor Smoothened/genética
Alcaloides de Veratrum/farmacologia
beta-Ciclodextrinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dehydrocholesterols); 0 (Hedgehog Proteins); 0 (SMO protein, human); 0 (Smo protein, mouse); 0 (Smoothened Receptor); 0 (Veratrum Alkaloids); 0 (beta-Cyclodextrins); 0 (methyl-beta-cyclodextrin); BK1IU07GKF (7-dehydrocholesterol); ZH658AJ192 (cyclopamine)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160511
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1604984113



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