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[PMID]:28701464
[Au] Autor:Johnson KM; Phan TTN; Albertolle ME; Guengerich FP
[Ad] Endereço:From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
[Ti] Título:Human mitochondrial cytochrome P450 27C1 is localized in skin and preferentially desaturates -retinol to 3,4-dehydroretinol.
[So] Source:J Biol Chem;292(33):13672-13687, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently, zebrafish and human cytochrome P450 (P450) 27C1 enzymes have been shown to be retinoid 3,4-desaturases. The enzyme is unusual among mammalian P450s in that the predominant oxidation is a desaturation and in that hydroxylation represents only a minor pathway. We show by proteomic analysis that P450 27C1 is localized to human skin, with two proteins of different sizes present, one being a cleavage product of the full-length form. P450 27C1 oxidized all- -retinol to 3,4-dehydroretinol, 4-hydroxy (OH) retinol, and 3-OH retinol in a 100:3:2 ratio. Neither 3-OH nor 4-OH retinol was an intermediate in desaturation. No kinetic burst was observed in the steady state; neither the rate of substrate binding nor product release was rate-limiting. Ferric P450 27C1 reduction by adrenodoxin was 3-fold faster in the presence of the substrate and was ∼5-fold faster than the overall turnover. Kinetic isotope effects of 1.5-2.3 (on / ) were observed with 3,3-, 4,4-, and 3,3,4,4-deuterated retinol. Deuteration at C-4 produced a 4-fold increase in 3-hydroxylation due to metabolic switching, with no observable effect on 4-hydroxylation. Deuteration at C-3 produced a strong kinetic isotope effect for 3-hydroxylation but not 4-hydroxylation. Analysis of the products of deuterated retinol showed a lack of scrambling of a putative allylic radical at C-3 and C-4. We conclude that the most likely catalytic mechanism begins with abstraction of a hydrogen atom from C-4 (or possibly C-3) initiating the desaturation pathway, followed by a sequential abstraction of a hydrogen atom or proton-coupled electron transfer. Adrenodoxin reduction and hydrogen abstraction both contribute to rate limitation.
[Mh] Termos MeSH primário: Família 27 do Citocromo P450/metabolismo
Regulação Enzimológica da Expressão Gênica
Mitocôndrias/enzimologia
Pele/enzimologia
Vitamina A/análogos & derivados
Vitamina A/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Família 27 do Citocromo P450/genética
Perfilação da Expressão Gênica
Seres Humanos
Hidrogenação
Hidroxilação
Isoenzimas/genética
Isoenzimas/metabolismo
Cinética
Estrutura Molecular
Especificidade de Órgãos
Oxirredução
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Proteólise
Proteômica/métodos
Estereoisomerismo
Especificidade por Substrato
Vitamina A/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3,4-dehydroretinol); 0 (4-hydroxy-retinol); 0 (Isoenzymes); 0 (Peptide Fragments); 11103-57-4 (Vitamin A); 6890-93-3 (3-hydroxyretinol); EC 1.14.14.1 (CYP27C1 protein, human); EC 1.14.15.15 (Cytochrome P450 Family 27)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.773937


  2 / 4 MEDLINE  
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[PMID]:27059013
[Au] Autor:Kramlinger VM; Nagy LD; Fujiwara R; Johnson KM; Phan TT; Xiao Y; Enright JM; Toomey MB; Corbo JC; Guengerich FP
[Ad] Endereço:Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
[Ti] Título:Human cytochrome P450 27C1 catalyzes 3,4-desaturation of retinoids.
[So] Source:FEBS Lett;590(9):1304-12, 2016 05.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In humans, a considerable fraction of the retinoid pool in skin is derived from vitamin A2 (all-trans 3,4-dehydroretinal). Vitamin A2 may be locally generated by keratinocytes, which can convert vitamin A1 (all-trans retinol) into vitamin A2 in cell culture. We report that human cytochrome P450 (hP450) 27C1, a previously 'orphan' enzyme, can catalyze this reaction. Purified recombinant hP450 27C1 bound and desaturated all-trans retinol, retinal, and retinoic acid, as well as 11-cis-retinal. Although the physiological role of 3,4-dehydroretinoids in humans is unclear, we have identified hP450 27C1 as an enzyme capable of efficiently mediating their formation.
[Mh] Termos MeSH primário: Família 27 do Citocromo P450/metabolismo
Retinoides/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:LETTER; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Retinoids); EC 1.14.14.1 (CYP27C1 protein, human); EC 1.14.15.15 (Cytochrome P450 Family 27)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160410
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12167


  3 / 4 MEDLINE  
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[PMID]:24885631
[Au] Autor:Jones KS; Assar S; Harnpanich D; Bouillon R; Lambrechts D; Prentice A; Schoenmakers I
[Ad] Endereço:Medical Research Council Human Nutrition Research (K.S.J., S.A., D.H., A.P., I.S.), Cambridge CB1 9NL, United Kingdom; Medical Research Council Keneba (K.S.J., A.P.), The Gambia; Clinic and Laboratory of Experimental Medicine and Endocrinology (R.B.) and Laboratory for Translational Genetics (D.L.), Katholieke Universiteit, B-3000 Leuven, Belgium; and Vesalius Research Center (D.L.), VIB, Katholieke Universiteit, B-3000, Leuven, Belgium.
[Ti] Título:25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype.
[So] Source:J Clin Endocrinol Metab;99(9):3373-81, 2014 Sep.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: There is uncertainty over the equivalence of vitamins D2 and D3 to maintain plasma 25-hydroxyvitamin D (25(OH)D). OBJECTIVE: The objective of the study was to compare the plasma half-lives of 25(OH)D2 and 25(OH)D3 in two distinct populations with different dietary calcium intake and 25(OH)D status. PARTICIPANTS: Healthy men (aged 24 and 39 y), resident in The Gambia (n = 18) or the United Kingdom (n = 18) participated in the study. INTERVENTIONS: The intervention included an oral tracer dose of deuterated-25(OH)D2 and deuterated-25(OH)D3 (both 40 nmol). Blood samples were collected over 33 days. MAIN OUTCOME MEASURES: 25(OH)D2 and 25(OH)D3 plasma half-lives, concentrations of 25(OH)D, and vitamin D binding protein (DBP) and DBP genotypes were measured. RESULTS: 25(OH)D2 half-life [mean (SD)] [13.9 (2.6) d] was shorter than 25(OH)D3 half-life [15.1 (3.1) d; P = .001] for countries combined, and in Gambians [12.8 (2.3) d vs 14.7 (3.5) d; P < .001], but not in the United Kingdom [15.1 (2.4) d vs 15.6 (2.5) d; P = .3]. 25(OH)D concentration was 69 (13) and 29 (11) nmol/L (P < .0001), and the DBP concentration was 259 (33) and 269 (23) mg/L (P = .4) in The Gambia and United Kingdom, respectively. Half-lives were positively associated with plasma DBP concentration for countries combined [25(OH)D2 half-life: regression coefficient (SE) 0.03 (0.01) d per 1 mg/L DBP, P = .03; 25(OH)D3 half-life: 0.04 (0.02) d, P = .02] and in Gambians [25(OH)D2 half-life: 0.04 (0.01) d; P = .02; 25(OH)D3 half-life: 0.06 (0.02) d, P = .01] but not in UK participants. The DBP concentration × country interactions were not significant. DBP Gc1f/1f homozygotes had shorter 25(OH)D2 half-lives compared with other combined genotypes (P = .007) after correction for country. CONCLUSIONS: 25(OH)D2 half-life was shorter than 25(OH)D3 half-life, and half-lives were affected by DBP concentration and genotype. The stable isotope 25(OH)D half-life measurements provide a novel tool to investigate vitamin D metabolism and vitamin D expenditure and aid in the assessment of vitamin D requirements.
[Mh] Termos MeSH primário: 24,25-Di-Hidroxivitamina D 3/sangue
25-Hidroxivitamina D 2/sangue
Calcifediol/sangue
Cálcio na Dieta/metabolismo
Proteína de Ligação a Vitamina D/genética
[Mh] Termos MeSH secundário: 25-Hidroxivitamina D 2/farmacocinética
Adulto
Calcifediol/farmacocinética
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Família 27 do Citocromo P450
Deutério
Gâmbia
Genótipo
Seres Humanos
Modelos Lineares
Masculino
Modelos Biológicos
Hormônio Paratireóideo/genética
Hormônio Paratireóideo/metabolismo
Reino Unido
Proteína de Ligação a Vitamina D/metabolismo
Vitamina D3 24-Hidroxilase/genética
Vitamina D3 24-Hidroxilase/metabolismo
Vitaminas/sangue
Vitaminas/farmacocinética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Calcium, Dietary); 0 (Parathyroid Hormone); 0 (Vitamin D-Binding Protein); 0 (Vitamins); 21343-40-8 (25-Hydroxyvitamin D 2); 40013-87-4 (24,25-Dihydroxyvitamin D 3); 9035-51-2 (Cytochrome P-450 Enzyme System); AR09D82C7G (Deuterium); EC 1.14.14.1 (CYP27C1 protein, human); EC 1.14.15.15 (Cytochrome P450 Family 27); EC 1.14.15.16 (CYP24A1 protein, human); EC 1.14.15.16 (Vitamin D3 24-Hydroxylase); P6YZ13C99Q (Calcifediol)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:140603
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2014-1714


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[PMID]:16360114
[Au] Autor:Wu ZL; Bartleson CJ; Ham AJ; Guengerich FP
[Ad] Endereço:Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
[Ti] Título:Heterologous expression, purification, and properties of human cytochrome P450 27C1.
[So] Source:Arch Biochem Biophys;445(1):138-46, 2006 Jan 01.
[Is] ISSN:0003-9861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 (P450) 27C1 is one of the "orphan" P450 enzymes without a known biological function. A human P450 27C1 cDNA with a nucleotide sequence modified for Escherichia coli usage was prepared and modified at the N-terminus, based on the expected mitochondrial localization. A derivative with residues 3-60 deleted was expressed at a level of 1350nmol/L E. coli culture and had the characteristic P450 spectra. The identity of the expressed protein was confirmed by mass spectrometry of proteolytic fragments. The purified P450 was in the low-spin iron state, and the spin equilibrium was not perturbed by any of the potential substrates vitamin D(3), 1alpha- or 25-hydroxy vitamin D(3), or cholesterol. P450s 27A1 and 27B1 are known to catalyze the 25-hydroxylation of vitamin D(3) and the 1alpha-hydroxylation of 25-hydroxy vitamin D(3), respectively. In the presence of recombinant human adrenodoxin and adrenodoxin reductase, recombinant P450 27C1 did not catalyze the oxidation of vitamin D(3), 1alpha- or 25-hydroxy vitamin D(3), or cholesterol at detectable rates. P450 27C1 mRNA was determined to be expressed in liver, kidney, pancreas, and several other human tissues.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/biossíntese
Proteínas Recombinantes/biossíntese
[Mh] Termos MeSH secundário: Adrenodoxina/química
Sequência de Aminoácidos
Calcifediol/química
Catálise
Colecalciferol/química
Colesterol/química
Clonagem Molecular
Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/isolamento & purificação
Família 27 do Citocromo P450
Escherichia coli/metabolismo
Ferredoxina-NADP Redutase/química
Seres Humanos
Espectrometria de Massas
Mitocôndrias/metabolismo
Dados de Sequência Molecular
Mutação
Especificidade de Órgãos
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
RNA Mensageiro/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Peptide Fragments); 0 (RNA, Messenger); 0 (Recombinant Proteins); 12687-22-8 (Adrenodoxin); 1C6V77QF41 (Cholecalciferol); 9035-51-2 (Cytochrome P-450 Enzyme System); 97C5T2UQ7J (Cholesterol); EC 1.14.14.1 (CYP27C1 protein, human); EC 1.14.15.15 (Cytochrome P450 Family 27); EC 1.18.1.2 (Ferredoxin-NADP Reductase); P6YZ13C99Q (Calcifediol)
[Em] Mês de entrada:0603
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:051220
[St] Status:MEDLINE



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