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[PMID]:29317208
[Au] Autor:Xiao XH; Qi XY; Wang YD; Ran L; Yang J; Zhang HL; Xu CX; Wen GB; Liu JH
[Ad] Endereço:Department of Metabolism and Endocrinology, University of South China, Hengyang, 421001, Hunan Province, China.
[Ti] Título:Zinc alpha2 glycoprotein promotes browning in adipocytes.
[So] Source:Biochem Biophys Res Commun;496(2):287-293, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.
[Mh] Termos MeSH primário: Adipócitos Marrons/metabolismo
Proteínas de Transporte/genética
Regulação da Expressão Gênica
Glicoproteínas/genética
Metabolismo dos Lipídeos/genética
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos Marrons/citologia
Adipócitos Marrons/efeitos dos fármacos
Animais
Proteínas Reguladoras de Apoptose/genética
Proteínas Reguladoras de Apoptose/metabolismo
Carbono-Carbono Ligases/genética
Carbono-Carbono Ligases/metabolismo
Carnitina O-Palmitoiltransferase/genética
Carnitina O-Palmitoiltransferase/metabolismo
Proteínas de Transporte/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Glicoproteínas/metabolismo
Imidazóis/farmacologia
Isoquinolinas/farmacologia
Lipase/genética
Lipase/metabolismo
Camundongos
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Fator 1 Nuclear Respiratório/genética
Fator 1 Nuclear Respiratório/metabolismo
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
Piridinas/farmacologia
Transdução de Sinais
Sulfonamidas/farmacologia
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Proteína Desacopladora 1/genética
Proteína Desacopladora 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AZGP1 protein, mouse); 0 (Apoptosis Regulatory Proteins); 0 (Carrier Proteins); 0 (Cidea protein, mouse); 0 (DNA-Binding Proteins); 0 (Glycoproteins); 0 (Imidazoles); 0 (Isoquinolines); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Nrf1 protein, mouse); 0 (Nuclear Respiratory Factor 1); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (Prdm16 protein, mouse); 0 (Pyridines); 0 (Sulfonamides); 0 (Transcription Factors); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1); EC 2.3.1.21 (CPT1B protein, mouse); EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (PNPLA2 protein, mouse); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase); M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide); OU13V1EYWQ (SB 203580)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:29199980
[Au] Autor:Stewart C; Woods K; Macias G; Allan AC; Hellens RP; Noel JP
[Ad] Endereço:Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
[Ti] Título:Molecular architectures of benzoic acid-specific type III polyketide synthases.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 12):1007-1019, 2017 Dec 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Biphenyl synthase and benzophenone synthase constitute an evolutionarily distinct clade of type III polyketide synthases (PKSs) that use benzoic acid-derived substrates to produce defense metabolites in plants. The use of benzoyl-CoA as an endogenous substrate is unusual for type III PKSs. Moreover, sequence analyses indicate that the residues responsible for the functional diversification of type III PKSs are mutated in benzoic acid-specific type III PKSs. In order to gain a better understanding of structure-function relationships within the type III PKS family, the crystal structures of biphenyl synthase from Malus × domestica and benzophenone synthase from Hypericum androsaemum were compared with the structure of an archetypal type III PKS: chalcone synthase from Malus × domestica. Both biphenyl synthase and benzophenone synthase contain mutations that reshape their active-site cavities to prevent the binding of 4-coumaroyl-CoA and to favor the binding of small hydrophobic substrates. The active-site cavities of biphenyl synthase and benzophenone synthase also contain a novel pocket associated with their chain-elongation and cyclization reactions. Collectively, these results illuminate structural determinants of benzoic acid-specific type III PKSs and expand the understanding of the evolution of specialized metabolic pathways in plants.
[Mh] Termos MeSH primário: Aciltransferases/química
Hypericum/enzimologia
Malus/enzimologia
[Mh] Termos MeSH secundário: Acil Coenzima A/química
Acil Coenzima A/metabolismo
Aciltransferases/metabolismo
Carbono-Carbono Ligases/química
Carbono-Carbono Ligases/metabolismo
Domínio Catalítico
Clonagem Molecular
Cristalografia por Raios X
Evolução Molecular
Modelos Moleculares
Estrutura Molecular
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acyl Coenzyme A); 6756-74-7 (benzoyl-coenzyme A); EC 2.3.- (Acyltransferases); EC 2.3.1.74 (flavanone synthetase); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.- (benzophenone synthase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317016618


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[PMID]:28683917
[Au] Autor:Tong L
[Ad] Endereço:Columbia University, New York, NY, United States. Electronic address: ltong@columbia.edu.
[Ti] Título:Striking Diversity in Holoenzyme Architecture and Extensive Conformational Variability in Biotin-Dependent Carboxylases.
[So] Source:Adv Protein Chem Struct Biol;109:161-194, 2017.
[Is] ISSN:1876-1623
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Biotin-dependent carboxylases are widely distributed in nature and have central roles in the metabolism of fatty acids, amino acids, carbohydrates, and other compounds. The last decade has seen the accumulation of structural information on most of these large holoenzymes, including the 500-kDa dimeric yeast acetyl-CoA carboxylase, the 750-kDa α ß dodecameric bacterial propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and geranyl-CoA carboxylase, the 720-kDa hexameric bacterial long-chain acyl-CoA carboxylase, the 500-kDa tetrameric bacterial single-chain pyruvate carboxylase, the 370-kDa α ß bacterial two-subunit pyruvate carboxylase, and the 130-kDa monomeric eukaryotic urea carboxylase. A common theme that has emerged from these studies is the dramatic structural flexibility of these holoenzymes despite their strong overall sequence conservation, evidenced both by the extensive diversity in the architectures of the holoenzymes and by the extensive conformational variability of their domains and subunits. This structural flexibility is crucial for the function and regulation of these enzymes and identifying compounds that can interfere with it represents an attractive approach for developing novel modulators and drugs. The extensive diversity observed in the structures so far and its biochemical and functional implications will be the focus of this review.
[Mh] Termos MeSH primário: Bactérias/enzimologia
Biotina/metabolismo
Carbono-Carbono Ligases/química
Carbono-Carbono Ligases/metabolismo
Fungos/enzimologia
[Mh] Termos MeSH secundário: Animais
Bactérias/química
Bactérias/metabolismo
Carbono-Nitrogênio Ligases/química
Carbono-Nitrogênio Ligases/metabolismo
Descoberta de Drogas
Fungos/química
Fungos/metabolismo
Holoenzimas/química
Holoenzimas/metabolismo
Seres Humanos
Modelos Moleculares
Conformação Proteica
Multimerização Proteica
Piruvato Carboxilase/química
Piruvato Carboxilase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Holoenzymes); 6SO6U10H04 (Biotin); EC 6.3.- (Carbon-Nitrogen Ligases); EC 6.3.4.14 (biotin carboxylase); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase); EC 6.4.1.1 (Pyruvate Carboxylase); EC 6.4.1.3 (propionyl CoA carboxylase (ATP-hydrolyzing)); EC 6.4.1.4 (methylcrotonoyl-CoA carboxylase); EC 6.4.1.5 (geranoyl-CoA carboxylase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE


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[PMID]:28644956
[Au] Autor:Zaganjor E; Vyas S; Haigis MC
[Ad] Endereço:Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:SIRT4 Is a Regulator of Insulin Secretion.
[So] Source:Cell Chem Biol;24(6):656-658, 2017 Jun 22.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In a recent issue of Cell Metabolism, Anderson et al. (2017) report that SIRT4 regulates insulin sensitivity in the pancreas via activation of methylcrotonyl-CoA carboxylase 1 (MCCC1) by removal of dicarboxyacyl-lysine modifications. Thus, SIRT4 activates leucine catabolism and causes decreased secretion of insulin from the pancreas.
[Mh] Termos MeSH primário: Insulina/secreção
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Animais
Carbono-Carbono Ligases/metabolismo
Resistência à Insulina
Camundongos
Pâncreas/secreção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); EC 3.5.1.- (Sirtuins); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.4 (methylcrotonoyl-CoA carboxylase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE


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[PMID]:28559140
[Au] Autor:Krycer JR; Fisher-Wellman KH; Fazakerley DJ; Muoio DM; James DE
[Ad] Endereço:School of Life and Environmental Sciences and Charles Perkins Centre, The University of Sydney, Sydney, 2050, Australia.
[Ti] Título:Bicarbonate alters cellular responses in respiration assays.
[So] Source:Biochem Biophys Res Commun;489(4):399-403, 2017 Aug 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic assay buffers often omit bicarbonate, which is susceptible to alkalinisation in an open environment. Here, we assessed the effect of including bicarbonate in respirometry experiments. By supplementing HEPES-buffered media with low concentrations of bicarbonate, we found increased respiration in adipocytes and hepatocytes, but not myotubes. This was observed across multiple respirometry platforms and was independent of effects on enhanced insulin sensitivity, pH drift, or mitochondrial function. Permeabilised cell experiments suggest that bicarbonate increases substrate availability, likely by acting as a cofactor for carboxylase enzymes. This emphasises the importance of buffer choice in experimental biology.
[Mh] Termos MeSH primário: Adipócitos/efeitos dos fármacos
Bicarbonatos/farmacologia
Respiração Celular/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos/metabolismo
Animais
Carbono-Carbono Ligases/metabolismo
Células Cultivadas
Hepatócitos/metabolismo
Camundongos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bicarbonates); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


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[PMID]:28494010
[Au] Autor:Okubo Y; Masuyama R; Iwanaga A; Koike Y; Kuwatsuka Y; Ogi T; Yamamoto Y; Endo Y; Tamura H; Utani A
[Ad] Endereço:Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
[Ti] Título:Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules.
[So] Source:PLoS One;12(5):e0177375, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gamma-glutamyl carboxylase (GGCX) gene mutation causes GGCX syndrome (OMIM: 137167), which is characterized by pseudoxanthoma elasticum (PXE)-like symptoms and coagulation impairment. Here, we present a 55-year-old male with a novel homozygous deletion mutation, c.2,221delT, p.S741LfsX100, in the GGCX gene. Histopathological examination revealed calcium deposits in elastic fibers and vessel walls, and collagen accumulation in the mid-dermis. Studies of dermal fibroblasts from the patient (GGCX dermal fibroblasts) demonstrated that the mutated GGCX protein was larger, but its expression level and intracellular distribution were indistinguishable from those of the wild-type GGCX protein. Immunostaining and an enzyme-linked immunosorbent assay showed an increase in undercarboxylated matrix gamma-carboxyglutamic acid protein (ucMGP), a representative substrate of GGCX and a potent calcification inhibitor, indicating that mutated GGCX was enzymatically inactive. Under osteogenic conditions, calcium deposition was exclusively observed in GGCX dermal fibroblasts. Furthermore, GGCX dermal fibroblast cultures contained 23- and 7.7-fold more alkaline phosphatase (ALP)-positive cells than normal dermal fibroblast cultures (n = 3), without and with osteogenic induction, respectively. Expression and activity of ALP were higher in GGCX dermal fibroblasts than in normal dermal fibroblasts upon osteogenic induction. mRNA levels of other osteogenic markers were also higher in GGCX dermal fibroblasts than in normal dermal fibroblasts, which including bone morphogenetic protein 6, runt-related transcription factor 2, and periostin (POSTN) without osteogenic induction; and osterix, collagen type I alpha 2, and POSTN with osteogenic induction. Together, these data indicate that GGCX dermal fibroblasts trans-differentiate into the osteogenic lineage. This study proposes another mechanism underlying aberrant calcification in patients with GGCX syndrome.
[Mh] Termos MeSH primário: Calcinose/genética
Carbono-Carbono Ligases/genética
Derme/patologia
Fibroblastos/patologia
Osteogênese/genética
Regulação para Cima/genética
[Mh] Termos MeSH secundário: Fosfatase Alcalina/metabolismo
Biomarcadores/metabolismo
Proteínas Morfogenéticas Ósseas/metabolismo
Calcinose/patologia
Proteínas de Ligação ao Cálcio/metabolismo
Transdiferenciação Celular
Proteínas da Matriz Extracelular/metabolismo
Deleção de Genes
Homozigoto
Seres Humanos
Espaço Intracelular/metabolismo
Masculino
Meia-Idade
Transporte Proteico
Pseudoxantoma Elástico/enzimologia
Pseudoxantoma Elástico/patologia
Transdução de Sinais
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Bone Morphogenetic Proteins); 0 (Calcium-Binding Proteins); 0 (Extracellular Matrix Proteins); 0 (matrix Gla protein); EC 3.1.3.1 (Alkaline Phosphatase); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.- (glutamyl carboxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177375


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[PMID]:28380376
[Au] Autor:Anderson KA; Huynh FK; Fisher-Wellman K; Stuart JD; Peterson BS; Douros JD; Wagner GR; Thompson JW; Madsen AS; Green MF; Sivley RM; Ilkayeva OR; Stevens RD; Backos DS; Capra JA; Olsen CA; Campbell JE; Muoio DM; Grimsrud PA; Hirschey MD
[Ad] Endereço:Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
[Ti] Título:SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.
[So] Source:Cell Metab;25(4):838-855.e15, 2017 Apr 04.
[Is] ISSN:1932-7420
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sirtuins are NAD -dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.
[Mh] Termos MeSH primário: Amidoidrolases/metabolismo
Insulina/secreção
Leucina/metabolismo
Lisina/metabolismo
Proteínas Mitocondriais/metabolismo
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Carbono-Carbono Ligases/metabolismo
Glucose/metabolismo
Células HEK293
Homeostase
Seres Humanos
Resistência à Insulina
Análise do Fluxo Metabólico
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas Mitocondriais/química
Modelos Moleculares
Filogenia
Sirtuínas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Mitochondrial Proteins); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (SIRT4 protein, mouse); EC 3.5.1.- (Sirtuins); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.4 (methylcrotonoyl-CoA carboxylase); GMW67QNF9C (Leucine); IY9XDZ35W2 (Glucose); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE


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[PMID]:28376131
[Au] Autor:Au NT; Reyes M; Boyer BB; Hopkins SE; Black J; O'Brien D; Fohner AE; Yracheta J; Thornton T; Austin MA; Burke W; Thummel KE; Rettie AE
[Ad] Endereço:Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
[Ti] Título:Dietary and genetic influences on hemostasis in a Yup'ik Alaska Native population.
[So] Source:PLoS One;12(4):e0173616, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fish and marine animals are important components of the subsistence diet of Alaska Native people, resulting in a high ω3 PUFA intake. The historical record for circumpolar populations highlights a tendency for facile bleeding, possibly related to ω3 PUFA effects on platelet activation and/or vitamin K-dependent clotting factors. To evaluate these two scenarios in Yup'ik people of southwestern Alaska, we examined the association between dietary ω3 PUFA intake and activities of clotting factor II, V, fibrinogen, PT, INR, PTT, and sP-selectin in 733 study participants, using the nitrogen isotope ratio of red blood cells as a biomarker of ω3 PUFA consumption. sP-selectin alone correlated strongly and inversely with ω3 PUFA consumption. Approximately 36% of study participants exhibited PIVKA-II values above the threshold of 2 ng/ml, indicative of low vitamin K status. To assess genetic influences on vitamin K status, study participants were genotyped for common vitamin K cycle polymorphisms in VKORC1, GGCX and CYP4F2. Only CYP4F2*3 associated significantly with vitamin K status, for both acute (plasma vitamin K) and long-term (PIVKA-II) measures. These findings suggest: (i) a primary association of ω3 PUFAs on platelet activation, as opposed to vitamin K-dependent clotting factor activity, (ii) that reduced CYP4F2 enzyme activity associates with vitamin K status. We conclude that high ω3 PUFA intake promotes an anti-platelet effect and speculate that the high frequency of the CYP4F2*3 allele in Yup'ik people (~45%) evolved in response to a need to conserve body stores of vitamin K due to environmental limitations on its availability.
[Mh] Termos MeSH primário: Nativos do Alasca/genética
Dieta
Hemostasia/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Alaska
Animais
Biomarcadores/sangue
Coagulação Sanguínea/genética
Fatores de Coagulação Sanguínea/genética
Fatores de Coagulação Sanguínea/metabolismo
Carbono-Carbono Ligases/genética
Estudos Transversais
Família 4 do Citocromo P450/genética
Ácidos Graxos Ômega-3/administração & dosagem
Feminino
Genótipo
Seres Humanos
Inuítes/genética
Masculino
Meia-Idade
Selectina-P/sangue
Ativação Plaquetária/genética
Polimorfismo de Nucleotídeo Único
Precursores de Proteínas/sangue
Protrombina
Vitamina K/sangue
Vitamina K Epóxido Redutases/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Blood Coagulation Factors); 0 (Fatty Acids, Omega-3); 0 (P-Selectin); 0 (Protein Precursors); 12001-79-5 (Vitamin K); 53230-14-1 (acarboxyprothrombin); 9001-26-7 (Prothrombin); EC 1.14.13.30 (CYP4F2 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 4); EC 1.17.4.4 (VKORC1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.- (glutamyl carboxylase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173616


  9 / 713 MEDLINE  
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[PMID]:28222482
[Au] Autor:Bazet Lyonnet B; Diacovich L; Gago G; Spina L; Bardou F; Lemassu A; Quémard A; Gramajo H
[Ad] Endereço:Laboratory of Physiology and Genetics of Actinomycetes, Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Universidad Nacional de Rosario, Argentina.
[Ti] Título:Functional reconstitution of the Mycobacterium tuberculosis long-chain acyl-CoA carboxylase from multiple acyl-CoA subunits.
[So] Source:FEBS J;284(7):1110-1125, 2017 Apr.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mycobacterium tuberculosis produces a large number of structurally diverse lipids that have been implicated in the pathogenicity, persistence and antibiotic resistance of this organism. Most building blocks involved in the biosynthesis of all these lipids are generated by acyl-CoA carboxylases whose subunit composition and physiological roles have not yet been clearly established. Inconclusive data in the literature refer to the exact protein composition and substrate specificity of the enzyme complex that produces the long-chain α-carboxy-acyl-CoAs, which are substrates involved in the last step of condensation mediated by the polyketide synthase 13 to synthesize mature mycolic acids. Here we have successfully reconstituted the long-chain acyl-CoA carboxylase (LCC) complex from its purified components, the α subunit (AccA3), the ε subunit (AccE5) and the two ß subunits (AccD4 and AccD5), and demonstrated that the four subunits are essential for its activity. Furthermore, we also showed by substrate competition experiments and the use of a specific inhibitor that the AccD5 subunit's role in the carboxylation of the long acyl-CoAs, as part of the LCC complex, was structural rather than catalytic. Moreover, AccD5 was also able to carboxylate its natural substrates, acetyl-CoA and propionyl-CoA, in the context of the LCC enzyme complex. Thus, the supercomplex formed by these four subunits has the potential to generate the main substrates, malonyl-CoA, methylmalonyl-CoA and α-carboxy-C -CoA, used as condensing units for the biosynthesis of all the lipids present in this pathogen.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Carbono-Carbono Ligases/metabolismo
Mycobacterium tuberculosis/metabolismo
Policetídeo Sintases/metabolismo
Subunidades Proteicas/metabolismo
[Mh] Termos MeSH secundário: Acetilcoenzima A/metabolismo
Acil Coenzima A/metabolismo
Proteínas de Bactérias/genética
Carbono-Carbono Ligases/genética
Clonagem Molecular
Ensaios Enzimáticos
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Cinética
Malonil Coenzima A/metabolismo
Mycobacterium tuberculosis/genética
Ácidos Micólicos/metabolismo
Policetídeo Sintases/genética
Engenharia de Proteínas
Subunidades Proteicas/genética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acyl Coenzyme A); 0 (Bacterial Proteins); 0 (Mycolic Acids); 0 (Protein Subunits); 0 (Recombinant Proteins); 1264-45-5 (methylmalonyl-coenzyme A); 317-66-8 (propionyl-coenzyme A); 524-14-1 (Malonyl Coenzyme A); 72-89-9 (Acetyl Coenzyme A); 79956-01-7 (Polyketide Synthases); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.1.- (acyl-CoA carboxylase)
[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:170222
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14046


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[PMID]:28125048
[Au] Autor:De Vilder EY; Debacker J; Vanakker OM
[Ad] Endereço:Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium. eva.devilder@ugent.be.
[Ti] Título:GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.
[So] Source:Int J Mol Sci;18(2), 2017 Jan 25.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype-phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations-a frequent problem in orphan diseases-we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype-phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.
[Mh] Termos MeSH primário: Carbono-Carbono Ligases/genética
Carbono-Carbono Ligases/metabolismo
Estudos de Associação Genética
Genótipo
Fenótipo
[Mh] Termos MeSH secundário: Transtornos Herdados da Coagulação Sanguínea/diagnóstico
Transtornos Herdados da Coagulação Sanguínea/genética
Carbono-Carbono Ligases/química
Anormalidades Congênitas/diagnóstico
Anormalidades Congênitas/genética
Olho/patologia
Técnicas de Inativação de Genes
Aconselhamento Genético
Predisposição Genética para Doença
Seres Humanos
Mutação
Polimorfismo de Nucleotídeo Único
Domínios e Motivos de Interação entre Proteínas
Pele/metabolismo
Pele/patologia
Vitamina K/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
12001-79-5 (Vitamin K); EC 6.4.- (Carbon-Carbon Ligases); EC 6.4.- (glutamyl carboxylase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170127
[St] Status:MEDLINE



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