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[PMID]:29317615
[Au] Autor:An JU; Song YS; Kim KR; Ko YJ; Yoon DY; Oh DK
[Ad] Endereço:Department of Integrative Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
[Ti] Título:Biotransformation of polyunsaturated fatty acids to bioactive hepoxilins and trioxilins by microbial enzymes.
[So] Source:Nat Commun;9(1):128, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hepoxilins (HXs) and trioxilins (TrXs) are involved in physiological processes such as inflammation, insulin secretion and pain perception in human. They are metabolites of polyunsaturated fatty acids (PUFAs), including arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, formed by 12-lipoxygenase (LOX) and epoxide hydrolase (EH) expressed by mammalian cells. Here, we identify ten types of HXs and TrXs, produced by the prokaryote Myxococcus xanthus, of which six types are new, namely, HXB , HXD , HXE , TrXB , TrXD and TrXE . We succeed in the biotransformation of PUFAs into eight types of HXs (>35% conversion) and TrXs (>10% conversion) by expressing M. xanthus 12-LOX or 11-LOX with or without EH in Escherichia coli. We determine 11-hydroxy-eicosatetraenoic acid, HXB , HXB , HXD , TrXB and TrXD as potential peroxisome proliferator-activated receptor-γ partial agonists. These findings may facilitate physiological studies and drug development based on lipid mediators.
[Mh] Termos MeSH primário: Ácido 8,11,14-Eicosatrienoico/análogos & derivados
Ácidos Graxos Insaturados/metabolismo
Myxococcus xanthus/enzimologia
[Mh] Termos MeSH secundário: Ácido 8,11,14-Eicosatrienoico/química
Ácido 8,11,14-Eicosatrienoico/metabolismo
Araquidonato 12-Lipoxigenase/genética
Araquidonato 12-Lipoxigenase/metabolismo
Araquidonato Lipoxigenases/genética
Araquidonato Lipoxigenases/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biotransformação
Epóxido Hidrolases/genética
Epóxido Hidrolases/metabolismo
Ácidos Graxos Insaturados/química
Redes e Vias Metabólicas/genética
Estrutura Molecular
Myxococcus xanthus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Fatty Acids, Unsaturated); 68860-46-8 (8,11,12-trihydroxy-5,9,14-eicosatrienoic acid); 7324-41-6 (8,11,14-Eicosatrienoic Acid); 85589-24-8 (8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid); EC 1.13.11.- (11-lipoxygenase); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.31 (Arachidonate 12-Lipoxygenase); EC 3.3.2.- (Epoxide Hydrolases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02543-8


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[PMID]:27556049
[Au] Autor:Pasková L; Kuncírová V; Ponist S; Mihálová D; Nosál R; Harmatha J; Hrádková I; Cavojský T; Bilka F; Sisková K; Paulíková I; Bezáková L; Bauerová K
[Ad] Endereço:Department of Cell and Molecular Biology of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia.
[Ti] Título:Effect of N-Feruloylserotonin and Methotrexate on Severity of Experimental Arthritis and on Messenger RNA Expression of Key Proinflammatory Markers in Liver.
[So] Source:J Immunol Res;2016:7509653, 2016.
[Is] ISSN:2314-7156
[Cp] País de publicação:Egypt
[La] Idioma:eng
[Ab] Resumo:Rheumatoid arthritis (RA) is a chronic inflammatory disease, leading to progressive destruction of joints and extra-articular tissues, including organs such as liver and spleen. The purpose of this study was to compare the effects of a potential immunomodulator, natural polyphenol N-feruloylserotonin (N-f-5HT), with methotrexate (MTX), the standard in RA therapy, in the chronic phase of adjuvant-induced arthritis (AA) in male Lewis rats. The experiment included healthy controls (CO), arthritic animals (AA), AA given N-f-5HT (AA-N-f-5HT), and AA given MTX (AA-MTX). N-f-5HT did not affect the body weight change and clinical parameters until the 14th experimental day. Its positive effect was rising during the 28-day experiment, indicating a delayed onset of N-f-5HT action. Administration of either N-f-5HT or MTX caused reduction of inflammation measured as the level of CRP in plasma and the activity of LOX in the liver. mRNA transcription of TNF-α and iNOS in the liver was significantly attenuated in both MTX and N-f-5HT treated groups of arthritic rats. Interestingly, in contrast to MTX, N-f-5HT significantly lowered the level of IL-1ß in plasma and IL-1ß mRNA expression in the liver and spleen of arthritic rats. This speaks for future investigations of N-f-5HT as an agent in the treatment of RA in combination therapy with MTX.
[Mh] Termos MeSH primário: Artrite Experimental/genética
Artrite Experimental/patologia
Mediadores da Inflamação
Fígado/efeitos dos fármacos
Fígado/metabolismo
Metotrexato/farmacologia
Serotonina/análogos & derivados
Transcriptoma
[Mh] Termos MeSH secundário: Animais
Araquidonato Lipoxigenases/genética
Araquidonato Lipoxigenases/metabolismo
Artrite Experimental/tratamento farmacológico
Biomarcadores
Proteína C-Reativa
Citocinas/sangue
Citocinas/genética
Citocinas/metabolismo
Modelos Animais de Doenças
Regulação da Expressão Gênica/efeitos dos fármacos
Masculino
Especificidade de Órgãos
Ratos
Serotonina/farmacologia
Índice de Gravidade de Doença
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Cytokines); 0 (Inflammation Mediators); 2PP8322487 (N-feruloylserotonin); 333DO1RDJY (Serotonin); 9007-41-4 (C-Reactive Protein); EC 1.13.11.- (Arachidonate Lipoxygenases); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170316
[Lr] Data última revisão:
170316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160825
[St] Status:MEDLINE
[do] DOI:10.1155/2016/7509653


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[PMID]:26756638
[Au] Autor:Imig JD; Khan MA
[Ad] Endereço:Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
[Ti] Título:Cytochrome P450 and Lipoxygenase Metabolites on Renal Function.
[So] Source:Compr Physiol;6(1):423-41, 2015 Dec 15.
[Is] ISSN:2040-4603
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.
[Mh] Termos MeSH primário: Araquidonato Lipoxigenases/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Rim/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Araquidonato Lipoxigenases/genética
Sistema Enzimático do Citocromo P-450/genética
Hemodinâmica
Seres Humanos
Rim/fisiologia
Reabsorção Renal
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.13.11.- (Arachidonate Lipoxygenases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170504
[Lr] Data última revisão:
170504
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160113
[St] Status:MEDLINE
[do] DOI:10.1002/cphy.c150009


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[PMID]:26415844
[Au] Autor:Bushnell EA; Berryman VE; Gauld JW; Boyd RJ
[Ad] Endereço:Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Chemistry, Brandon University, Brandon, Manitoba, Canada. Electronic address: Eric.Bushnell@Dal.Ca.
[Ti] Título:The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations: Applications to Enzymatic Reactions.
[So] Source:Adv Protein Chem Struct Biol;100:153-85, 2015.
[Is] ISSN:1876-1623
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In this chapter, we discuss the influence of an anisotropic protein environment on the reaction mechanisms of saccharopine reductase and uroporphyrinogen decarboxylase, respectively, via the use of a quantum mechanical and molecular mechanical (QM/MM) approach. In addition, we discuss the importance of selecting a suitable DFT functional to be used in a QM/MM study of a key intermediate in the mechanism of 8R-lipoxygenase, a nonheme iron enzyme. In the case of saccharopine reductase, while the enzyme utilizes a substrate-assisted catalytic pathway, it was found that only through treating the polarizing effect of the active site, via the use of an electronic embedding formalism, was agreement with experimental kinetic data obtained. Similarly, in the case of uroporphyrinogen decarboxylase, the effect of the protein environment on the catalytic mechanism was found to be such that the calculated rate-limiting barrier is in good agreement with related experimentally determined values for the first decarboxylation of the substrate. For 8R-lipoxygenase, it was found that the geometries and energies of the multicentered open-shell intermediate complexes formed during the mechanism are quite sensitive to the choice of the density functional theory method. Thus, while density functional theory has become the method of choice in QM/MM studies, care must be taken in the selection of a particular high-level method.
[Mh] Termos MeSH primário: Araquidonato Lipoxigenases/química
Simulação de Dinâmica Molecular
Sacaropina Desidrogenases/química
Uroporfirinogênio Descarboxilase/química
[Mh] Termos MeSH secundário: Animais
Anisotropia
Antozoários/química
Antozoários/enzimologia
Domínio Catalítico
Seres Humanos
Cinética
Teoria Quântica
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.40 (arachidonate 8-lipoxygenase); EC 1.5.1.- (Saccharopine Dehydrogenases); EC 1.5.1.10 (saccharopine dehydrogenase (NADP, L-glutamate-forming)); EC 4.1.1.37 (Uroporphyrinogen Decarboxylase)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:150929
[Lr] Data última revisão:
150929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150930
[St] Status:MEDLINE


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[PMID]:25278440
[Au] Autor:Bader A; Martini F; Schinella GR; Rios JL; Prieto JM
[Ad] Endereço:Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia.
[Ti] Título:Modulation of Cox-1, 5-, 12- and 15-Lox by popular herbal remedies used in southern Italy against psoriasis and other skin diseases.
[So] Source:Phytother Res;29(1):108-13, 2015 Jan.
[Is] ISSN:1099-1573
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Acanthus mollis (Acanthaceae), Achillea ligustica, Artemisia arborescens and Inula viscosa (Asteraceae) are used in Southern Italy against psoriasis and other skin diseases that occur with an imbalanced production of eicosanoids. We here assessed their in vitro effects upon 5-, 12-, 15-LOX and COX-1 enzymes as well as NFκB activation in intact cells as their possible therapeutic targets. All methanol crude extracts inhibited both 5-LOX and COX-1 activities under 200 µg/mL, without significant effects on the 12-LOX pathway or any relevant in vitro free radical scavenging activity. NFκB activation was prevented by all extracts but A. mollis. Interestingly, A. ligustica, A. arborescens and A. mollis increased the biosynthesis of 15(S)-HETE, an anti-inflammatory eicosanoid. A. ligustica (IC50 =49.5 µg/mL) was superior to Silybum marianum (IC50 =147.8 µg/mL), which we used as antipsoriatic herbal medicine of reference. Its n-hexane, dichloromethane and ethyl acetate fractions had also inhibitory effects on the LTB4 biosynthesis (IC50 s=9.6, 20.3 and 68 µg/mL, respectively) evidencing that the apolar extracts of A. ligustica are promising active herbal ingredients for future phytotherapeutical products targeting psoriasis.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Fármacos Dermatológicos/farmacologia
Extratos Vegetais/farmacologia
Psoríase/tratamento farmacológico
Dermatopatias/tratamento farmacológico
[Mh] Termos MeSH secundário: Acanthaceae/química
Achillea/química
Animais
Araquidonato Lipoxigenases/metabolismo
Artemisia/química
Plaquetas/efeitos dos fármacos
Ciclo-Oxigenase 1/metabolismo
Células HeLa
Seres Humanos
Inula/química
Itália
Leucócitos/efeitos dos fármacos
NF-kappa B/metabolismo
Fitoterapia
Plantas Medicinais/química
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Dermatologic Agents); 0 (NF-kappa B); 0 (Plant Extracts); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (PTGS1 protein, human)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141004
[St] Status:MEDLINE
[do] DOI:10.1002/ptr.5234


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[PMID]:25231982
[Au] Autor:Neau DB; Bender G; Boeglin WE; Bartlett SG; Brash AR; Newcomer ME
[Ad] Endereço:the Department of Chemistry and Chemical Biology, Cornell University, Northeastern Collaborative Access Team, Argonne National Laboratory, Argonne, Illinois 60439, and.
[Ti] Título:Crystal structure of a lipoxygenase in complex with substrate: the arachidonic acid-binding site of 8R-lipoxygenase.
[So] Source:J Biol Chem;289(46):31905-13, 2014 Nov 14.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipoxygenases (LOX) play critical roles in mammalian biology in the generation of potent lipid mediators of the inflammatory response; consequently, they are targets for the development of isoform-specific inhibitors. The regio- and stereo-specificity of the oxygenation of polyunsaturated fatty acids by the enzymes is understood in terms of the chemistry, but structural observation of the enzyme-substrate interactions is lacking. Although several LOX crystal structures are available, heretofore the rapid oxygenation of bound substrate has precluded capture of the enzyme-substrate complex, leaving a gap between chemical and structural insights. In this report, we describe the 2.0 Å resolution structure of 8R-LOX in complex with arachidonic acid obtained under anaerobic conditions. Subtle rearrangements, primarily in the side chains of three amino acids, allow binding of arachidonic acid in a catalytically competent conformation. Accompanying experimental work supports a model in which both substrate tethering and cavity depth contribute to positioning the appropriate carbon at the catalytic machinery.
[Mh] Termos MeSH primário: Araquidonato Lipoxigenases/química
[Mh] Termos MeSH secundário: Animais
Ácido Araquidônico/química
Sítios de Ligação
Catálise
Cristalografia por Raios X
Seres Humanos
Inflamação
Ferro/química
Lipídeos/química
Modelos Moleculares
Mutagênese
Mutação
Oxigênio/química
Ligação Proteica
Conformação Proteica
Coelhos
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Lipids); 27YG812J1I (Arachidonic Acid); E1UOL152H7 (Iron); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.40 (arachidonate 8-lipoxygenase); S88TT14065 (Oxygen)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:161202
[Lr] Data última revisão:
161202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140919
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.599662


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[PMID]:24796762
[Au] Autor:Xu Z; Zhao F; Lin F; Xiang H; Wang N; Ye D; Huang Y
[Ad] Endereço:Department of Gynecology and Obstetrics, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
[Ti] Título:Preeclampsia is associated with a deficiency of lipoxin A4, an endogenous anti-inflammatory mediator.
[So] Source:Fertil Steril;102(1):282-290.e4, 2014 Jul.
[Is] ISSN:1556-5653
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To test whether lipoxin A4 (LXA4) deficiency results in preeclampsia. DESIGN: Prospective experimental study. SETTING: Patient and animal research facilities. ANIMAL(S): Sprague-Dawley rats. INTERVENTION(S): We measured LXA4 and its biosynthetic enzymes, blocked the LXA4 signaling pathway, treated experimental rats with preeclampsia with LXA4, and detected inflammatory factors, FPR2/ALX, and 11ß-HSD2 to systematically test whether lack of LXA4 results in preeclampsia. MAIN OUTCOME MEASURE(S): We measured serum levels of LXA4 and inflammatory factors using enzyme-linked immunosorbent assay; detected LXA4 biosynthetic enzymes, inflammatory factors, FPR2/ALX, and 11ß-HSD2 mRNA expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR; and localized protein expression using immunohistochemistry. RESULT(S): FPR2/ALX and LXA4 and its biosynthetic enzymes were found to be decreased in women with preeclampsia. Replenishing LXA4 improved the symptoms of lipopolysaccharide-induced rats with preeclampsia, while blocking LXA4 signaling resulted in preeclampsia. LXA4 significantly reduced interleukin-6 (IL-6), tumor necrosis factor-α, and IFN-γ but increased IL-10, LXA4 up-regulated 11ß-HSD2. CONCLUSION(S): A deficiency of LXA4 may result in preeclampsia, which might be ascribed to a reduction in inflammation response, oxidative stress, and regulation of 11ß-HSD2.
[Mh] Termos MeSH primário: Lipoxinas/deficiência
Pré-Eclâmpsia/metabolismo
Trofoblastos/metabolismo
[Mh] Termos MeSH secundário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo
Animais
Araquidonato Lipoxigenases/metabolismo
Biomarcadores/sangue
Estudos de Casos e Controles
Linhagem Celular
Modelos Animais de Doenças
Feminino
Ácidos Heptanoicos/farmacologia
Seres Humanos
Mediadores da Inflamação/sangue
Interferon gama/sangue
Interleucina-6/sangue
Lipopolissacarídeos
Lipoxinas/sangue
Lipoxinas/farmacologia
Pré-Eclâmpsia/sangue
Pré-Eclâmpsia/induzido quimicamente
Pré-Eclâmpsia/diagnóstico
Pré-Eclâmpsia/tratamento farmacológico
Pré-Eclâmpsia/genética
Gravidez
RNA Mensageiro/metabolismo
Ratos
Ratos Sprague-Dawley
Receptores de Lipoxinas/sangue
Transdução de Sinais
Fatores de Tempo
Trofoblastos/efeitos dos fármacos
Trofoblastos/enzimologia
Fator de Necrose Tumoral alfa/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester); 0 (Biomarkers); 0 (Heptanoic Acids); 0 (Inflammation Mediators); 0 (Interleukin-6); 0 (Lipopolysaccharides); 0 (Lipoxins); 0 (RNA, Messenger); 0 (Receptors, Lipoxin); 0 (Tumor Necrosis Factor-alpha); 0 (lipoxin A(4) receptor, rat); 0 (lipoxin A4); 82115-62-6 (Interferon-gamma); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 2); EC 1.1.1.146 (HSD11B2 protein, human); EC 1.13.11.- (Arachidonate Lipoxygenases)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140507
[St] Status:MEDLINE


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[PMID]:23361122
[Au] Autor:Bushnell EA; Jamil R; Gauld JW
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, Canada.
[Ti] Título:Gaining insight into the chemistry of lipoxygenases: a computational investigation into the catalytic mechanism of (8R)-lipoxygenase.
[So] Source:J Biol Inorg Chem;18(3):343-55, 2013 Mar.
[Is] ISSN:1432-1327
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Lipoxygenases (LOXs) are ubiquitous in nature and catalyze a range of life-essential reactions within organisms. In particular they are critical to the formation of eicosanoids, which are critical for normal cell function. However, a number of important questions about the reactivity and mechanism of these enzymes still remain. Specifically, although the initial step in the mechanism of LOXs has been well studied, little is known of subsequent steps. Thus, with use of a quantum mechanical/molecular mechanical approach, the complete catalytic mechanism of (8R)-LOX was investigated. The results have provided a better understanding of the general chemistry of LOXs as a whole. In particular, from comparisons with soybean LOX-1, it appears that the initial proton-coupled electron transfer may be very similar among all LOXs. Furthermore, LOXs appear to undergo multistate reactivity where potential spin inversion of an electron may occur either in the attack of O(2) or in the regeneration of the active site. Lastly, it is shown that with the explicit modeling of the environment, the regeneration of the active center likely occurs via the rotation of the intermediate followed by an outer-sphere [Formula: see text] transfer as opposed to the formation of a "purple intermediate" complex.
[Mh] Termos MeSH primário: Antozoários/enzimologia
Araquidonato Lipoxigenases/química
Araquidonato Lipoxigenases/metabolismo
[Mh] Termos MeSH secundário: Animais
Antozoários/química
Domínio Catalítico
Ativação Enzimática
Lipoxigenase/química
Lipoxigenase/metabolismo
Simulação de Acoplamento Molecular
Peróxidos/química
Peróxidos/metabolismo
Conformação Proteica
Teoria Quântica
Feijão de Soja/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Peroxides); 3170-83-0 (perhydroxyl radical); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.12 (Lipoxygenase)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130131
[St] Status:MEDLINE
[do] DOI:10.1007/s00775-013-0978-4


  9 / 726 MEDLINE  
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[PMID]:22822060
[Au] Autor:Wennman A; Jernerén F; Hamberg M; Oliw EH
[Ad] Endereço:Department of Pharmaceutical Biosciences, Uppsala University, Biomedical Center, SE-751 24 Uppsala, Sweden.
[Ti] Título:Catalytic convergence of manganese and iron lipoxygenases by replacement of a single amino acid.
[So] Source:J Biol Chem;287(38):31757-65, 2012 Sep 14.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipoxygenases (LOXs) contain a hydrophobic substrate channel with the conserved Gly/Ala determinant of regio- and stereospecificity and a conserved Leu residue near the catalytic non-heme iron. Our goal was to study the importance of this region (Gly(332), Leu(336), and Phe(337)) of a lipoxygenase with catalytic manganese (13R-MnLOX). Recombinant 13R-MnLOX oxidizes 18:2n-6 and 18:3n-3 to 13R-, 11(S or R)-, and 9S-hydroperoxy metabolites (∼80-85, 15-20, and 2-3%, respectively) by suprafacial hydrogen abstraction and oxygenation. Replacement of Phe(337) with Ile changed the stereochemistry of the 13-hydroperoxy metabolites of 18:2n-6 and 18:3n-3 (from ∼100% R to 69-74% S) with little effect on regiospecificity. The abstraction of the pro-S hydrogen of 18:2n-6 was retained, suggesting antarafacial hydrogen abstraction and oxygenation. Replacement of Leu(336) with smaller hydrophobic residues (Val, Ala, and Gly) shifted the oxygenation from C-13 toward C-9 with formation of 9S- and 9R-hydroperoxy metabolites of 18:2n-6 and 18:3n-3. Replacement of Gly(332) and Leu(336) with larger hydrophobic residues (G332A and L336F) selectively augmented dehydration of 13R-hydroperoxyoctadeca-9Z,11E,15Z-trienoic acid and increased the oxidation at C-13 of 18:1n-6. We conclude that hydrophobic replacements of Leu(336) can modify the hydroperoxide configurations at C-9 with little effect on the R configuration at C-13 of the 18:2n-6 and 18:3n-3 metabolites. Replacement of Phe(337) with Ile changed the stereospecific oxidation of 18:2n-6 and 18:3n-3 with formation of 13S-hydroperoxides by hydrogen abstraction and oxygenation in analogy with soybean LOX-1.
[Mh] Termos MeSH primário: Aminoácidos/química
Ferro/química
Lipoxigenase/química
Lipoxigenase/genética
Manganês/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Antozoários
Araquidonato Lipoxigenases/química
Catálise
Cromatografia Líquida de Alta Pressão/métodos
Seres Humanos
Hidrogênio/química
Cinética
Espectrometria de Massas/métodos
Dados de Sequência Molecular
Mutagênese Sítio-Dirigida
Mutação
Oxigênio/química
Pichia/metabolismo
Homologia de Sequência de Aminoácidos
Feijão de Soja/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids); 42Z2K6ZL8P (Manganese); 7YNJ3PO35Z (Hydrogen); E1UOL152H7 (Iron); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.12 (Lipoxygenase); EC 1.13.11.40 (arachidonate 8-lipoxygenase); S88TT14065 (Oxygen)
[Em] Mês de entrada:1212
[Cu] Atualização por classe:150224
[Lr] Data última revisão:
150224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120724
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M112.364331


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[PMID]:22573333
[Au] Autor:Eek P; Järving R; Järving I; Gilbert NC; Newcomer ME; Samel N
[Ad] Endereço:Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
[Ti] Título:Structure of a calcium-dependent 11R-lipoxygenase suggests a mechanism for Ca2+ regulation.
[So] Source:J Biol Chem;287(26):22377-86, 2012 Jun 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipoxygenases (LOXs) are a key part of several signaling pathways that lead to inflammation and cancer. Yet, the mechanisms of substrate binding and allosteric regulation by the various LOX isoforms remain speculative. Here we report the 2.47-Å resolution crystal structure of the arachidonate 11R-LOX from Gersemia fruticosa, which sheds new light on the mechanism of LOX catalysis. Our crystallographic and mutational studies suggest that the aliphatic tail of the fatty acid is bound in a hydrophobic pocket with two potential entrances. We speculate that LOXs share a common T-shaped substrate channel architecture that gives rise to the varying positional specificities. A general allosteric mechanism is proposed for transmitting the activity-inducing effect of calcium binding from the membrane-targeting PLAT (polycystin-1/lipoxygenase/α-toxin) domain to the active site via a conserved π-cation bridge.
[Mh] Termos MeSH primário: Araquidonato Lipoxigenases/química
Cálcio/metabolismo
Regulação da Expressão Gênica
[Mh] Termos MeSH secundário: Sítio Alostérico
Animais
Antozoários
Proteínas de Ligação ao Cálcio/metabolismo
Domínio Catalítico
Membrana Celular/metabolismo
Cromatografia Líquida de Alta Pressão/métodos
Cristalografia por Raios X/métodos
Dimerização
Eicosanoides/química
Seres Humanos
Cinética
Lipossomos/metabolismo
Espectrometria de Massas/métodos
Modelos Químicos
Conformação Molecular
Mutagênese Sítio-Dirigida
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Eicosanoids); 0 (Liposomes); EC 1.13.11.- (11-lipoxygenase); EC 1.13.11.- (Arachidonate Lipoxygenases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1209
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120511
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M112.343285



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