First Structural Evidence of a Specific Inhibition of Phospholipase A2 by α-Tocopherol (Vitamin E) and its Implications in Inflammation: Crystal Structure of the Complex Formed Between Phospholipase A2 and α-Tocopherol at 1.8Å Resolution

Chandra, Vikas; Jasti, J.; Kaur, Punit; Betzel, C.; Srinivasan, Alagiri; Singh, T.P.

doi:10.1016/s0022-2836(02)00473-4

Cited by 110 publications

(68 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, some of the plant extracts evidenced antioxidant activity, in accordance to previous reports which demonstrated that antioxidant compounds are group II PLA 2 inhibitors (Chandra et al, 2002;Lindahl et al, 1993Lindahl et al, , 1997. Our results were supported by the significant correlation between both activities (Table 1).…”

Section: Discussionsupporting

confidence: 90%

“…In this direction, it was also suggested that vitamin E has the ability to bind to the hydrophobic pocket of PLA 2 , inhibiting free access of substrate to the catalytic site (Takeda et al, 2004). In relation to the mode of action, several studies have concluded that the inhibition of polyphenolic compounds on PLA 2 , is due to the interactions between the enzyme and the hydroxyl groups present in this type of metabolites, through hydrogen bonds that results in the formation of a stable complex (Chandra et al, 2002;Da Silva et al, 2009;Lindahl et al, 1997;Toyama et al, 2009). However, the activity of polyphenolic compounds may involve varying degrees of interactions such as hydrophobic connections mediated by aromatic rings, which should also be considered.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, some authors have shown that flavonoids present in different plant families induce a dosedependent inhibition of in vitro phospholipid hydrolysis by secretory PLA 2 s (Lindahl & Tagesson, 1997). Recently, studies concluded that α-tocopherol (Vitamin E), a well known antioxidant, is an effective inhibitor of PLA 2 (Chandra et al, 2002;Takeda et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Correlation of the inhibitory activity of phospholipase A2 snake venom and the antioxidant activity of Colombian plant extracts

Pereañez¹,

Lobo-Echeverri²,

Rojano³

et al. 2010

Rev. bras. farmacogn.

View full text Add to dashboard Cite

RESUMO:Veneno de cobra continua a ser um problema importante de saúde em muitos países da América Latina. Apesar dos avanços na terapia antiveneno, os efeitos locais causados por fosfolipases A 2 miotóxica (PLA 2 ) presentes no veneno, ainda persistem. Em busca de alternativas para antagonizar a atividade da PLA 2 do veneno de Bothrops asper, foram selecionados 36 extratos pertencentes a dezessete famílias de plantas vasculares e briófitas. Uma inibição significativa da atividade enzimática de PLA 2 presente no veneno de B. asper foi observada em onze extratos. Além disso, a atividade antioxidante dos extratos foi avaliada. Os resultados evidenciaram uma correlação estatisticamente significativa entre os extratos com ação inibitória contra a PLA 2 e aqueles com atividade antioxidante. Também, a quantidade de fenóis foi avaliada e foi encontrada uma relação entre a atividade biológica e a presença dessas substâncias. Nove extratos foram testados contra uma fração do veneno rico em PLA 2 básica (Fx-V B. asper), resultando em um efeito inibitório na atividade desta fração da PLA 2 na faixa de 30-80%. Esta atividade foi apoiada pela inibição que esses extratos apresentaram na citotoxicidade causada pelo Fx-V B. asper sobre mioblastos C2C12 de músculo esquelético de murino. Os resultados podem indicar a minimização dos esforços na busca de inibidores da PLA 2 , com foco nas amostras com propriedades antioxidantes conhecidas.Unitermos: fosfolipase A 2 , veneno de cobra, Bothrops asper, extratos de plantas, antioxidantes, DPPH.ABSTRACT: Snakebite continues to be a significant health problem in many countries of Latin America. Even though, there has been an improvement in the antivenom therapy, the local effects caused by myotoxic phospholipases A 2 (PLA 2 ) present in the venoms, still persist. In search for alternatives to antagonize the PLA 2 activity of Bothrops asper's venom, 36 extracts belonging to seventeen families of vascular plants and bryophytes were screened. A significant inhibition of the enzymatic activity of PLA 2 present in B. asper's whole venom was seen in eleven of these extracts. In addition, the antioxidant activity of all the extracts was evaluated. The results evidenced a significant statistical correlation between extracts with an inhibitory effect against PLA 2 and those with an antioxidant activity. Moreover, the amount of phenols was quantified finding a relationship between the bioactivity and the presence of these compounds. Nine extracts were screened against a fraction of the venom rich in basic PLA 2 (Fx-V B. asper), exhibiting an inhibitory effect on PLA 2 activity of this fraction in a range of 30-80%. This activity was supported by the inhibition that these extracts presented on the cytotoxicity caused by Fx-V B. asper on murine skeletal muscle C2C12 myoblasts. The results obtained, could point to minimize efforts in the search of PLA 2 inhibitors by focusing in samples with known antioxidant properties.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Correlation of the inhibitory activity of phospholipase A2 snake venom and the antioxidant activity of Colombian plant extracts

Pereañez¹,

Lobo-Echeverri²,

Rojano³

et al. 2010

Rev. bras. farmacogn.

View full text Add to dashboard Cite

show abstract

“…The formation of a complex and a possible competitive inhibition by a-tocopherol were described for phospholipase A2 isoenzymes [24,25], and other mechanisms that include the control of substrate and cofactor availability could be responsible of the modulation of COX-2, 5-lipoxygenase and cPLA 2 (reviewed in [19,26]). The c form of vitamin E and more recently long chain metabolites were confirmed to be the most efficient COX-2 inhibitors in vitro and in vivo [5].…”

Section: Cellular Effects and Signaling Of Vitamin Ementioning

confidence: 99%

Present trends in vitamin E research

2010

View full text Add to dashboard Cite

Abstract.Nearly after one century of research and thousands of publications, the physiological function(s) of vitamin E remain unclear. Available evidence suggests a role in cell homeostasis that occurs through the modulation of specific signaling pathways and genes involved in proliferative, metabolic, inflammatory, and antioxidant pathways. Vitamin E presence in the human body is under close metabolic control so that only a-tocopherol and, to a lower extent, c-tocopherol are retained and delivered to tissues. Other vitamin E forms that are not retained in the body in significant amounts, exhibit responses in vitro that are different form those of a-tocopherol and may include tumor cell specific toxicity and apoptosis. These responses provide a therapeutic potential for these minor forms, either as such or metabolically modified, to produce bioactive metabolites. These cellular effects go beyond the properties of lipophilic antioxidant attributed to a-tocopherol particularly investigated for its alleged protective role in atherosclerosis or other oxidative stress conditions. Understanding signaling and gene expression effects of vitamin E could help assign a physiological role to this vitamin, which will be discussed in this review. Besides vitamin E signaling, attention will be given to tocotrienols as one of the emerging topics in vitamin E research and a critical re-examination of the most recent clinical trials will be provided together with the potential use of vitamin E in disease prevention and therapy.

show abstract

“…Then, it is very important to know the exact way the interaction of this inhibitor with PLA 2 s occurs. The first attempt with this goal was the structural study of the complex formed by a dimeric PLA 2 from Daboia pulchella and -tocopherol (Chandra JMB 2002) [26]. In this structure it was observed -tocopherol bound to the catalytic site for only one monomer while the other was inaccessible due the conformation of Trp31 residue.…”

Section: Introductionmentioning

confidence: 99%

Crystallization and Preliminary X-Ray Crystallographic Studies of a Myotoxic Lys49-phospholipase A2 from Bothrops jararacussu Venom Complexed with α-Tocopherol Inhibitor

Takeda¹,

Santos²,

Marchi-Salvador³

et al. 2008

TOCRYJ

View full text Add to dashboard Cite

Bothropstoxin I (BthTX-I), a non-catalytic and myotoxic Lys49-PLA 2 from Bothrops jararacussu venom, has been crystallized alone and complexed with -tocopherol inhibitor. These crystals have been shown to diffract X-rays between 2.17 and 1.83 Å resolution. The BthTX-I/ -tocopherol complex crystals are not isomorphous with those of the native protein. This suggests the inhibitor binding has lead to changes in the quaternary structure and a different conformation may have been obtained.

show abstract

First Structural Evidence of a Specific Inhibition of Phospholipase A2 by α-Tocopherol (Vitamin E) and its Implications in Inflammation: Crystal Structure of the Complex Formed Between Phospholipase A2 and α-Tocopherol at 1.8Å Resolution

Cited by 110 publications

References 21 publications

Correlation of the inhibitory activity of phospholipase A2 snake venom and the antioxidant activity of Colombian plant extracts

Correlation of the inhibitory activity of phospholipase A2 snake venom and the antioxidant activity of Colombian plant extracts

Present trends in vitamin E research

Crystallization and Preliminary X-Ray Crystallographic Studies of a Myotoxic Lys49-phospholipase A2 from Bothrops jararacussu Venom Complexed with α-Tocopherol Inhibitor

Contact Info

Product

Resources

About