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A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor ?.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is an important regulator of hepatic lipid metabolism which functions through ligand binding. Despite high amino acid sequence identity (>90%), marked differences in PPAR? ligand binding, activation and gene regulation have been noted across species. Similar to previous observations with synthetic agonists, we have recently reported differences in ligand affinities and extent of activation between human PPAR? (hPPAR?) and mouse PPAR? (mPPAR?) in response to long chain fatty acids (LCFA). The present study was aimed to determine if structural alterations could account for these differences. The binding of PPAR? to LCFA was examined through in silico molecular modeling and docking simulations. Modeling suggested that variances at amino acid position 272 are likely to be responsible for differences in saturated LCFA binding to hPPAR? and mPPAR?. To confirm these results experimentally, LCFA binding, circular dichroism, and transactivation studies were performed using a F272I mutant form of mPPAR?. Experimental data correlated with in silico docking simulations, further confirming the importance of amino acid 272 in LCFA binding. Although the driving force for evolution of species differences at this position are yet unidentified, this study enhances our understanding of ligand-induced regulation by PPAR? and demonstrates the efficacy of molecular modeling and docking simulations.

SUBMITTER: Oswal DP

PROVIDER: S-EPMC4079465 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor α.

Oswal Dhawal P DP Alter Gerald M GM Rider S Dean SD Hostetler Heather A HA

Journal of molecular graphics & modelling 20140429

Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of hepatic lipid metabolism which functions through ligand binding. Despite high amino acid sequence identity (>90%), marked differences in PPARα ligand binding, activation and gene regulation have been noted across species. Similar to previous observations with synthetic agonists, we have recently reported differences in ligand affinities and extent of activation between human PPARα (hPPARα) and mouse PPARα (mPPARα) ...[more]

PMID: 24858253

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Project description:BackgroundPeroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach. But synthetically developed PPARalpha/gamma dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases.Presentation of hypothesisDocosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that alpha or beta derivatives of fatty acids would fit into PPARalpha/gamma binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds.Testing of the hypothesisLigand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins.Implications of the hypothesisPresent hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.

Dataset Information

A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor ?.

Publications

A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor α.

Similar Datasets

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