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Molecular docking of Glyceroneogenesis pathway intermediates with Peroxisome Proliferator- Activated Receptor-Alpha (PPAR-?).

ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPAR-?) belongs to the nuclear receptor superfamily of proteins. It is one of the principle regulators of metabolism and lipid homeostasis whose malfunction leads to complications including obesity and type 2 diabetes. In the adipose tissue, glyceroneogenesis is a unique pathway through which pyruvate is converted into glycerol-3- phosphate (G3P) in a multistep process. Previous findings demonstrated that glyceroneogenesis regulates triacylglycerol synthesis and adipogenesis. This led us to hypothesize that one of the pathway intermediate is physiologically relevant PPAR-? ligand. In the present study using in silico docking, we proved that glycerate, dihydroxy acetone phosphate, glyceraldehyde-3-phosphate, and G3P are key glyceroneogenesis pathway intermediates which bind to PPAR-?. They bind PPAR-? with comparable binding energy and docking score to that of (2s)-2-ethoxy-3-[4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]propanoic acid(AZ-2), a synthetic high affinity ligand of PPAR-?. These intermediates could be studied further as potential physiologically relevant activators of PPAR-? in vitro and in vivo.

SUBMITTER: Subramani PA

PROVIDER: S-EPMC3725004 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular docking of Glyceroneogenesis pathway intermediates with Peroxisome Proliferator- Activated Receptor-Alpha (PPAR-α).

Subramani Parasuraman Aiya PA Panati Kalpana K Narala Venkata Ramireddy VR

Bioinformation 20130712 12

Peroxisome proliferator-activated receptor alpha (PPAR-α) belongs to the nuclear receptor superfamily of proteins. It is one of the principle regulators of metabolism and lipid homeostasis whose malfunction leads to complications including obesity and type 2 diabetes. In the adipose tissue, glyceroneogenesis is a unique pathway through which pyruvate is converted into glycerol-3- phosphate (G3P) in a multistep process. Previous findings demonstrated that glyceroneogenesis regulates triacylglycer ...[more]

PMID: 23904740

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Project description:Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Dataset Information

Molecular docking of Glyceroneogenesis pathway intermediates with Peroxisome Proliferator- Activated Receptor-Alpha (PPAR-?).

Publications

Molecular docking of Glyceroneogenesis pathway intermediates with Peroxisome Proliferator- Activated Receptor-Alpha (PPAR-α).

Similar Datasets

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