Sandbox Reserved 323: Difference between revisions

<scene name='Sandbox_Reserved_323/1k7l/1'>PPAR alpha</scene> structure shares common characteristics with the other isoforms in this nuclear receptor superfamily, as it displays '''five distinguishable domains designated the A/B, C, D, E and F domains'''. The A/B domain, on the N-terminus of PPAR-alpha, contains an activation function region (AF-1), which has a low level of basal transcriptional activity and functions independently of ligand-binding. <scene name='Sandbox_Reserved_323/1k7l/6'>The DNA binding domain</scene> (C) contains two very highly conserved [http://en.wikipedia.org/wiki/Zinc_finger zinc finger motifs] and architectural elements capable of sequence-specific binding to DNA <ref name="PPAR4">PMID:10529898</ref>. A <scene name='Sandbox_Reserved_323/1k7l/9'>flexible hinge region</scene> (D) connects the DNA binding domain to the ligand-binding domain (E). '''The ligand-binding domain in the human PPAR alpha protein contains the activation function-2 (AF-2) region composed of two alpha helices flanking one four-sided beta sheet'''. Following ligand interaction, the AF-2 domain undergoes a conformational change which promotes the hydrogen bonding between <scene name='Sandbox_Reserved_323/1k7l/10'>Tyr-314 and Tyr-464</scene>, as well as the formation of the “charge clamp” between <scene name='Sandbox_Reserved_323/1k7l/8'>Lys-292 and Glu-462</scene>.<ref name="PPAR4"/>

PPAR alpha ligands can consist of either synthetic drugs (exogenous) or biological molecules (endogenous). '''Most common biological molecules that serve as ligands for human PPAR alpha are fatty acids and fatty acid derivatives''' <ref name="PPAR1"/><ref name="PPAR2"/>. Several enzymes such as 8-, 12-, 15-, and 5-[http://en.wikipedia.org/wiki/Lipoxygenase lipoxygenases], the [http://en.wikipedia.org/wiki/Cyclooxygenase cyclooxygenases] and [http://en.wikipedia.org/wiki/Cytochrome_P450 cytochrome P450] utilize fatty acids as substrates to produce putative PPAR alpha ligands. [http://en.wikipedia.org/wiki/Leukotriene_B4 Leukotriene B4} is a well-known putative PPAR alpha ligand, as well as 19- and 20- hydroxyeicosatetraeonic acid, generated from cytochrome P450 as a conversion of arachidonic acid. Oleylethanolamide, a naturally occurring lipid, has also been identified as a high affinity PPAR alpha ligand regulating PPAR alpha activity and lipid metabolism <ref name="PPAR6">PMID:20414453</ref>.

All three isoforms of PPAR are becoming more and more of an interest in scientific communities as possible mechanisms of treatment in various diseases and metabolic disorders such as Diabetes Mellitus and obesity.  Fibrates, which include fenofibrate, bind with PPAR alpha in high affinity and act to lower plasma triglyceride levels and increase high density lipoprotein levels<ref name="PPAR10">PMID:10839530</ref>. Therefore, fibrates may also have an anti-diabetic effect as a consequence of their hypolipidaemic action. PPAR alpha may also have a hand in the prevention of atherosclerosis by decreasing the plasma concentrations of pro-atherosclerosis proteins such as fibrinogen and C-reactive protein <ref name="PPAR10"/>. Much of the current research involved with PPARs is directed towards the identification of highly specific agonists and antagonists for treatment of numerous metabolic diseases and conditions.