Peroxisome Proliferator-Activated Receptors: Difference between revisions
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==Binding of Synthetic Agonists and Medical Implications== | ==Binding of Synthetic Agonists and Medical Implications== | ||
<applet load=" 3dzy2.pdb" size="400" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/> | <applet load=" 3dzy2.pdb" size="400" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/> | ||
A number of synthetic agonists have been developed to bind to PPAR to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([www.avandia.com Avandia]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a **number of interactions that stabilize the agonist**. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282 and Leu469, and the central benzene ring of the ligand occupies a pocket formed by Cys285 and Met364.<ref>PMID:9744270</ref> | A number of synthetic agonists have been developed to bind to PPAR to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([http://www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([http://www.avandia.com Avandia]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a **number of interactions that stabilize the agonist**. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282 and Leu469, and the central benzene ring of the ligand occupies a pocket formed by Cys285 and Met364.<ref>PMID:9744270</ref> | ||
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | [[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | ||
Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.<ref>PMID:11818483</ref> Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets. <ref>PMID:9748221</ref> PPARα has been shown to play a critical role in the regulation of cellular uptake and oxidation of fatty acids. This makes PPARα an excellent target for Atherosclerosis drugs which aim at reducing [http://en.wikipedia.org/wiki/Low-density_lipoprotein LDL cholesterol] and increasing [http://en.wikipedia.org/wiki/High-density_lipoprotein HDL cholesterol], the two most common traits of atherosclerosis. The fibrates are a class of amphipathic carboxylic acids that are PPARα agonists used to treat hypercholesterolemia and hyperlipidemia along with the [[HMGR]] inhibitor statins . Some fibrates are [http://en.wikipedia.org/wiki/Bezafibrate Bezafibrate] (Marketed by Roche as [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20B)/BEZALIP.html Bezalip]) and [http://en.wikipedia.org/wiki/Ciprofibrate Ciprofibrate] ([http://www.netdoctor.co.uk/medicines/100001714.html Modalim]).<ref>PMID:11818483</ref> PPARδ is broadly expressed across the human body and thus is suspected to play a role in a number of diseases. It has been implicated in disorders ranging from Fertility problems to types of cancer. Perhaps the most important use of PPARδ agonists will be in treating [http://en.wikipedia.org/wiki/Central_nervous_system central nervous system] (CNS) diseases as PPARδ has been implicated in neuron [http://en.wikipedia.org/wiki/Myelin myelinogenesis] and neuronal signaling as well as lipid metabolism in the CNS. <ref>PMID:11818483</ref> | Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.<ref>PMID:11818483</ref> Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets. <ref>PMID:9748221</ref> PPARα has been shown to play a critical role in the regulation of cellular uptake and oxidation of fatty acids. This makes PPARα an excellent target for Atherosclerosis drugs which aim at reducing [http://en.wikipedia.org/wiki/Low-density_lipoprotein LDL cholesterol] and increasing [http://en.wikipedia.org/wiki/High-density_lipoprotein HDL cholesterol], the two most common traits of atherosclerosis. The fibrates are a class of amphipathic carboxylic acids that are PPARα agonists used to treat hypercholesterolemia and hyperlipidemia along with the [[HMGR]] inhibitor statins . Some fibrates are [http://en.wikipedia.org/wiki/Bezafibrate Bezafibrate] (Marketed by Roche as [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20B)/BEZALIP.html Bezalip]) and [http://en.wikipedia.org/wiki/Ciprofibrate Ciprofibrate] ([http://www.netdoctor.co.uk/medicines/100001714.html Modalim]).<ref>PMID:11818483</ref> PPARδ is broadly expressed across the human body and thus is suspected to play a role in a number of diseases. It has been implicated in disorders ranging from Fertility problems to types of cancer. Perhaps the most important use of PPARδ agonists will be in treating [http://en.wikipedia.org/wiki/Central_nervous_system central nervous system] (CNS) diseases as PPARδ has been implicated in neuron [http://en.wikipedia.org/wiki/Myelin myelinogenesis] and neuronal signaling as well as lipid metabolism in the CNS. <ref>PMID:11818483</ref> | ||