Peroxisome Proliferator-Activated Receptors: Difference between revisions
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[[Image: 3dzy2.png| | [[Image: 3dzy2.png|420px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]] | ||
{{STRUCTURE_1fm9| right| PDB=1fm9 | SCENE= |CAPTION= Crystal Structure of Human PPAR γ, [[1fm9]] }} | {{STRUCTURE_1fm9| right| PDB=1fm9 | SCENE= |CAPTION= Crystal Structure of Human PPAR γ, [[1fm9]] }} | ||
The Peroxisome Proliferator-Activated Receptors (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factor to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases. <ref>PMID:15860251 </ref> | The Peroxisome Proliferator-Activated Receptors (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factor to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases. <ref>PMID:15860251 </ref> | ||
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===DNA Binding Domain Structure=== | ===DNA Binding Domain Structure=== | ||
<applet load=" 3dzy2.pdb" size="400" color="white" frame="true" spin="on" Scene ="" 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 ="" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/> | ||
[[Image:Rosiglitazone.png| | [[Image:Rosiglitazone.png|300px|left|thumb| Human PPARγ agonist, Rosiglitazone (Avandia)]] | ||
PPARs also contain a **DNA binding domain (DBD)** The DBD consist of **two zinc fingers**, one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428 </ref> It is believed that the DNA PPRE actually allosterically contributes to its own binding by directing a head-to-tail interaction between the PPAR DBD and RXR DBD via residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | PPARs also contain a **DNA binding domain (DBD)** The DBD consist of **two zinc fingers**, one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428 </ref> It is believed that the DNA PPRE actually allosterically contributes to its own binding by directing a head-to-tail interaction between the PPAR DBD and RXR DBD via residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | ||
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==Binding of Synthetic Agonists and Medical Implications== | ==Binding of Synthetic Agonists and Medical Implications== | ||
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] ([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> | ||
[[Image: Ciprofibrate.PNG| | [[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> | ||