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David Canner (talk | contribs) New page: 350px|left|thumb| Human HMG-CoA Reductase Catalytic Domain, [[1dqa]] HMG-CoA Reductase (or '''3-hydroxy-3-methyl-glutaryl-CoA reductasese''' or '''HMGR''') i... |
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[[Image:1dqa opening.png| | [[Image:1dqa opening.png|250px|left|thumb| Human HMG-CoA Reductase Catalytic Domain, [[1dqa]]]] | ||
[[HMG-CoA Reductase]] (or '''3-hydroxy-3-methyl-glutaryl-CoA reductasese''' or '''HMGR''') is the rate-controlling enzyme of the metabolic pathway responsible for [http://en.wikipedia.org/wiki/Cholesterol cholesterol] and other isoprenoid biosynthesis, the [http://en.wikipedia.org/wiki/Mevalonate mevalonate pathway]. HMGR is a polytopic, transmembrane protein, containing 8 domains, that is anchored in the membrane of the [http://en.wikipedia.org/wiki/Endoplasmic_Reticulum endoplasmic reticulum].<ref name="Roitelman"/> It is the major target of the Statins, a cholesterol lowering drug class and the best selling pharmaceutical drugs in the world. | [[HMG-CoA Reductase]] (or '''3-hydroxy-3-methyl-glutaryl-CoA reductasese''' or '''HMGR''') is the rate-controlling enzyme of the metabolic pathway responsible for [http://en.wikipedia.org/wiki/Cholesterol cholesterol] and other isoprenoid biosynthesis, the [http://en.wikipedia.org/wiki/Mevalonate mevalonate pathway]. HMGR is a polytopic, transmembrane protein, containing 8 domains, that is anchored in the membrane of the [http://en.wikipedia.org/wiki/Endoplasmic_Reticulum endoplasmic reticulum].<ref name="Roitelman"/> It is the major target of the Statins, a cholesterol lowering drug class and the best selling pharmaceutical drugs in the world. | ||
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==Biological Role== | ==Biological Role== | ||
[[Image: HMG-CoA_reductase_pathway.png| | [[Image: HMG-CoA_reductase_pathway.png|250px|left|thumb| Mevalonate Pathway. Note the early stage at which the Statins interfere in the pathway]] | ||
HMGR is among the most highly regulated enzymes in the human body. It catalyzes the formation of mevalonic acid, the committed step in the biosynthesis of sterols, notably cholesterol and isoprenoids. This reaction can be seen below where HMG-CoA is reduced by NADPH. Despite the poor reputation cholesterol has in the media, it is a critical component of cellular membranes as it is required to establish proper membrane permeability and fluidity. The mevalonate pathway is also responsible for synthesis of the oxygen transporting heme found in red blood cells. <ref name="Meigs">PMID:8626470</ref> | HMGR is among the most highly regulated enzymes in the human body. It catalyzes the formation of mevalonic acid, the committed step in the biosynthesis of sterols, notably cholesterol and isoprenoids. This reaction can be seen below where HMG-CoA is reduced by NADPH. Despite the poor reputation cholesterol has in the media, it is a critical component of cellular membranes as it is required to establish proper membrane permeability and fluidity. The mevalonate pathway is also responsible for synthesis of the oxygen transporting heme found in red blood cells. <ref name="Meigs">PMID:8626470</ref> | ||
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===Substrate Binding & Catalytic Mechanism=== | ===Substrate Binding & Catalytic Mechanism=== | ||
[[Image: Reactin_scheme.PNG| | [[Image: Reactin_scheme.PNG|200px|left|thumb| Chemical Reaction Catalyzed by HMGR]] | ||
The HMG-CoA and NADPH molecules make numerous contacts with the L and S domains in forming the four active sites. The CoA is located in a <scene name='HMG-CoA_Reductase/1dqa_nadp_and_coa/1'>positively charged pocket near the enzyme surface</scene>, with the pantothenic acid moiety extending into the interior of the protein. <scene name='HMG-CoA_Reductase/1dqa_tyr_491/2'>Tyrosine 479 forms a hydrophobic lid</scene> over the CoA adenine base, shielding the extended binding pocket from solution. The NADPH binding site is formed primarily by the S-domain with <scene name='HMG-CoA_Reductase/1dqa_loop/2'>a loop region</scene> playing a critical role in binding. <ref name="Roitelman"/> | The HMG-CoA and NADPH molecules make numerous contacts with the L and S domains in forming the four active sites. The CoA is located in a <scene name='HMG-CoA_Reductase/1dqa_nadp_and_coa/1'>positively charged pocket near the enzyme surface</scene>, with the pantothenic acid moiety extending into the interior of the protein. <scene name='HMG-CoA_Reductase/1dqa_tyr_491/2'>Tyrosine 479 forms a hydrophobic lid</scene> over the CoA adenine base, shielding the extended binding pocket from solution. The NADPH binding site is formed primarily by the S-domain with <scene name='HMG-CoA_Reductase/1dqa_loop/2'>a loop region</scene> playing a critical role in binding. <ref name="Roitelman"/> | ||
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==Medical Implications== | ==Medical Implications== | ||
[[Image: HMGCoA to Lovastatin Comparison.jpg| | [[Image: HMGCoA to Lovastatin Comparison.jpg|250px|left|thumb| Comparison of Chemical Structure of HMG-CoA and Lovastatin]] | ||
Elevated cholesterol levels have been identified as a major risk factor for coronary artery disease, the narrowing of arteries of the heart, which affected over 13 million people in the United States alone. It is a major cause of disability and death, killing over 500 thousand people in the USA in 2001. <ref>www.nhlbi.nih.gov/health/.../Diseases/.../CAD_WhatIs.html</ref> | Elevated cholesterol levels have been identified as a major risk factor for coronary artery disease, the narrowing of arteries of the heart, which affected over 13 million people in the United States alone. It is a major cause of disability and death, killing over 500 thousand people in the USA in 2001. <ref>www.nhlbi.nih.gov/health/.../Diseases/.../CAD_WhatIs.html</ref> | ||
