HMG-CoA Reductase: Difference between revisions
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<StructureSection load='1dq8' size='450' side='right' scene='HMG-CoA_Reductase/1dq8_starting_scene/1' caption='Crystal Structure of HMG-CoA, [[1dq8]])'>[[HMG-CoA Reductase]] (or '''3-hydroxy-3-methyl-glutaryl-CoA reductase''' or '''HMGR''') is the rate-controlling enzyme of the mevalonate pathway, responsible for cholesterol and other isoprenoid biosynthesis. HMGR is a transmembrane protein, containing 8 domains, that is anchored in the membrane of the endoplasmic reticulum.<ref name="Roitelman">PMID:1374417</ref> It is the major target of the Statins, a cholesterol lowering drug class and the best selling pharmaceutical drugs in the world. See also [[Ephrin Type-A Receptor]] and [[Neurodevelopmental Disorders]]. | <StructureSection load='1dq8' size='450' side='right' scene='HMG-CoA_Reductase/1dq8_starting_scene/1' caption='Crystal Structure of HMG-CoA, [[1dq8]])'>[[HMG-CoA Reductase]] (or '''3-hydroxy-3-methyl-glutaryl-CoA reductase''' or '''HMGR''') is the rate-controlling enzyme of the mevalonate pathway, responsible for cholesterol and other isoprenoid biosynthesis. HMGR is a transmembrane protein, containing 8 domains, that is anchored in the membrane of the endoplasmic reticulum.<ref name="Roitelman">PMID:1374417</ref> It is the major target of the Statins, a cholesterol lowering drug class and the best selling pharmaceutical drugs in the world. See also [[Ephrin Type-A Receptor]] and [[Neurodevelopmental Disorders]]. | ||
[[Image: HMG-CoA_reductase_pathway.png| | [[Image: HMG-CoA_reductase_pathway.png|350px|left|thumb| Mevalonate Pathway. Note the early stage at which the statins interfere in the pathway]] | ||
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The 1985 Nobel Prize in Physiology or Medicine was awarded to Michael S. Brown and Joseph L. Goldstein, “for their discoveries concerning the regulation of cholesterol metabolism.” Their work on HMGR and LDL elucidated the regulatory complexity of cholesterol synthesis.<ref>http://nobelprize.org/nobel_prizes/medicine/laureates/1985/</ref> | |||
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==Biological Role== | ==Biological Role== | ||
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===Substrate Binding & Catalytic Mechanism=== | ===Substrate Binding & Catalytic Mechanism=== | ||
[[Image: Reactin_scheme.PNG| | [[Image: Reactin_scheme.PNG|350px|left|thumb| Chemical Reaction Catalyzed by HMGR]] | ||
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The HMG-CoA and NADPH molecules make numerous contacts with the <scene name='HMG-CoA_Reductase/Ls_domains/3'>L and S domains</scene> in forming the four active sites. The CoA is located in a <scene name='HMG-CoA_Reductase/1dqa_nadp_and_coa/2'>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 <scene name='HMG-CoA_Reductase/Ls_domains/3'>L and S domains</scene> in forming the four active sites. The CoA is located in a <scene name='HMG-CoA_Reductase/1dqa_nadp_and_coa/2'>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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A final level of HMGR regulation is achieved by inhibition via <scene name='HMG-CoA_Reductase/1dqa_phosphorylation_871/1'>phosphorylation of Serine 872</scene>. HMGR is phosphorylated and inactivated by an AMP-activated protein kinase, when the energy charge of the cell is low and AMP concentrations are high. Since Serine 872 is in the vicinity of the pohsphate of NADP, phosphorylation likely results in a decreased affinity for NADPH, halting the formation of Mevaldyl-CoA from HMG-CoA. | A final level of HMGR regulation is achieved by inhibition via <scene name='HMG-CoA_Reductase/1dqa_phosphorylation_871/1'>phosphorylation of Serine 872</scene>. HMGR is phosphorylated and inactivated by an AMP-activated protein kinase, when the energy charge of the cell is low and AMP concentrations are high. Since Serine 872 is in the vicinity of the pohsphate of NADP, phosphorylation likely results in a decreased affinity for NADPH, halting the formation of Mevaldyl-CoA from HMG-CoA. | ||
<ref>PMID:1967820</ref><br /> | <ref>PMID:1967820</ref><br /> | ||
==Medical Implications== | ==Medical Implications== | ||
