HMG-CoA Reductase: Difference between revisions
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<StructureSection load='1dq8' size='500' side='left' 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]]. | [[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]]. | ||
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==Structure== | ==Structure== | ||
===General Structure=== | ===General Structure=== | ||
There are two distinct classes of HMGRs, class I HMGRs, which are only found in eukaryotes and are membrane bound and class II HMGRs, which are found in prokaryotes and are soluble.<ref>PMID:11349148</ref> HMGR contains 8 transmembrane domains that have yet to be successfully crystallized, which anchor the protein to the membrane of the endoplasmic reticulum.<ref name="Roitelman"/> The catalytic portion of human HMGR forms a tetramer, with the individual monomers winding around each other.<ref name="Roitelman">PMID:1374417</ref> Within the tetramer, the monomers are arranged into <scene name='HMG-CoA_Reductase/1dq8_2_dimers/3'>two dimers</scene>, each of which contains <scene name='HMG-CoA_Reductase/1dq8_2_active_sites/2'>two active sites </scene>which are formed by residues form both monomers. Each monomer contains <scene name='HMG-CoA_Reductase/1dq8_star3_domains/2'>three domains </scene>, the <scene name='HMG-CoA_Reductase/1dq8_n_domain/2'>N-domain</scene>, the <scene name='HMG-CoA_Reductase/1dq8_l_domain/1'>L-Domain</scene>, and the <scene name='HMG-CoA_Reductase/1dq8_s_domain/1'>S-Domain</scene>. The L-domain is unique to HMGRs while the S-domain, which forms the binding site for NADP, resembles that of [[ferredoxin]]. The S and L domains are connected by a <scene name='HMG-CoA_Reductase/1dq8_cis_loop/5'>“cis-loop”</scene> which is essential for the HMG-binding site.<ref name="Roitelman"/> Salt bridges between residues R641 and E782 as well as <scene name='HMG-CoA_Reductase/1dq8_cis_loop/4'>hydrogen bonds</scene> between E700 and E700 on neighboring monomers compliment the largely hydrophobic dimer-dimer interface.<ref name="Roitelman"/> | There are two distinct classes of HMGRs, class I HMGRs, which are only found in eukaryotes and are membrane bound and class II HMGRs, which are found in prokaryotes and are soluble.<ref>PMID:11349148</ref> HMGR contains 8 transmembrane domains that have yet to be successfully crystallized, which anchor the protein to the membrane of the endoplasmic reticulum.<ref name="Roitelman"/> The catalytic portion of human HMGR forms a tetramer, with the individual monomers winding around each other.<ref name="Roitelman">PMID:1374417</ref> Within the tetramer, the monomers are arranged into <scene name='HMG-CoA_Reductase/1dq8_2_dimers/3'>two dimers</scene>, each of which contains <scene name='HMG-CoA_Reductase/1dq8_2_active_sites/2'>two active sites </scene>which are formed by residues form both monomers. Each monomer contains <scene name='HMG-CoA_Reductase/1dq8_star3_domains/2'>three domains </scene>, the <scene name='HMG-CoA_Reductase/1dq8_n_domain/2'>N-domain</scene>, the <scene name='HMG-CoA_Reductase/1dq8_l_domain/1'>L-Domain</scene>, and the <scene name='HMG-CoA_Reductase/1dq8_s_domain/1'>S-Domain</scene>. The L-domain is unique to HMGRs while the S-domain, which forms the binding site for NADP, resembles that of [[ferredoxin]]. The S and L domains are connected by a <scene name='HMG-CoA_Reductase/1dq8_cis_loop/5'>“cis-loop”</scene> which is essential for the HMG-binding site.<ref name="Roitelman"/> Salt bridges between residues R641 and E782 as well as <scene name='HMG-CoA_Reductase/1dq8_cis_loop/4'>hydrogen bonds</scene> between E700 and E700 on neighboring monomers compliment the largely hydrophobic dimer-dimer interface.<ref name="Roitelman"/> | ||
