HMG-CoA Reductase: Difference between revisions
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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"/> | ||
The HMG binding pocket is the site of catalysis in HMGR. <scene name='HMG-CoA_Reductase/1dqa_cis_loop2/2'> | The HMG binding pocket is the site of catalysis in HMGR. <scene name='HMG-CoA_Reductase/1dqa_cis_loop2/2'> The “cis-loop” that bends over the top of HMG </scene> ([[1dqa]]) is a critical structural element of this binding site. Residues <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> and are positioned in the active site as is <scene name='HMG-CoA_Reductase/1dqa_k691/2'>K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen</scene>. It is this K691 that likely stabilizes the negatively charged oxygen of the first mevaldyl-CoA intermediate.<ref name="Roitelman"/> The mevaldyl CoA intermediate is subsequently converted to Mavaldehyde with added stabilization from <scene name='HMG-CoA_Reductase/1dqa_h866/2'>H866, which is within hydrogen bonding distance of the thiol group</scene>. It is then believed that the close proximity of <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate.<ref name="Roitelman"/> | ||
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==Medical Implications== | ==Medical Implications== | ||
===Medical Implications for HMGR=== | ===Medical Implications for HMGR=== | ||
[[Image: HMGCoA to Lovastatin Comparison.jpg|200px|left|thumb| Comparison of Chemical Structure of HMG-CoA and Lovastatin]] | [[Image: HMGCoA to Lovastatin Comparison.jpg|200px|left|thumb| Comparison of Chemical Structure of HMG-CoA and Lovastatin]] | ||
