Simvastatin Synthase: Difference between revisions
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{{Template:Sandbox_Reserved_BCMB307}} | |||
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{{STRUCTURE_3hle | PDB=3hle | SCENE= }} | {{STRUCTURE_3hle | PDB=3hle | SCENE= }} | ||
==Introduction== | ==Introduction== | ||
'''Simvastatin synthase''' (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis<ref name="paper4">PMID: | [[Image:svs.jpg]]'''Simvastatin synthase''' (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis<ref name="paper4">PMID: | ||
17113998</ref>. | 17113998</ref>. Pictured here is the D5 mutant complexed with monacolin J acid (Figure 1). | ||
This enzyme is isolated from the natural product biosynthetic pathways of ''Aspergillus terreus''. Simvastatin Synthase converts the inactive monacolin J acid (<scene name='Sandbox_Reserved_316/Blah/ | This enzyme is isolated from the natural product biosynthetic pathways of ''Aspergillus terreus''. Simvastatin Synthase converts the inactive monacolin J acid (<scene name='Sandbox_Reserved_316/Blah/2'>MJA</scene>) by dimethylbutyryl chloride to yield the protected form of simvastatin (Figure 2), which subsequently undergoes lactonization to yield simvastatin<ref name="paper5">PMID:19875080</ref>. | ||
[[Image:Sim_mja.jpg]] | |||
LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester<ref name="paper1">PMID:17277201</ref>. | |||
==Exploring the structure== | ==Exploring the structure== | ||
LovD is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis<ref name="paper2">PMID:10334994</ref>. | <scene name='Sandbox_Reserved_316/Svs_1/1'>TextToBeDisplayed</scene> LovD is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis<ref name="paper2">PMID:10334994</ref>. | ||
LovD has of two domains. The <scene name='Sandbox_Reserved_316/First_domain_1/1'>first domain</scene>, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face<ref name="paper1">PMID:17277201</ref>. The <scene name='Sandbox_Reserved_316/Second_domain_1/1'>second domain</scene> is smaller, consists of residues 93–203 and is primarily α-helical<ref name="paper1">PMID:17277201</ref>. | LovD has of two domains. The <scene name='Sandbox_Reserved_316/First_domain_1/1'>first domain</scene>, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face<ref name="paper1">PMID:17277201</ref>. The <scene name='Sandbox_Reserved_316/Second_domain_1/1'>second domain</scene> is smaller, consists of residues 93–203 and is primarily α-helical<ref name="paper1">PMID:17277201</ref>. | ||
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LovD has <scene name='Sandbox_Reserved_316/Cysteines/1'>nine cysteines</scene> at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395<ref name="paper3">PMID:18988191</ref>. | LovD has <scene name='Sandbox_Reserved_316/Cysteines/1'>nine cysteines</scene> at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395<ref name="paper3">PMID:18988191</ref>. | ||
==Significance== | |||
As simvastatin is an active pharmaceutical ingredient in the cholesterol-lowering drug Zocor®, its efficient synthesis from lovastatin, via LovD is intensely pursued <ref name="paper4">PMID:19875080</ref>. | |||
==References== | ==References== | ||
<references/> | <references/> | ||