Sandbox Reserved 316: Difference between revisions
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==Introduction== | ==Introduction== | ||
[[Image:svs.jpg| | [[Image:svs.jpg|300px|left|thumb|]]'''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>. Pictured here is the generated double mutant C40A/C60N (G0), from wild type LovD (Figure 1). | 17113998</ref>. Pictured here is the generated double mutant C40A/C60N (G0), from wild type LovD (Figure 1). | ||
This enzyme is isolated from the natural product biosynthetic pathways of ''Aspergillus terreus'', specifically the polyketide biosynthetic pathway. Simvastatin Synthase converts the inactive monacolin J acid ( | This enzyme is isolated from the natural product biosynthetic pathways of [http://en.wikipedia.org/wiki/Aspergillus_terreus ''Aspergillus terreus''], specifically the polyketide biosynthetic pathway. Simvastatin Synthase converts the inactive monacolin J acid (MJA) by dimethylbutyryl chloride to yield the protected form of simvastatin (Figure 2), which subsequently undergoes lactonization to yield [http://en.wikipedia.org/wiki/Simvastatin ''simvastatin'']<ref name="paper5">PMID:19875080</ref>. | ||
[[Image:Sim_mja.jpg]] | |||
[[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>. | 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>. | {{STRUCTURE_3hle | PDB=3hle | SCENE=Sandbox_Reserved_316/Default/1}} | ||
LovD has of two domains. The <scene name='Sandbox_Reserved_316/ | <scene name='Sandbox_Reserved_316/Default/1'>LovD</scene> 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/Firsstdomain/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/Seconddomainn/1'>second domain</scene> is smaller, consists of residues 93–203 and is primarily α-helical<ref name="paper1">PMID:17277201</ref>. | |||
At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. Upon ligand binding LovD undergoes a conformational change analogous to the closing of a catcher's mitt by these loops. This ringshaped ridge over the active site with fingers is composed of <scene name='Sandbox_Reserved_316/5_loops/2'>five loops</scene>: residues 114–125, 147–173, 243–258, 321–327, and 388–391<ref name="paper1">PMID:17277201</ref>. | At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. Upon ligand binding LovD undergoes a conformational change analogous to the closing of a catcher's mitt by these loops. This ringshaped ridge over the active site with fingers is composed of <scene name='Sandbox_Reserved_316/5_loops/2'>five loops</scene>: residues 114–125, 147–173, 243–258, 321–327, and 388–391<ref name="paper1">PMID:17277201</ref>. | ||
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==Additional Information== | ==Additional Information== | ||
<Structure load='1CI8' size='300' frame='true' align='right' caption='' scene='Sandbox_Reserved_316/Estb/1'/> | |||
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>. | 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>. | ||
The protein-protein interaction between LovD and the acyl carrier protein domain of LovF facilitates the highly efficient tailoring reaction during LVA biosynthesis <ref name="paper4">PMID: | The protein-protein interaction between LovD and the acyl carrier protein domain of LovF facilitates the highly efficient tailoring reaction during LVA biosynthesis <ref name="paper4">PMID: | ||
17113998</ref>. The | 17113998</ref>. The α-''S''-methylbutyrate side chain is synthesized by the lovastatin diketide synthase (LDKS) LovF and then transferred by LovD regioselectively to the C8 hydroxyl of <scene name='Sandbox_Reserved_316/Blah/3'>MJA</scene><ref name="paper3">PMID:18988191</ref>. | ||
Among enzymes that of known structures,<scene name='Sandbox_Reserved_316/Estb/1'>EstB</scene> (cephalosporin esterase), is homologous to LovD: 26% sequence identity <ref name="paper6">PMID: | Among enzymes that of known structures, <scene name='Sandbox_Reserved_316/Estb/1'>EstB</scene> (cephalosporin esterase), is homologous to LovD: 26% sequence identity <ref name="paper6">PMID: | ||
11847270</ref>. | 11847270</ref>. | ||
==References== | ==References== | ||
<references/> | <references/> | ||