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{{STRUCTURE_3hle |  PDB=3hle |  SCENE= }}
<StructureSection load='3hle' size='350' side='right' scene='' caption='Structure of Simvastatin Synthase complex with monacolin J acid and dithiothreitol [[3hle]]'>
==Introduction==
[[Image:svs.jpg|300px|left|thumb|]]
'''Simvastation synthase''' (LovD) is an enzyme isolatied from the natural product biosynthetic pathways of''Aspergillus terreus''.
Simvastation synthase (LovD) is an enzyme isolatied from the natural product biosynthetic pathways ofAspergillus terreus. Simvastatin Synthase is an acyltransferase that converts the inactive monacolin J acid (MJA) by dimethylbutyryl chloride to yield the protected form of simvastatin, which is subsequently undergoes lactonization to yield simvastatin (Figure 1):


  LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic alpha-dimethylbutyryl thioester, albeit with suboptimal properties as a biocatalyst<ref name="paper">PMID:17277201</ref>.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__TOC__
==Function==
'''Simvastatin synthase''' or '''transesterase''' (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).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 [[Simvastatin]]<ref name="paper5">PMID:19875080</ref>.
 
[[Image:Sim_mja.jpg|center]]
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==
 
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/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>.
 
LovD has <scene name='Sandbox_Reserved_316/Cysteines/2'>nine cysteines</scene> at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395<ref name="paper3">PMID:18988191</ref>.
==Additional Information==
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:
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:
11847270</ref>.
 
==3D structures of simvastatin synthase==
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
 
[[3hl9]], [[3hlb]], [[3hlc]], [[4lcl]], [[4lcm]] – AtLovD (mutant) – ''Aspergillus terreus''
 
[[3hld]], [[3hle]] – AtLovD (mutant) + monacolin J acid
 
[[3hlf]] – AtLovD (mutant) + simvastatin
 
[[3hlg]] – AtLovD (mutant) + lovastatin


==References==
==References==
<references/>
<references/>
</StructureSection>
[[Category:Topic Page]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Eric Ginter, David Canner, Michal Harel, Alexander Berchansky
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