View source for Simvastatin Synthase

<StructureSection load='3hle' size='350' side='right' scene='' caption='Structure of Simvastatin Synthase complex with monacolin J acid and dithiothreitol [[3hle]]'>
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==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/>
</StructureSection>
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