Simvastatin Synthase

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==Introduction==
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<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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[[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:
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[[Image:svs.jpg|300px|left|thumb|]]
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17113998</ref>. Pictured here is the generated double mutant C40A/C60N (G0), from wild type LovD (Figure 1).
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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>.
 
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[[Image:Sim_mja.jpg]]
 
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'''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>.
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[[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>.
LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester<ref name="paper1">PMID:17277201</ref>.
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==Exploring the structure==
==Exploring the structure==
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{{STRUCTURE_3hle | PDB=3hle | SCENE= }}
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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 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
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
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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>.
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>.
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==Additional Information==
==Additional Information==
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<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>.
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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>.
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</StructureSection>
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==3D structures of simvastatin synthase==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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[[3hl9]], [[3hlb]], [[3hlc]], [[4lcl]], [[4lcm]] – AtLovD (mutant) – ''Aspergillus terreus''
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[[3hld]], [[3hle]] – AtLovD (mutant) + monacolin J acid
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[[3hlf]] – AtLovD (mutant) + simvastatin
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[[3hlg]] – AtLovD (mutant) + lovastatin
==References==
==References==
<references/>
<references/>
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[[Category:Topic Page]]

Current revision

Structure of Simvastatin Synthase complex with monacolin J acid and dithiothreitol 3hle

Drag the structure with the mouse to rotate

3D structures of simvastatin synthase

Updated on 09-November-2020

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

  1. ↑ 1.0 1.1 1.2 Xie X, Watanabe K, Wojcicki WA, Wang CC, Tang Y. Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem Biol. 2006 Nov;13(11):1161-9. PMID:17113998 doi:10.1016/j.chembiol.2006.09.008
  2. ↑ Gao X, Xie X, Pashkov I, Sawaya MR, Laidman J, Zhang W, Cacho R, Yeates TO, Tang Y. Directed evolution and structural characterization of a simvastatin synthase. Chem Biol. 2009 Oct 30;16(10):1064-74. PMID:19875080 doi:10.1016/j.chembiol.2009.09.017
  3. ↑ 3.0 3.1 3.2 3.3 Xie X, Tang Y. Efficient synthesis of simvastatin by use of whole-cell biocatalysis. Appl Environ Microbiol. 2007 Apr;73(7):2054-60. Epub 2007 Feb 2. PMID:17277201 doi:10.1128/AEM.02820-06
  4. ↑ Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science. 1999 May 21;284(5418):1368-72. PMID:10334994
  5. ↑ 5.0 5.1 Xie X, Pashkov I, Gao X, Guerrero JL, Yeates TO, Tang Y. Rational improvement of simvastatin synthase solubility in Escherichia coli leads to higher whole-cell biocatalytic activity. Biotechnol Bioeng. 2009 Jan 1;102(1):20-8. PMID:18988191 doi:10.1002/bit.22028
  6. ↑ Wagner UG, Petersen EI, Schwab H, Kratky C. EstB from Burkholderia gladioli: a novel esterase with a beta-lactamase fold reveals steric factors to discriminate between esterolytic and beta-lactam cleaving activity. Protein Sci. 2002 Mar;11(3):467-78. PMID:11847270

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