Simvastatin Synthase: Difference between revisions
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{{STRUCTURE_3hle | PDB=3hle | SCENE= }} | {{STRUCTURE_3hle | PDB=3hle | SCENE= }} | ||
==Introduction== | ==Introduction== | ||
'''Simvastatin synthase''' (LovD) is | '''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>. | |||
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/1'>MJA</scene>) by dimethylbutyryl chloride to yield the protected form of simvastatin, which subsequently undergoes lactonization to yield simvastatin. LovD can also | |||
synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester<ref name="paper1">PMID:17277201</ref>. | synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester<ref name="paper1">PMID:17277201</ref>. | ||
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==References== | ==References== | ||
<references/> | <references/> | ||
Revision as of 18:29, 24 March 2011
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| 3hle, resolution 2.06Å (default scene) | |||||||||||||
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| Ligands: | DTT, MJA | ||||||||||||
| Related: | 1hld | ||||||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
Introduction
Simvastatin synthase (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis[1].
This enzyme is isolated from the natural product biosynthetic pathways of Aspergillus terreus. Simvastatin Synthase converts the inactive monacolin J acid (MJA) by dimethylbutyryl chloride to yield the protected form of simvastatin, which subsequently undergoes lactonization to yield simvastatin. LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester[2].
LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic alpha-dimethylbutyryl thioester, albeit with suboptimal properties as a biocatalyst[2].
Exploring the structure
LovD is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis[3]. LovD has of two domains. The first domain, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face[2]. The second domain is smaller, consists of residues 93–203 and is primarily α-helical[2].
At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. In LovD, these loops give the impression of a ringshaped ridge or baseball catcher’s mitt over the active site with fingers composed of five loops: residues 114–125, 147–173, 243–258, 321–327, and 388–391[2].
LovD has nine cysteines at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395[4].
References
- ↑ 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
- ↑ 2.0 2.1 2.2 2.3 2.4 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
- ↑ 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
- ↑ 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
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