Simvastatin Synthase
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| 3hle, resolution 2.06Å () | |||||||||
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| Ligands: | , | ||||||||
| Related: | 1hld | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
IntroductionIntroduction
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 () 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 structureExploring 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 , 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 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 : residues 114–125, 147–173, 243–258, 321–327, and 388–391[2].
LovD has at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395[4].
ReferencesReferences
- ↑ 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