Simvastatin Synthase: Difference between revisions
Eric Ginter (talk | contribs) No edit summary |
Eric Ginter (talk | contribs) No edit summary |
||
| Line 5: | Line 5: | ||
{{STRUCTURE_3hle | PDB=3hle | SCENE= }} | {{STRUCTURE_3hle | PDB=3hle | SCENE= }} | ||
==Introduction== | ==Introduction== | ||
[[Image:svs.jpg|300px|left|thumb| Human]]'''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>. Pictured here is the D5 mutant complexed with monacolin J acid (Figure 1). | 17113998</ref>. Pictured here is the D5 mutant complexed with monacolin J acid (Figure 1). | ||
Revision as of 02:42, 2 April 2011
| This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada. |
To get started:
More help: Help:Editing |
| |||||||||
| 3hle, resolution 2.06Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||||
| Related: | 1hld | ||||||||
| |||||||||
| |||||||||
| 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]. Pictured here is the D5 mutant complexed with monacolin J acid (Figure 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 (Figure 2), which subsequently undergoes lactonization to yield simvastatin[2].
LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester[3].
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[4]. 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[3]. The is smaller, consists of residues 93–203 and is primarily α-helical[3].
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[3].
LovD has at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395[5].
SignificanceSignificance
As simvastatin is an active pharmaceutical ingredient in the cholesterol-lowering drug Zocor®, its efficient synthesis from lovastatin, via LovD is intensely pursued [1].
ReferencesReferences
- ↑ 1.0 1.1 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 Cite error: Invalid
<ref>tag; name "paper4" defined multiple times with different content - ↑ 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
- ↑ 3.0 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
- ↑ 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