Sandbox Reserved 316: Difference between revisions

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17113998</ref>.
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 is subsequently undergoes lactonization to yield simvastatin. LovD can also
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/2'>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>.


Revision as of 18:37, 24 March 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:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • Click the 3D button (when editing, above the wikitext box) to insert Jmol.
  • show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
  • Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing


Drag the structure with the mouse to rotate
3hle, resolution 2.06Å (default scene)
Ligands: DTT, MJA
Related: 1hld
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

  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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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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