Sandbox Reserved 316

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.

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spinqualitylabelsall models PDB ID 3hle Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
3hle, resolution 2.06Å ()
Ligands:	,
Related:	1hld
Structural annotation: Resources: InterPro : Ipr012338, Ipr001466 Pfam : PF00144
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
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. 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.

LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester.

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. 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. The is smaller, consists of residues 93–203 and is primarily α-helical.

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.

LovD has at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395.

Exploring the structureExploring the structure

As simvastatin is an active pharmaceutical ingredient in the cholesterol-lower drug Zocor®, so that efficient synthesis of simvastatin from lovastatin is highly pursued .