3HLD: Simvastatin Synthase (LovD), from Aspergillus terreus, S5 mutant complex with monacolin J acid

Citation:
Abstract
Enzymes from natural product biosynthetic pathways are attractive candidates for creating tailored biocatalysts to produce semisynthetic pharmaceutical compounds. LovD is an acyltransferase that converts the inactive monacolin J acid (MJA) into the cholesterol-lowering lovastatin. LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic alpha-dimethylbutyryl thioester, albeit with suboptimal properties as a biocatalyst. Here we used directed evolution to improve the properties of LovD toward semisynthesis of simvastatin. Mutants with improved catalytic efficiency, solubility, and thermal stability were obtained, with the best mutant displaying an approximately 11-fold increase in an Escherichia coli-based biocatalytic platform. To understand the structural basis of LovD enzymology, seven X-ray crystal structures were determined, including the parent LovD, an improved mutant G5, and G5 cocrystallized with ligands. Comparisons between the structures reveal that beneficial mutations stabilize the structure of G5 in a more compact conformation that is favorable for catalysis.
PDB ID: 3HLDDownload
MMDB ID: 77662
PDB Deposition Date: 2009/5/27
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 3HLD: monomeric; determined by author and by software (PISA)
Molecular Components in 3HLD
Label Count Molecule
Protein (1 molecule)
1
Transesterase
Molecule annotation
Chemicals (6 molecules)
1
2
2
4
* Click molecule labels to explore molecular sequence information.

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