The molecular equivalent of converting a mouse into a human!

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The extent of changes made in the course of a protein improvement has increased dramatically in the past decade. In the early 2000's one or two mutations were typical, while by 2010, 30-40 amino acid substitutions are not unusual. For example, directed evolution of halohydrin dehalogenase for manufacture of the atorvastatin (Lipitor) side chain changed at least 35 of the 254 amino acids (>14%; Fox et al. 2007) and directed evolution of the transaminase for sitagliptin manufacture changed 27 of the 330 amino acids (8.2%; Savile et al. 2010). Similarly, computational design of a retro aldolase required 8 or 12 amino acid substitutions (4-6%) in the starting enzyme, a 197-aa xylanase (Jiang et al., 2008).
Amino acid sequences of proteins in mice and human typically differ by 13% (Waterston et al., 2002), so this laboratory evolution of enzymes is equivalent to compressing the 75 million-year-evolution from an early mammal to today's mice and humans into several months of laboratory work. 

Fox, R. J. et al. (2007), Improving catalytic function by ProSAR-driven enzyme evolution, Nature Biotechnol., 25, 338-344.

Jiang, L. et al. (2008), De novo computational design of retro-aldol enzymes, Science, 319, 1387-1391.

Savile, C. K. et al. (2010), Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture, Science, 329, 305-309.

Waterston, R. H. et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature, 420, 520-62.

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This page contains a single entry by rjk published on September 23, 2011 3:55 PM.

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