Document Detail

Directed evolution of a model primordial enzyme provides insights into the development of the genetic code.
MedLine Citation:
PMID:  23300488     Owner:  NLM     Status:  MEDLINE    
The contemporary proteinogenic repertoire contains 20 amino acids with diverse functional groups and side chain geometries. Primordial proteins, in contrast, were presumably constructed from a subset of these building blocks. Subsequent expansion of the proteinogenic alphabet would have enhanced their capabilities, fostering the metabolic prowess and organismal fitness of early living systems. While the addition of amino acids bearing innovative functional groups directly enhances the chemical repertoire of proteomes, the inclusion of chemically redundant monomers is difficult to rationalize. Here, we studied how a simplified chorismate mutase evolves upon expanding its amino acid alphabet from nine to potentially 20 letters. Continuous evolution provided an enhanced enzyme variant that has only two point mutations, both of which extend the alphabet and jointly improve protein stability by >4 kcal/mol and catalytic activity tenfold. The same, seemingly innocuous substitutions (Ile→Thr, Leu→Val) occurred in several independent evolutionary trajectories. The increase in fitness they confer indicates that building blocks with very similar side chain structures are highly beneficial for fine-tuning protein structure and function.
Manuel M Müller; Jane R Allison; Narupat Hongdilokkul; Laurent Gaillon; Peter Kast; Wilfred F van Gunsteren; Philippe Marlière; Donald Hilvert
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  PLoS genetics     Volume:  9     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2013  
Date Detail:
Created Date:  2013-01-09     Completed Date:  2013-05-30     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1003187     Citation Subset:  IM    
Laboratory of Organic Chemistry, ETH Zurich, Zurich, Switzerland.
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MeSH Terms
Amino Acid Sequence
Amino Acid Substitution
Amino Acids* / chemistry,  genetics
Chorismate Mutase / chemistry,  genetics
Directed Molecular Evolution*
Genetic Code*
Methanococcales / genetics
Molecular Dynamics Simulation
Molecular Sequence Data
Point Mutation
Protein Conformation
Protein Stability
Proteins / genetics*
Structure-Activity Relationship
Reg. No./Substance:
0/Amino Acids; 0/Proteins; EC Mutase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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