Synthesis of alanyl nucleobase amino acids and their incorporation into proteins

Poulami Talukder, Larisa Dedkova, Andrew D. Ellington, Petro Yakovchuk, Jaebum Lim, Eric V. Anslyn, Sidney Hecht

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Proteins which bind to nucleic acids and regulate their structure and functions are numerous and exceptionally important. Such proteins employ a variety of strategies for recognition of the relevant structural elements in their nucleic acid substrates, some of which have been shown to involve rather subtle interactions which might have been difficult to design from first principles. In the present study, we have explored the preparation of proteins containing unnatural amino acids having nucleobase side chains. In principle, the introduction of multiple nucleobase amino acids into the nucleic acid binding domain of a protein should enable these modified proteins to interact with their nucleic acid substrates using Watson-Crick and other base pairing interactions. We describe the synthesis of five alanyl nucleobase amino acids protected in a fashion which enabled their attachment to a suppressor tRNA, and their incorporation into each of two proteins with acceptable efficiencies. The nucleobases studied included cytosine, uracil, thymine, adenine and guanine, i.e. the major nucleobase constituents of DNA and RNA. Dihydrofolate reductase was chosen as one model protein to enable direct comparison of the facility of incorporation of the nucleobase amino acids with numerous other unnatural amino acids studied previously. The Klenow fragment of DNA polymerase I was chosen as a representative DNA binding protein whose mode of action has been studied in detail.

Original languageEnglish (US)
Pages (from-to)4177-4187
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number18
StatePublished - 2016


  • DNA polymerase I
  • DNAprotein interaction
  • N-Boc-L-serine β-lactone
  • Nucleobases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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