Syntheses of stable, synthetic diadenosine polyphosphate analogues using recombinant histidine-tagged lysyl tRNA synthetase (LysU)

Michael Wright, M. Ameruddin Azhar, Ahmed Kamal, Andrew D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Recombinant Escherichia coli lysyl-tRNA synthase (LysU) has been previously utilised in the production of stabile, synthetic diadenosine polyphosphate (ApnA) analogues. Here we report on the extended use of a new recombinant histidine residue-tagged LysU as a tool for highly controlled phosphateAphosphate bond formation between nucleotides, avoiding the need for complex protecting group chemistries. Resulting high yielding tandem LysU-based biosynthetic-synthetic/synthetic-biosynthetic strategies emerge for the preparation of varieties of ApnA analogues directly from inexpensive natural nucleotides and nucleosides. Analogues so formed make a useful small library with which to probe ApnA activities in vitro and in vivo leading to the discovery of new, potentially potent biopharmaceuticals active against chronic pain and other chronic, high-burden disease states.

Original languageEnglish
Pages (from-to)2346-2352
Number of pages7
JournalBIOORGANIC AND MEDICINAL CHEMISTRY LETTERS
Volume24
Issue number10
DOIs
Publication statusPublished - 15 May 2014

Keywords

  • Dinucleoside polyphosphates
  • Diadenosine polyphosphate
  • Analogues
  • Lysyl tRNA synthetase (LysU)
  • Biosynthesis
  • STRESS-PROTEIN LYSU
  • DINUCLEOSIDE POLYPHOSPHATES
  • TETRAPHOSPHATE AP(4)A
  • REVERSE-TRANSCRIPTASE
  • DEPENDENT MECHANISM
  • ENZYMATIC-SYNTHESIS
  • 5',5'''-P-1,P-4-TETRAPHOSPHATE
  • PENTAPHOSPHATE
  • NUCLEOTIDES
  • RECEPTORS

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