title: Syntheses of stable, synthetic diadenosine polyphosphate analogues using recombinant histidine-tagged lysyl tRNA synthetase (LysU).
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 phosphatephosphate 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.
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Organic-I Division, Indian Institute of Chemical Technology, Habsigida, Hyderabad, India.
authors.forename: M Ameruddin
authors.initials: MA
authors.lastname: Azhar
authors.affiliation: Organic-I Division, Indian Institute of Chemical Technology, Habsigida, Hyderabad, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK. Electronic address: a.miller07@btinternet.com.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
mesh_terms: D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis* / Q000737:chemistry; D006639:Histidine / Q000031:analogs & derivatives / Q000737:chemistry; D008250:Lysine-tRNA Ligase / Q000737:chemistry* / Q000378:metabolism; D011122:Polyphosphates / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000227:Adenine Nucleotides; D015226:Dinucleoside Phosphates; D011122:Polyphosphates; D006639:Histidine; C020733:diadenosine tetraphosphate; D008250:Lysine-tRNA Ligase
keywords: Analogues; Biosynthesis; Diadenosine polyphosphate; Dinucleoside polyphosphates; Lysyl tRNA synthetase (LysU)