David WilliamsDr David M. Williams

Reader in Chemical Biology

Room: C79

Tel: +44-(0)114-22-29502

Fax: +44-(0)114-22-29436

email:

 


 

Biographical Sketch

Dr. Williams obtained a BSc in Chemistry from the University of Liverpool in 1985, which was followed by a PhD from the same institution in 1988. From 1988, he was a Postdoctoral Research Fellow at the Max-Planck Institute for Experimental Medicine in Göttingen and from 1992-1995 at the MRC Laboratory of Molecular Biology in Cambridge. In 1995 he became a demonstrator at the University of Sheffield. In 1999 he became a lecturer and in 2006 a senior lecturer.  In 2014 he was promoted to Reader.

Research Keywords

Nucleic acid chemistry, heterocyclic chemistry, nucleotide chemistry, DNA damage, DNA repair, O6-alkylguanine-DNA alkyltransferases, alkyltransferase-like proteins

Teaching Keywords

Organic Chemistry

Selected Publications:

 

Research Interests

Our main areas of research are in the synthesis of modified nucleosides and nucleotides and their applications.

Currently we are interested in the chemical synthesis of 5'-triphosphates of base-modified, nucleoside analogues that have altered base pairing specificities. We are studying the incorporation of these analogues into DNA by polymerase enzymes in order to gain an insight into the role of base pairing during DNA replication and DNA mutagenesis.

Exposure to alkylating agents can lead to the formation of highly toxic O6-alkylguanine lesions within DNA. We have developed chemical methodology for the preparation of oligodeoxyribonucleotides containing a variety of O6-alkylguanine analogues and these are being used to study DNA recognition and repair by the human protein O6-methylguanine-DNA methyltransferase (MGMT) and the alkyltransferase-like protein Atl1.

Other areas of interest include the use SELEX for the design of nucleic acid-based ligands and catalysts containing chemically synthesised imidazolyl and amino modified nucleotides of dUTP and 7-deazadATP, studying the structural properties of nucleic acids containing modified pyrimidine and purine bases and the design and synthesis of modified oligodeoxyribonucleotides for DNA-DNA and DNA-protein cross-linking.

Teaching Section

Organic Chemistry

Courses Taught

  • Aromatic chemistry (Year 2)
    This segment reviews the concept of aromaticity and the mechanisms of reactions of aromatic systems, particularly benzene and its derivatives.
  • Introduction to organic synthesis 1 (Year 2)
    This segment revises the reactions of carbonyl compounds with nucleophiles, introduces conjugate addition reactions (electrophilic alkenes), and discusses the acid and base-catalysed reactions of carbonyl compounds at the α-carbon via enols and enolates. Methods for the synthesis of amines are also discussed.
  • Heterocyclic Chemistry (Year 3)
    This segment introduces aromatic and non-aromatic heterocyclic compounds.

Tutorial & Workshop Support

  • First Year General Tutorials.
  • Second Year Organic Chemistry Tutorials
  • Third Year Literature Review.

Laboratory Teaching

  • Fourth Year Research Project.

Books

  • Blackburn GM (2006) Nucleic Acids in Chemistry and Biology. Royal Society of Chemistry.

Journal articles

Conference proceedings papers

  • Senthong P, Millington CL, Wilkinson OJ, Marriott AS, Watson AJ, Reamtong O, Eyers CE, Williams DM, Margison GP & Povey AC (2013) The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase. Nucleic Acids Res, Vol. 41(5) (pp 3047-3055)
  • Senthong P, Williams DM, Wilkinson O, Millington C, Marriott A, Watson AJ, Kelly JR, Latypov V, McGown G, Thorncroft MR, Eyers CE, Margison GP & Povey AC (2012) The Nitrosated Bile Acid DNA Lesion, O-6-carboxymethylguanine, Is a Substrate for Human O-6-alkylguanine DNA Alkyltransferase. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol. 53 (pp S36-S36)
  • Sultana T, Wilkinson OJ, Heath AW, Williams DM & Carlring J (2012) Impact of a novel conjugation method on the efficiency of CD40mAb-antigen conjugate vaccines in vivo. IMMUNOLOGY, Vol. 137 (pp 763-763)
  • Millington CL, Shibata T, Margison G & Williams DM (2008) Novel post DNA synthesis chemistry and biological evaluation of O-6-alkylguanine-containing oligodeoxyribonucleotides. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 10 (pp 133-136)
  • Araujo ARH, Edmont D & Williams DM (2002) Synthesis and applications of a tricyclic analogue of N-6-methoxy-2,6-diamino-2 '-deoxyriboside. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 328-331)
  • Brazier JA & Williams DM (2002) Synthesis and applications of C5-amino modified 2 '-deoxyuridines. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 221-224)
  • Harris VH, Smith C, Cummins J, Hamilton A, Hornby DP & Williams DM (2002) DNA replication with the mutagenic nucleotide dPTP; Effects of tautomerism on nucleotide incorporation. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 215-220)
  • Harris VH, Hamilton A, Williams DM & Hornby DP (1999) Studying the function of methyltransferases using nucleotide analogue based random mutagenesis. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 2 (pp 209-212)
  • Jakeman DL, Bernstein B, Hol W, Williams DM, Williamson MP & Blackburn GM (1999) Highly potent bisphosphonate ligands for phosphoglycerate kinase and protein binding studies. PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS, Vol. 146 (pp 533-536)
  • Hill F, Loakes D, Smith CL, Williams DM & Brown DM (1999) Synthesis and polymerase incorporation properties of a tricyclic pyrrolopyrimidine related to N-6-hydroxy-2 '-deoxyadenosine. NUCLEOSIDES & NUCLEOTIDES, Vol. 18(4-5) (pp 573-574)
  • Williams DM, Jakeman DL, Vyle JS, Williamson MP & Blackburn GM (1996) Synthesis and kinetic studies of bisubstrate analogues of phosphoglycerate kinase. COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, Vol. 61 (pp S88-S91)