research

 

photo of Dr. O'Donoghue

 

Dr. Patrick O'Donoghue

Assistant Professor

Depts. of Biochemistry and Chemistry

Medical Sciences Building MSB 388

519-850-2373

patrick.odonoghue@uwo.ca

 


Research Interests


The fact that humans are 99.9% genetically identical appears in contrast with the great diversity of human behaviour, health, and disease that results from a few nucleotide changes. The genome is only part of the story. The biological cell uses genetic information stored in genes and DNA to build proteins from 20 different amino acids or building blocks. Proteins play important structural and functional roles in the cell by, for example, establishing communication between cells, converting food molecules (like sugar) into chemical energy that the cell can use, and even copying or replicating the genetic information that is passed on to the next generation. Similar processes occur across the great diversity of life, from single-celled microbes to complex multicellular organisms, including humans.

Despite the fact that proteins are normally made from only 20 typical amino acids, over 400 different kinds of amino acids are found in mature proteins. These non-canonical amino acids (ncAAs) are essential to life because proteins involved in fundamental cellular processes undergo significant posttranslational modification (PTM). In this process, certain (many times unknown) enzymes chemically modify those 20 building block amino acids after the original protein is made. PTMs relay chemical signals that alter cell fate and gene expression. Mis-modified proteins lead to defects in signalling and epigenetic networks that result in oncogenic cells and protein aggregates, i.e., the molecular basis of cancers and neurodegenerative diseases. To define the role of PTMs and to produce therapeutic agents against mis-modified proteins, an urgent need exists to synthesize specifically modified proteins.

The long-term objective of our laboratory is to create systems for protein synthesis with multiple (more than 10) ncAAs in diverse genetic backgrounds, such as Escherichia coli, mammalian, and human cells. In the near-term, the laboratory will engineer translation systems in E. coli to site-specifically hardwire proteins with PTMs, create new biosynthetic and chemical synthetic routes to ncAAs, and design selenocysteine-containing enzymes for industrial and medical applications.

 

Selected publications

*Co-first author, contributing equally.
†Corresponding author.

  1. M.J. Bröcker, J.M.L. Ho, G.M. Church, D. Söll†, & P. O'Donoghue† (2013) Recoding the genetic code with selenocysteine. Angewandte Chemie. DOI: 10.1002/anie.201308584, in press.  
  2. P. O’Donoghue*, J. Ling*, Y-S. Wang*, & D. Söll (2013). Upgrading protein synthesis for synthetic biology. Nature Chem. Biol. 9: 594-598.
  3. J.H. Campbell*, P. O'Donoghue*, A.G. Campbell, P. Schwientek, A. Sczyrba, T. Woyke, D. Söll, & M. Podar (2013). UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota. Proc Natl Acad Sci USA 110:5540-5545. Faculty of 1000 recommended as exceptional.
  4. P. O’Donoghue, L. Prat, I.U. Heinemann, J. Ling, K. Odoi, W.R. Liu, & D. Söll (2012). Near-cognate suppression of amber, opal and quadruplet codons competes with aminoacyl-tRNAPyl for genetic code expansion. FEBS Lett, 586: 3931-3937.
  5. L. Prat, I.U. Heinemann, H.R. Aerni, J. Rinehart, P. O’Donoghue†, & D. Söll†. (2012). Carbon source dependent expansion of the genetic code in bacteria. Proc Natl Acad Sci USA 109: 21070-21075.
  6. P. O’Donoghue, K. Sheppard, O. Nureki, & D. Söll. (2011) Rational design of an evolutionary precursor of glutaminyl-tRNA synthetase. Proc Natl Acad Sci USA 108: 20485-20490.
  7. K. Nozawa*, P. O’Donoghue*, S. Gundliapalli*, Y. Araiso, R. Ishitani, T. Umehara, D. Söll & O. Nureki. (2009) Pyrrolysyl-tRNA synthetase-tRNAPyl structure reveals the molecular basis of orthogonality. Nature 457, 1163-1167. Faculty of 1000 must read.
  8. M. J. Hohn*, H. S. Park*, P. O’Donoghue*, M. Schnitzbauer, & D. Söll. (2006) Emergence of the universal genetic code imprinted in an RNA record. Proc Natl Acad Sci USA. 103: 18095-18100. Faculty of 1000 recommended. Featured in Nature Research Highlights (Vol. 444|23 November 2006).
  9. P. O’Donoghue*, A. Sethi*, C. R. Woese & Z. Luthey-Schulten. (2005) The evolutionary history of Cys-tRNACys formation. Proc Natl Acad Sci USA. 102: 19003-19008.
  10. P. O’Donoghue & Z. Luthey-Schulten. (2003) On the evolution of structure in aminoacyl-tRNA synthetases. Microbiol Mol Biol Rev. 67: 550-573.

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Last updated by Lynn Weir, Nov 2013.