A pinboard by
Joe Kaczmarski

PhD Student, Australian National University


Ancestral Protein Reconstruction highlights structural changes required for emergence of catalysis

Enzymes are remarkable protein catalysts - speeding up important biochemical reactions in cells that are required for life. As protein engineers, we are always looking for ways to harness the incredible power of enzymes. For years, we have been stealing naturally occurring enzymes from living cells and using them to speed up chemical reactions in industry to make useful products - from paper to life-saving drugs. However, we are limited by the types of enzymes available in nature - it would be great if we could design and engineer our own! Advances in protein engineering mean that we can now reproduce nature's enzymes well, but whenever we try and make our own they never work very well. This highlights a gap in our understanding of how enzymes work. My research hopes to fill this gap, by studying how enzymes evolve in nature from proteins that were initially specialised for binding onto chemicals, but not for speeding up chemical reactions. We use a technique called ancestral protein reconstruction, which allows us to infer the likely amino-acid sequences of ancient ancestral forms of present-day enzymes. We study these in the lab, using X-ray crystallography to understand their atomic structures, and test for specific activities such as binding and enzyme activity. Doing this we can connect how small structural changes have allowed for the emergence and evolution of new enzymatic activity. We hope this research will help develop improved approaches to enzyme design.