My research focuses on using biochemistry, structural biology and computation tools to investigate systems important to agriculture and health. The majority of my work is into “megasynthase” enzymes, large protein assembly lines that synthesise diverse bioactive molecules. Products of megasynthase enzymes include many antibiotics and other pharmacologically important molecules. The majority my work is conducted with Shaun Lott.
Megasynthases from rumen methanogens
A set of megasynthases has recently been identified in methanogenic archaea living in the rumens of livestock (Leahy et al. 2010). Megasynthases are common in eubacteria and eukaryotes (fungi) but this is the first time they have been found in archaea.
Methanogens are the organisms responsible for producing methane in the rumens of livestock. As rumen methanogen have an extremely energy-limited lifestyle, it is expected that the energetic cost of producing these large megasynthases means that the natural products that they produce have a crucial role to play in methanogen biology. However, nothing is currently known about these natural products.
We aim to express and purify the megasynthase proteins and use them to synthesise their products in vitro. This will allow use to characterise the natural products and determine their function. Our research is expected to lead to novel targets for mitigating methane emissions from livestock, which make up 30-35% of New Zealand’s total greenhouse gas emissions and a significant and increasing proportion of global emissions. This research is being conducted in collaboration with AgResearch.
Fungal megasynthases
A large proportion of the megasynthase products that are in practical use today are of fungal origin. However, technical challenges have meant that the majority of research to date has focused on bacterial megasynthases. Large numbers of “orphan” megasynthases (megasynthases for which their products are unknown) have been identified in fungal genomes. This represents a vast pool of potentially useful novel natural products.
I have previously determined the first protein structure of a fungal megasynthase protein (Lee et al. 2010) from the grass endophyte, Neotyphodium lolii. I was also involved in elucidating the structure of the product of this megasynthase, an unusual iron-binding siderophore (Koulman et al. 2012), which has been shown to have a remarkable influence on the mutualistic relationship between the endophytic fungus and its host plant (Johnson et al. 2013).
I am continuing to be involved in research on the structural biology of fungal megasynthases in collaboration with the NANORIPES centre at Aarhus University, Denmark. Recently, I have been focusing primarily on investigating the use of structural bioinformatics tools (more commonly used for drug discovery) to predict the products of orphan fungal megasynthases.
Health researchI am also involved in a number of research projects aimed at improving human and animal health. These include research into understanding the role of keratin associated proteins in human hair and wool formation, targeting megasynthases to develop novel antibacterials and research aimed and improving human and animal reproductive health in collaboration with Larry Chamley and Bayer Animal Health NZ.
References
Johnson, Linda J.; Albert Koulman; Michael Christensen; Geoffrey A. Lane; Karl Fraser; Natasha Forester; Richard D. Johnson; Gregory T. Bryan; and Susanne Rasmussen (2013) An extracellular siderophore is required to maintain the mutualistic interaction of Epichloë Festucae with Lolium Perenne. PLoS Pathogens 9 (5), e1003332. doi:10.1371/journal.ppat.1003332
Koulman, Albert; T. Verne Lee; Karl Fraser; Linda Johnson; Vickery Arcus; J. Shaun Lott; Susanne Rasmussen and Geoffrey Lane (2012) Identification of extracellular siderophores and a related peptide from the endophytic fungus Epichloë festucae in culture and endophyte-infected Lolium perenne. Phytochemistry 75, 128-139. doi:10.1016/j.phytochem.2011.11.020
Leahy, Sinead C; William J Kelly; Eric Altermann; Ron S Ronimus; et al. (2010) The Genome Sequence of the Rumen Methanogen Methanobrevibacter Ruminantium Reveals New Possibilities for Controlling Ruminant Methane Emissions. PLoS ONE 5 (1), e8926. doi: 10.1371/journal.pone.0008926
About me
