Location, location, location – glycosyltransferase goes rogue

In two papers just published in eLife and PNAS the Ferguson lab, in collaboration with Steve Beverley and colleagues at Washington University, St Louis, USA, describe the presence of a fucosyltransferase in the mitochondria of the protozoan parasites Trypanosoma brucei and Leishmania major.

Glycosyltransferases, including fucosyltransferases, are generally found in the Golgi apparatus or the endoplasmic reticulum, and occasionally in the cytoplasm. The discovery of a mitochondrial fucosyltransferase is unprecedented in eukaryotic biology and leaves more questions than answers – like what is there for? and do functionally similar glycosylation systems occur in the mitochondria of higher eukaryotes?

One thing is for sure though, the enzyme is essential to both T. brucei, causative agent of tsetse-transmitted human and animal African trypanosomiasis, and L. major, causative agent of sandfly-transmitted cutaneous leishmaniasis.

The absence of closely related fucosyltransferase sequences in the hosts of these two parasites, man and domestic livestock, further suggest that TbFUT1 and LmjFUT1 could be good drug targets against the serious neglected tropical diseases caused by T. brucei, L. major and other closely related disease-causing parasites.

Mike Ferguson said: “I am delighted to see this highly original work published. I thank our collaborators and I pay tribute to all involved. I pass my best wishes and congratulations to the co-first authors of our eLife paper: former PhD student Giulia Bandini, now a research fellow at York University, Department of Biology, and Sebastian Damerow, now working for German biotech Richter-Helm BioLogics.”

These papers come hot on the heels of another study by Lucia Guther and colleagues in the Ferguson lab, showing an equally strange and unique location for the pathways leading to five nucleotide sugars, including GDP-fucose required by TbFUT1. This work, published in PLoS Neglected Tropical Diseases, shows that 11 enzymes belonging to these pathways reside inside the parasite’s peroxisomes, also known as glycosomes. In all other eukaryotes the equivalent enzymes are located in the cytoplasm.

Mike notes: “The parasite makes the nucleotide sugar donors for its glycosyltransferases inside the peroxisomes and must transport them first into the cytoplasm and then into the ER and Golgi for conventional glycosylation pathways, as well as, we now know, into the mitochondria. There is always more to find out, and exploit, about the fascinating biology of these highly divergent eukaryotic pathogens.”