Abstract
De novo synthesis of threonine from aspartate occurs via the β-aspartyl phosphate pathway in plants, bacteria and fungi. However, the Trypanosoma brucei genome encodes only the last two steps in this pathway: homoserine kinase (HSK) and threonine synthase. Here, we investigated the possible roles for this incomplete pathway through biochemical, genetic and nutritional studies. Purified recombinant TbHSK specifically phosphorylates L-homoserine and displays kinetic properties similar to other HSKs. HSK null mutants generated in bloodstream forms displayed no growth phenotype in vitro or loss of virulence in vivo. However, following transformation into procyclic forms, homoserine, homoserine lactone and certain acyl homoserine lactones (AHLs) were found to substitute for threonine in growth media for wild-type procyclics, but not HSK null mutants. The tsetse fly is considered to be an unlikely source of these nutrients as it feeds exclusively on mammalian blood. Bioinformatic studies predict that tsetse endosymbionts possess part (up to homoserine in Wigglesworthia glossinidia) or all of the β-aspartyl phosphate pathway (Sodalis glossinidius). In addition S. glossinidius is known to produce 3-oxohexanoylhomoserine lactone which also supports trypanosome growth. We propose that T. brucei has retained HSK and threonine synthase in order to salvage these nutrients when threonine availability is limiting.
Highlights
Human African trypanosomiasis (African sleeping sickness), a disease caused by two subspecies of the protozoan parasite Trypanosoma brucei (T. b. gambiense and T. b. rhodesiense), is estimated to kill ∼ 10 000 people in sub-Saharan Africa every year (Aksoy, 2011)
Bioinformatic studies predict that tsetse endosymbionts possess part or all of the β-aspartyl phosphate pathway (Sodalis glossinidius)
We propose that T. brucei has retained homoserine kinase (HSK) and threonine synthase in order to salvage these nutrients when threonine availability is limiting
Summary
Human African trypanosomiasis (African sleeping sickness), a disease caused by two subspecies of the protozoan parasite Trypanosoma brucei (T. b. gambiense and T. b. rhodesiense), is estimated to kill ∼ 10 000 people in sub-Saharan Africa every year (Aksoy, 2011). Human African trypanosomiasis (African sleeping sickness), a disease caused by two subspecies of the protozoan parasite Trypanosoma brucei T. brucei infection is transmitted between mammalian hosts via the bite of an infected tsetse fly (Glossina spp.), an obligate blood feeder. These parasites undergo marked biological and biochemical changes during their life cycle, alternating predominantly between the bloodstream and procyclic trypomastigote forms in the mammalian bloodstream and tsetse mid-gut respectively (Jones et al, 2014). Current drugs (suramin, pentamidine, melarsoprol and nifurtimox-eflornithine combination therapy) used to treat African sleeping sickness are far from ideal in terms of efficacy, safety and cost (Fairlamb, 2003; Stuart et al, 2008). Given the high attrition rate in drug discovery, additional potential druggable targets or pathways are required
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