Regulation of Trypanosoma brucei Acetyl Coenzyme A Carboxylase by Environmental Lipids

Abstract

Trypanosoma brucei is a eukaryotic parasite that causes African sleeping sickness. T. brucei is transmitted by the blood-sucking tsetse fly. In order to adapt to its two very different hosts, T. brucei must sense the host environment and alter its metabolism to maximize utilization of host resources and minimize expenditure of its own resources. One key nutrient class is represented by fatty acids, which the parasite can either take from the host or make themselves. Our work describes a novel environmental regulatory pathway for fatty acid synthesis where the parasite turns off fatty acid synthesis when environmental lipids are abundant and turns on synthesis when the lipid supply is scarce. This pathway was observed in the tsetse midgut form but not the mammalian bloodstream form. However, pharmacological activation of this pathway in the bloodstream form to turn fatty acid synthesis off may be a promising new avenue for sleeping sickness drug discovery.

Lipid and fatty acid metabolism in trypanosomatids

“…In PCFs, ACC activity and protein levels were downregulated under lipid-rich growth conditions. However, this was not observed in BSFs, most likely because these forms require constitutively active ACC for myristate synthesis and GPI-anchor assembly [ 93 ].…”

Lipid hijacking: A unifying theme in vector-borne diseases

“…However, if there is an exogenous limitation on fatty acids, T. brucei may synthesize these lipids de novo from ketogenic carbon sources ( Millerioux et al, 2018 ; Figure 3B ). T. brucei may endogenously produce fatty acids from the type II fatty acid synthase pathway (FASII) or from the microsomal elongase pathway, which uses the enzyme acetyl coenzyme A carboxylase (ACC) ( Millerioux et al, 2018 ; Ray et al, 2018 ). The activity of this enzyme is regulated by lipid abundance in the tsetse fly, therefore maintaining a balance between lipid scavenging and synthesis ( Ray et al, 2018 ).…”

Co-interventions withClostridium butyricumand soluble dietary fiber targeting the gut microbiota improve MAFLDviathe Acly/Nrf2/NF-κB signaling pathway

“…64 However, ACC catalyzes the transformation of acetyl-CoA into malonyl-CoA, which is the first committed step in fatty acid synthesis. 65 ACC is the direct kinase downstream of AMPK. Phosphorylation at Ser79 in ACC by AMPK reduces the enzymatic activity of ACC.…”