Structural Characterization of Acidic M17 Leucine Aminopeptidases from the TriTryps and Evaluation of Their Role in Nutrient Starvation in Trypanosoma brucei

Abstract

Leucine aminopeptidases (LAPs) catalyze the hydrolysis of the N-terminal amino acid of peptides and are considered potential drug targets. They are involved in multiple functions ranging from host cell invasion and provision of essential amino acids to site-specific homologous recombination and transcription regulation. In kinetoplastid parasites, there are at least three distinct LAPs. The availability of the crystal structures provides important information for drug design. Here we report the structure of the acidic LAPs from three kinetoplastids in complex with different inhibitors and explore their role in Trypanosoma brucei survival under various nutrient conditions. Importantly, the acidic LAP is dispensable for growth both in vitro and in vivo, an observation that questions its use as a specific drug target. While LAP-A is not essential, leucine depletion and subcellular localization studies performed under starvation conditions suggest a possible function of LAP-A in the response to nutrient restriction.

Causes and Effects of Loss of Classical Nonhomologous End Joining Pathway in Parasitic Eukaryotes

“…Mapping of insertions in the “jaculum” proteins onto structures of dihydrofolate reductase in complex with pyrimethamine (118) (A), leucyl aminopeptidase (119) (B), the phosphatase domain of phosphoglycerate mutase (120) (C), and adenosine kinase in complex with adenosine and AMPPNP (121) (D) from T. brucei.…”

The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

“…Indeed, there is evidence that BCAA are also essential in the TriTryp parasites. However, they seem to be able to catabolize them all [ 85 , 89 , 152 , 153 , 154 ]. The catabolic pathway of BCAA involves several enzymatic steps, some in common for all three amino acids and others specific for some of them.…”

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

“…To date, the essentiality of LAPs in T. cruzi has not been reported, and the information on closely related parasitic protozoa is not conclusive. For instance, LAP is essential for Plasmodium falciparum but disposable for T. brucei [12,18,42]. While T. brucei and T. cruzi are more closely related, the former is an extracellular parasite.…”

“…In the literature, the acidic enzyme leucyl-aminopeptidase from T. cruzi has been abbreviated as LAPTc or TcLAP (both of them correct) [12,14,17,18]. However, here we denoted the enzyme as TcLAP, following the recommendations of the genetic nomenclature for Trypanosoma and Leishmania proposed at the Woods Hole Molecular Parasitology Meeting (Massachusetts, USA, 1996) as well as at the WHO-sponsored workshop for the T. brucei and Leishmania genome project (Arcachon, France, 1998) [19].…”