Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

Abstract

Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania. Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in Leishmania parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host-parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites.

Keywords: Leishmania; S-adenosylmethionine decarboxylase; drug resistance; ornithine decarboxylase; polyamines; putrescine; spermidine; spermidine synthase; transport.

Figure 1

Chemical structures of the three main polyamines: putrescine, spermidine, and spermine.

Figure 2

The polyamine biosynthetic pathway. Enzymes are shown in bold. The polyamine biosynthetic enzymes are arginase (ARG), ornithine decarboxylase (ODC), spermidine synthase (SPDSYN), and S-adenosylmethionine decarboxylase (ADOMETDC), the latter depicted with prozyme. Downstream reactions are catalyzed by trypanothione synthetase/amidase (TSA), a bifunctional enzyme that forms trypanothione, and by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) that in consecutive reactions catalyze the hypusination and activation of eIF5A. The enzymes and metabolites unique to trypanosomatids, prozyme, TSA, and trypanothione, are shown in red, while the synthesis of spermine and the back-conversion of spermidine to putrescine, present only in mammalian cells and not in Leishmania, are denoted in green.

Figure 3

Differences in the polyamine biosynthetic pathways between trypanosomatids. The polyamine pathways of Leishmania spp., T. brucei, and T. cruzi are depicted. Enzymes are shown in bold. The polyamine biosynthetic enzymes spermidine synthase (SPDSYN), S-adenosylmethionine decarboxylase (ADOMETDC) with prozyme, trypanothione synthase (TSA), deoxyhypusine synthase (DHS), and deoxyhypusine hydroxylase (DOHH) are present in all three trypanosomatids. Ornithine decarboxylase (ODC) is missing in T. cruzi, and only Leishmania spp. appear to contain an active arginase (ARG). Dashed arrows represent the indispensable transport of polyamines or polyamine precursors.

Figure 4

Interaction of host–parasite polyamine pathways. The enzymes arginase (ARG), ornithine decarboxylase (ODC), spermidine synthase (SPDSYN), and S-adenosylmethionine decarboxylase (ADOMETDC) are present in both host and parasite, while the enzyme spermine synthase (SPMSYN), displayed in green, can only be found in the host. The enzyme trypanothione synthetase/amidase (TSA) and prozyme, shown in red, are unique to the parasite. Putrescine and spermidine are bracketed and depicted in gray in the macrophage to indicate that only low amounts may be present in host cells. The uptake of arginine, ornithine, putrescine, and spermidine is represented in the dotted arrows. The question marks denote that the extent of transport of ornithine, putrescine, and spermidine into the phagolysosome and intracellular amastigote under physiological conditions is unclear.

Figure 5

Structures of polyamine pathway metabolites and select ODC inhibitors. Structures of the metabolites (a) ornithine, (b) putrescine, and (c) agmatine are shown, as well as the following ODC inhibitors: (d) D, L-α-difluoromethylornithine (DFMO), the putrescine derivatives (e) 3-aminooxy-1-aminopropane (APA) and (f) 1,4-diamino-2-butanone (DAB), and the agmatine derivative (g) gamma-guanidinooxy propylamine (GAPA).