Polyamines in protozoan pathogens

Abstract

Polyamines are polycationic organic amines that are required for all eukaryotic life, exemplified by the polyamine spermidine, which plays an essential role in translation. They also play more specialized roles that differ across species, and their chemical versatility has been fully exploited during the evolution of protozoan pathogens. These eukaryotic pathogens, which cause some of the most globally widespread infectious diseases, have acquired species-specific polyamine-derived metabolites with essential cellular functions and have evolved unique mechanisms that regulate their core polyamine biosynthetic pathways. Many of these parasitic species have lost enzymes and or transporters from the polyamine metabolic pathway that are found in the human host. These pathway differences have prompted drug discovery efforts to target the parasite polyamine pathways, and indeed, the only clinically approved drug targeting the polyamine biosynthetic pathway is used to manage human African trypanosomiasis. This Minireview will primarily focus on polyamine metabolism and function in Trypanosoma, Leishmania, and Plasmodium species, which are the causative agents of human African trypanosomiasis (HAT) and Chagas disease, Leishmaniasis, and malaria, respectively. Aspects of polyamine metabolism across a diverse group of protozoan pathogens will also be explored.

Keywords: eukaryotic initiation factor 5A (eIF5A); plasmodium; polyamine; protozoan; pseudoenzyme; spermidine; trypanosome.

Figure 1.

Polyamine biosynthetic pathway in single-celled parasitic eukaryotes. A, core polyamine biosynthetic pathway. The enzymes found in the various species are indicated by italicized species names as follows: Tb, T. brucei; Ld, L. donovani; Tc, T. cruzi; Pf, P. falciparum; Tg, T. gondii; Cp, C. parvum; Tv, T. vaginalis; Gl, G. lamblia; Eh, E. histolytica. The inset identifies enzymes that are formed as either bifunctional enzymes or require oligomerization with a pseudoenzyme for activity. Abbreviations are defined in the text with the exception of DAP, diaminopropane. B, trypanothione biosynthetic pathway in the trypanosomatids. T(SH)₂, reduced trypanothione; TS₂, oxidized trypanothione. Gene resource sites are as follows: http://tritrypdb.org/tritrypdb/ (101), http://plasmodb.org/plasmo/ (102), http://toxodb.org/toxo/ (103), http://giardiadb.org/giardiadb/, and http://trichdb.org/trichdb/ (104), http://cryptodb.org/cryptodb/ (105), and http://amoebadb.org/amoeba/ (106) (see also Ref. 3). (Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site.) Available X-ray structures for parasite enzymes in these pathways are summarized in Table 1.

Figure 2.

Structures of ODC and AdoMetDC inhibitors with activity against T. brucei. A, DFMO (PDB code 2TOD) shown with nifurtimox, which is not an ODC inhibitor but is used together with DFMO for combination therapy to treat HAT. B, AdoMetDC inhibitors CGP 40215A (100) (PDB code 5TVF); MDL 73811 (92), and Genz644131 (91); pyrimidineamine UTSAM568 (N⁴-(3,5-dibromophenyl)-6-methylpyrimidine-2,4-diamine) (PDB code 6BM7) compound 44 from Ref. . PDB numbers for available co-crystal structures bound to the T. brucei enzymes are in parentheses.

Figure 3.

X-ray structure of T. brucei ODC. ODC K69A bound to DFMO (PDB code 2TOD) (86). A, ribbon diagram of the dimer with monomers colored in teal and tan. DFMO and PLP are shown as spheres. B, ODC active site showing select residues within the 4 Å shell of PLP and DFMO. DFMO is covalently bound to Cys-360. Catalytic residues with known function in catalysis or substrate binding are displayed.

Figure 4.

X-ray structure of T. brucei AdoMetDC. A comparison of the inactive monomer (PDB code 5TVO) and the active heterodimer in complex with CGP 40215A (PDB code 5TVF) (28) is shown. A, inactive monomeric structure. B, active heterodimer in complex with prozyme and the inhibitor CGP 40215a. Pyruvoyl (Pvl) is shown as spheres, and the autoinhibitory sequence is shown as sticks. cP31, cis-proline 31; tP31, trans-proline 31.

Figure 5.

X-ray structure of T. brucei DHS. A, DHS tetramer structure showing the active-site complementation that leads to formation of one catalytically active site and one dead site across the dimer interface (PDB code 6DFT) (27). B, DHS dimer interface showing the NAD⁺-binding sites with select amino acid residues in the catalytically active site and the remnant dead site. The catalytic lysine (Lys-418) in DHSc and the equivalent inactive residue (Leu-303) in DHSp found in the dead site are marked by #.