Glyoxalase pathway of trypanosomatid parasites: a promising chemotherapeutic target.
Trypanosomatids are pathogenic protozoa of the order Kinetoplastida. A unique feature of these parasitic protozoa is the presence of a unique dithiol trypanothione (N(1), N(8) -bis(glutathionyl)spermidine) and the flavoenzyme trypanothione reductase. This is in contrast to human and other eukaryotes, which contain ubiquitous glutathione/glutathione reductase system. An important function of thiols is to protect cells from toxic metabolic by-products such as methylglyoxal, a reactive 2-oxoaldehyde. Methylglyoxal is a mutagenic and a cytotoxic compound. The glyoxalase system is involved in the detoxification of methylglyoxal. The exceptionality of the glyoxalase enzyme in the parasitic protozoa is the dependence on the dithiol -trypanothione for detoxifying the toxic methylglyoxal. The detoxification process by the glyoxalase enzyme in eukaryotes and most other organisms is dependent on the tripeptide glutathione. The glyoxalase enzyme of trypanosomatids are also exceptional in a way that they use the divalent cation nickel as a cofactor like the glyoxalase enzyme of E. coli, whereas in eukaryotes the cofactor is zinc. This reflects that both the substrate as well as the cofactor of the kinetoplastids glyoxalase enzyme is distinct from that of the glyoxalase enzyme of eukaryotes. These differences reveal that the active site of the glyoxalase enzyme of the parasite and its mammalian counterpart are significantly different thereby proposing that the glyoxalase enzyme of the protozoan parasite can be a potential chemotherapeutic target.
Chauhan
Swati C
SC
School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
Padmanabhan
Prasad K
PK
Madhubala
Rentala
R
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism*; D015394:Molecular Structure; D010802:Phylogeny; D011528:Protozoan Infections / Q000188:drug therapy / Q000469:parasitology; D011765:Pyruvaldehyde / Q000737:chemistry / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism*; D014351:Trypanosomatina / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
D004791:Enzyme Inhibitors; D007791:Lactoylglutathione Lyase; D011765:Pyruvaldehyde; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase