Adenosine metabolism in Toxoplasma gondii: potential targets for chemotherapy.
Toxoplasma gondii is an intracellular parasitic protozoan that infects approximately a billion people worldwide. Infection with T. gondii represents a major health problem for immunocompromised individuals, such as AIDS patients, organ transplant recipients, and the unborn children of infected mothers. Currently available drugs usually do not eradicate infection and as many as 50% of the patients do not respond to this therapy. Furthermore, they are ineffective against T. gondii tissue cysts. In addition, prolonged exposure to these drugs induces serious host toxicity forcing the discontinuation of the therapy. Finally, there is no effective vaccine currently available for the treatment of toxoplasmosis. Therefore, it is necessary to develop new and effective drugs for the treatment and management of toxoplasmosis. The rational design of a drug depends on the exploitation of fundamental biochemical or physiological differences between pathogens and their host. Some of the most striking differences between T. gondii and their mammalian host are found in purine metabolism. T. gondii, like most parasites studied, lack the ability to synthesize purines do novo and depend on the salvage of purines from their host to satisfy their requirements of purines. In this respect, the salvage of adenosine is the major source of purines in T. gondii. Therefore, interference with adenosine uptake and metabolism in T. gondii can be selectively detrimental to the parasite. The host cells, on the other hand, can still obtain their purine requirements by their de novo pathways. This review will focus on the broad aspects of the adenosine transport and the enzyme adenosine kinase (EC 2.7.1.20) which are the two primary routes for adenosine utilization in T. gondii, in an attempt to illustrate their potentials as targets for chemotherapy against this parasite.
el Kouni
Mahmoud H
MH
Department of Pharmacology and Toxicology, Center for AIDS Research, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. m.elkouni@ccc.uab.edu
D000241:Adenosine / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000235:genetics / Q000469:parasitology*
D000981:Antiprotozoal Agents; D000241:Adenosine