Mitochondrial thymidine kinase inhibitors.
Mitochondrial thymidine kinase or TK-2 belongs to the family of mammalian deoxynucleoside kinases (dNKs) that catalyze the phosphorylation of deoxynucleosides to their corresponding deoxynucleoside monophosphates by gamma-phosphoryl transfer of ATP. These enzymes are instrumental in the activation of deoxynucleoside analogues with biological and therapeutic properties. Moreover, dNKs are fundamental to maintain dNTPs pools for DNA synthesis and repair. TK-2 has a mitochondrial localization and is the only thymidine kinase that is physiologically active in non-proliferating and resting cells. Several recent investigations point to an important role of TK-2 in the maintenance of mitochondrial dNTPs pools. Indeed, mutations in the gene encoding TK-2 have been associated with mitochondrial DNA (mtDNA) depletion that mostly affects skeletal muscle. Moreover, TK-2 has been suggested to be implicated in mitochondrial toxicity associated to prolonged treatments with nucleoside analogues (i.e AZT for the treatment of AIDS patients). In this scenario, TK-2 inhibitors could be a useful tool to further clarify both the physiological role of TK-2 in the maintenance of mitochondrial dNTP pools, and the possible contribution of TK-2 to the mitochondrial toxicity of pyrimidine nucleoside analogues. In the present article we review the most recent literature covering different aspects of TK-2 as well as published TK-2 inhibitors, with special emphasis on acyclic nucleoside analogues that have been described by our research groups and whose prototype compound is 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine.
Pérez-Pérez
María-Jesús
MJ
Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain. mjperez@iqm.csic.es
Hernández
Ana-Isabel
AI
Priego
Eva-María
EM
Rodríguez-Barrios
Fátima
F
Gago
Federico
F
Camarasa
María-José
MJ
Balzarini
Jan
J
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D009705:Nucleosides; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1