Thymidine Kinase 2 Enzyme Kinetics Elucidate the Mechanism of Thymidine-Induced Mitochondrial DNA Depletion

Biochemistry ◽  
2014 ◽  
Vol 53 (39) ◽  
pp. 6142-6150 ◽  
Author(s):  
Ren Sun ◽  
Liya Wang
Keyword(s):  
Mitochondrial Dna ◽  
Enzyme Kinetics ◽  
Thymidine Kinase ◽  
Mitochondrial Dna Depletion ◽  
Thymidine Kinase 2

Hematopoiesis in the thymidine kinase 2 deficient mouse model of mitochondrial DNA depletion syndrome

2010 ◽  
Vol 33 (3) ◽  
pp. 231-236 ◽  
Author(s):  
Xiaoshan Zhou ◽  
Magnus Johansson ◽  
Nicola Solaroli ◽  
Björn Rozell ◽  
Alf Grandien ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Model ◽  
Thymidine Kinase ◽  
Deficient Mouse ◽  
Mitochondrial Dna Depletion ◽  
Mitochondrial Dna Depletion Syndrome ◽  
Thymidine Kinase 2

scholarly journals The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs

2011 ◽  
Vol 55 (6) ◽  
pp. 2552-2558 ◽  
Author(s):  
Liya Wang ◽  
Ren Sun ◽  
Staffan Eriksson
Keyword(s):  
Mitochondrial Dna ◽  
Side Effects ◽  
Thymidine Kinase ◽  
Nucleoside Analogs ◽  
Pyrimidine Nucleoside ◽  
Mitochondrial Dna Depletion ◽  
Long Term Treatment ◽  
Feedback Inhibitor ◽  
Thymidine Kinase 2 ◽  
Thymidine Analogs

ABSTRACTMitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs.

scholarly journals Clinical Spectrum of Mitochondrial DNA Depletion Due to Mutations in the Thymidine Kinase 2 Gene

2006 ◽  
Vol 63 (8) ◽  
pp. 1122 ◽  
Author(s):  
Maryam Oskoui ◽  
Guido Davidzon ◽  
Juan Pascual ◽  
Ricardo Erazo ◽  
Juliana Gurgel-Giannetti ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Thymidine Kinase ◽  
Clinical Spectrum ◽  
Mitochondrial Dna Depletion ◽  
Thymidine Kinase 2

scholarly journals Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e29691 ◽  
Author(s):  
Joan Villarroya ◽  
Beatriz Dorado ◽  
Maya R. Vilà ◽  
Elena Garcia-Arumí ◽  
Pere Domingo ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Thymidine Kinase ◽  
Abnormal Development ◽  
Adipose Tissues ◽  
Mitochondrial Dna Depletion ◽  
Thymidine Kinase 2
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