Mutational analyses of human thymidine kinase 2 reveal key residues in ATP-Mg2+ binding and catalysis

Mitochondrial thymidine kinase 2 (TK2) is an essential enzyme for mitochondrial dNTP synthesis in many tissues. Deficiency in TK2 activity causes devastating mitochondrial diseases. Here we investigated several residues involved in substrate binding and catalysis. We showed that mutations of Gln-110...

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Bibliographic Details
Published in:Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2022, Vol.41 (3), p.264-272
Main Authors: Wang, Liya, Eriksson, Staffan
Format: Article
Language:English
Subjects:
ATP/Mg
binding
Biochemistry and Molecular Biology
Biokemi och molekylärbiologi
Catalysis
enzyme kinetics
Magnesium
Mitochondria
mutagenesis
Mutation
substrate binding
Thymidine
Thymidine kinase
thymidine kinase 2
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Summary:Mitochondrial thymidine kinase 2 (TK2) is an essential enzyme for mitochondrial dNTP synthesis in many tissues. Deficiency in TK2 activity causes devastating mitochondrial diseases. Here we investigated several residues involved in substrate binding and catalysis. We showed that mutations of Gln-110 and Glu-133 affected Mg 2+ and ATP binding, and thus are crucial for TK2 function. Furthermore, mutations of Gln-110 and Tyr-141 altered the kinetic behavior, suggesting their involvement in substrate binding through conformational changes. Since the 3 D structure of TK2 is still unknown, and thus, the identification of key amino acids for TK2 function may help to explain how TK2 mutations cause mitochondrial diseases.
ISSN:1525-7770
1532-2335
1532-2335
DOI:10.1080/15257770.2021.2001005