Mitochondrial deoxyguanosine kinase mutations and mitochondrial DNA depletion syndrome.
Mitochondrial deoxyguanosine kinase (dGK) catalyzes the initial phosphorylation of purine deoxynucleosides. Mutations in the dGK gene leading to deficiency in dGK activity is one of the causes of severe mitochondrial DNA depletion diseases. We used site-directed mutagenesis to introduce the clinically observed genetic alterations in the dGK gene and characterized the recombinant enzymes. The R142K enzyme had very low activity with deoxyguanosine and no activity with deoxyadenosine. The E227K mutant enzyme had unchanged K(m) values for all its substrates but very low V(max) values. C-terminal truncated dGK proteins were inactive. These results may help to define the role of dGK in mitochondrial DNA (mtDNA) precursor synthesis.
Wang
Liya
L
Department of Molecular Biosciences, Section of Veterinary Medical Biochemistry, SLU, The Biomedical Centre, P.O. Box 575, SE-751 23 Uppsala, Sweden. liya.wang@vmk.slu.se
Eriksson
Staffan
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D003839:Deoxyadenosines / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D004272:DNA, Mitochondrial; D003839:Deoxyadenosines; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D003849:Deoxyguanosine