Deleterious deoxyguanosinekinase (dGK) destroys lives (LB99)

Abstract

Mitochondrial Deficiency Syndrome (MDS) is characterized by a deficient amount of mitochondrial DNA (mtDNA). Without sufficient copies of mtDNA, the mitochondria cannot manufacture an adequate amount of ATP, leading to failure of energy expensive tissues such as the brain, skeletal muscle, and liver, ultimately causing death in early infancy. Deoxyguanosine kinase (dGK), an enzymatic protein, plays a role in regulating the replication of mtDNA by attaching a phosphate to a sugar/nitrogen‐base nucleoside at the active site, amino acids Glu70 and Arg142. Once phosphorylated, the assembly of mtDNA proceeds. Mutations in dGK prevent the phosphorylation of mtDNA and lead to a decrease in mitochondrial function. Two point mutations have been shown to have a deleterious impact on dGK: the R142K mutation is 0.2% active when compared to the wild type, and the E227K mutation is 5.5% active when compared to the wild type. The 3D model designed by the Westosha Central SMART (Students Modeling A Research Topic) Team displays the active site, two specific mutations and additional mutations reported in MDS patients. Screening for MDS is difficult because the condition can be caused by a wide variety of dysfunctional proteins. One such protein is dGK, therefore identifying its structure can hasten an accurate diagnosis. Grant Funding Source: The SMART team program is supported by a grant from NIH‐CTSA.