Figure 4.

Schematic representation of the l-lysine degradation pathway with a summary of the results. Knockout of GCDH in HEK-293 cells leads to increased levels of glutaryl-CoA and its metabolite C5DC. This condition mimics the biochemical state occurring in GA1. A substrate reduction therapy for treatment of GA1 by inhibition of DHTKD1 was evaluated by knocking out DHTKD1 in GCDH KO cells. Knocking out DHTKD1 increased AA and decreased C5DC levels by ~2-fold. Knockout of OGDH in GCDH/DHTKD1 double KO cells further decreased C5DC to control levels. High concentrations of OA (and AA) such as those that occur after DHTKD1 inhibition or KO stimulate OGDHc activity leading to near normal pathway flux.