Fig. 3. Kitchen sink model for metabolic pathway containing toxic metabolite.

Red dots and arrows represent metabolites and enzymatic reactions, respectively. Faucet and drain of kitchen sink are analogies of enzymatic reactions of upstream and downstream metabolic enzymes, respectively; the basin represents the accumulation level of the toxic metabolite. a The level of toxic metabolite candidate is constantly maintained at a nontoxic level as both faucet and drain are opened (active), balancing metabolite production and removal. b Example of toxic metabolite accumulation by targeting the downstream detoxification enzyme. SLC7A11 and SEPHS2 are the faucet and drain for toxic hydrogen selenide in the selenocysteine biosynthesis pathway. Many cancer cells have elevated SLC7A11 expression relative to normal cells and are able to import selenium and produce selenide at an elevated rate. Thus, their faucet is wide open, and disrupting SEPHS2 is akin to blocking the drain, resulting in toxic overflow. c However, in normal cells, disrupting SEPHS2/blocking the drain is not a problem as the faucet is relatively “closed”. In both b and c, building block metabolite cannot be produced, yet only b is toxic, indicating that the toxicity must have come from toxic metabolite accumulation rather than consequences of downstream building block production. d Similarly, in a cancer cell such as in scenario b, the preemptive KO of the upstream transporter SLC7A11 rescues the cells against the toxic effects of SEPHS2 KO, further demonstrating that toxicity in b was due to toxic metabolite accumulation. All diagrams were created with BioRender.com.