Blocked reactions have different SMILEY solutions depending upon their metabolic origin and were validated with experimental evidence. Blocked reactions were resolved by connecting their corresponding blocked metabolite back into RECON 1. A shows the number of blocked reactions resolved with each solution category and, directly below in B, the metabolic pathway distribution of the blocked reactions having that particular SMILEY solution. Some blocked reactions, such as those involved in amino acid metabolism, are easily bypassed using functionalities already described in the KEGG database. Others, such as those involved in glycan biosynthesis, can only be solved by transporting their causative dead-end metabolite out of the system. C) Proposed solutions were validated by comparing category I solutions to experimentally reported enzyme directionalities. Similarly, we investigated whether category II solutions were gene associated in humans and whether the dead-end metabolites, to which the category III solutions applied, have been detected in human biofluids.