Automated gap filling of RECON 1 using the SMILEY algorithm. A) A simplified metabolic network. Reactions that are able to carry flux are shown in blue. Reactions unable to carry flux (red) are blocked and are caused by a root no-consumption metabolite (a in 1) and a root no-production metabolite (b in 2). Dead end metabolites can cause multiple blocked reactions refferred to as a cascade of blocked reactions. Reactions 2 and 3 occur in a blocked cascade caused by b. Note that c is a blocked intermediate but not a root-no production metabolite. B) The SMILEY algorithm identified reactions in the metabolic reaction matrix S (e.g. RECON 1) that were unable to carry flux under steady state conditions and then computed resolving reactions found in either U or X that needed to be added to S in order to restore flux through the blocked reaction. C) SMILEY solutions were categorised based on the resolving reactions required to restore flux. A category I reversal solution, if added to the network shown in A, only restores flux through reaction 1. The category II solution, addition of a novel metabolic reaction, restores flux through reactions 1, 2 and 3. The category III transport solution restores flux through reactions 2 and 3 only. SMILEY can suggest multiple solutions for a blocked reaction.