(A) Simplified schematic of the model (see Figure 5—figure supplement 1 for details). Different shades of gray in the background highlight four modules as indicated (see text). Light blue circles represent metabolites. Reactions are shown as lines with dark gray boxes. The enzymes catalyzing reactions whose control coefficients with respect to the flux through the module are positive are named; other enzyme names are ommitted for clarity (see Table 5 and Table 6 for abbreviations). Three reactions, catalyzed by PGI, PFK, PGDH, for which the epistasis coefficients are shown in panel B are highlighted in dark blue, red, and orange, respectively. (B) Epistasis coefficients for flux through each module between mutations perturbing the respective reactions, computed at steady state (see text and Materials and methods for details). Reactions catalyzed by PGI and PGDH are strictly parallel (path g6p-f6p-fdp-gap contains only PGI, path g6p-6pg-ribu5p-gap contains only PGDH and there is no simple path in UGPP between g6p and gap that contains both PGI and PGDH). Reactions catalyzed by PGI and PFK are serial-parallel (path g6p-f6p-fdp-gap contains both reactions, path g6p-f6p-gap contains only PGI, path g6p-6pg-ribu5p-f6p-fdp-gap contains only PFK). Reactions catalyzed by PFK and PGDH are also serial-parallel (path g6p-6pg-ribu5p-f6p-fdp-gap contains both reactions, path g6p-f6p-fdp-gap contains only PFK, path g6p-6pg-ribu5p-gap contains only PGDH).