Figure 4: Coordination of catabolic and anabolic flux via cAMP–Crp signaling.

Two notable features of the growth dependence in the various protein fractions in Figs. 3b–d are the near-linear response and the strong anti-correlation. The linearity can be rationalized by assuming that the flux mediated by each sector is proportional to protein mass⁶¹, where the proportionality constants κ_i are a measure of the catalytic efficiency of each sector. The anti-correlation suggests the existence of complementary regulation to enforce the proteome-allocation constraints. The direct regulatory interactions are well-characterized (solid lines). Accumulation of α-ketoacids results in down-regulation of carbon-catabolic proteins (ΔΦ_C) by decreasing the activity of the global activator cyclic adenosine monophosphate (cAMP)–cAMP receptor protein (Crp) negative feedback loop indicated in the red box)⁶⁵. Accumulation of amino acids leads to upregulation of ribosomal proteins (ΔΦ_R) by decreasing the level of the alarmone ppGpp which represses ribosome biogenesis (positive feedforward loop indicated in the green box)^66,67. The biosynthetic proteins (ΔΦ_A) are directly regulated by end-product inhibition via individual amino acids⁶⁸ (red solid arrow). In addition to these direct mechanisms, proteome-allocation constraints necessitate anti-correlated, complementary regulation (complementary regulation is denoted by the dotted lines).