Total cell protein concentration as an evolutionary constraint on the metabolic control distribution in cells.

Cell protein occupies 15-35% of cell volume. This level is argued to be the maximum compatible with cell function. Because of this constraint, selection pressure during evolution is likely to have maximized pathway fluxes for minimum total protein level. Pathways optimized in this way are shown to have the following characteristics: (1) the "simple" flux control coefficients of all enzymes are equal, (2) the normal flux control coefficients depend on the relative kinetic constants of the enzymes, such that enzymes with low specific activity are present at relatively high levels and have high flux control, (3) the normal flux control coefficients are proportional to enzyme levels. A single rate limiting step located at the first step in a pathway is likely to be inefficient in terms of protein levels, and the major metabolic pathways are therefore expected to have control distributed throughout the pathway. This has important implications for metabolic control.