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How can biochemical reactions within cells differ from those in test tubes?

Introduction Although the time when a living cell was regarded naively as a 'bag of enzymes' is long past, the extent to which the high internal concentration of macromolecules and the constraints of cellular architecture (see Fig. 1) can influence intracellular biochemical reactions is still not generally appreciated. In this Commentary, I briefly describe three mechanisms by which features of the cellular interior can significantly alter, in a largely nonspecific manner, the equilibria and rates of biochemical reactions relative to the equilibria and rates of the same reactions in dilute solution. The three mechanisms correspond to three different types of interactions between a particular macromolecular reactant (X) and constituents of the local environment (the background). Types of background and background interactions Macromolecular crowding In some intracellular compartments, X may be surrounded by a variety of other soluble macromolecules that cumulatively occupy a significant fraction of the total volume (Fulton, 1982). Since no single macromolecular species need be present at high concentration, such media are referred to as crowded or volume occupied rather than concentrated (Minton and Wilf, 1981). Since macromolecules cannot interpenetrate, the fraction of volume into which a macromolecule can be placed at any instant is much less than the fraction of volume into which a small molecule can be placed (Fig. 2A,B). The total free energy of interaction between X and all of the other molecules in the crowded medium is inversely related to the probability of successful placement of X at a random location within the crowded medium (Lebowitz et al., 1965). Hence the extra work required to transfer X from a dilute to a crowded solution resulting from steric repulsion between X and background molecules depends upon the relative sizes and shapes of X and background species, and increases in a highly nonlinear fashion with increasing size of X and with fractional volume occupancy (Minton, 1998). Macromolecular confinement In eukaryotic cells, much of the fluid phase of cytoplasm exists within interstices between a variety of large fibrous and membranous structures (Knull and Minton, 1996). It has been estimated that between 10% and 100% of the fluid phase of the cytoplasm lies within one macromolecular diameter of the surface of one of these structures (Minton, 1989). By analogy with size exclusion columns, we may generically treat these interstitial elements of fluid volume as 'pores'. When the size of a pore is not much larger than that of …