Rate-limiting step (biochemistry)

In biochemistry, a rate-limiting step is a reaction step that controls the rate of a series of biochemical reactions.^[1][2] The statement is, however, a misunderstanding of how a sequence of enzyme-catalyzed reaction steps operate. Rather than a single step controlling the rate, it has been discovered that multiple steps control the rate. Moreover, each controlling step controls the rate to varying degrees.

Blackman (1905)^[3] stated as an axiom: "when a process is conditioned as to its rapidity by a number of separate factors, the rate of the process is limited by the pace of the slowest factor." This implies that it should be possible, by studying the behavior of a complicated system such as a metabolic pathway, to characterize a single factor or reaction (namely the slowest), which plays the role of a master or rate-limiting step. In other words, the study of flux control can be simplified to the study of a single enzyme since, by definition, there can only be one 'rate-limiting' step. Since its conception, the 'rate-limiting' step has played a significant role in suggesting how metabolic pathways are controlled. Unfortunately, the notion of a 'rate-limiting' step is erroneous, at least under steady-state conditions. Modern biochemistry textbooks have begun to play down the concept. For example, the seventh edition of Lehninger Principles of Biochemistry^[4] explicitly states: "It has now become clear that, in most pathways, the control of flux is distributed among several enzymes, and the extent to which each contributes to the control varies with metabolic circumstances". However, the concept is still incorrectly used in research articles.^[5][6]