The Michaelis-Menten equation is used to describe the dynamics of an enzymatic reaction, in which an enzyme interacts with a substrate to generate some product before the enzyme is released. Cells are reliant, however, on many different enzymes for various purposes, including metabolism, in which products are broken down or built up, or signaling that allows cells or proteins to communicate with one another. Recent work reported in the Proceedings of the National Academy of Sciences has suggested that the classic equation is not sufficient to characterize all enzyme dynamics.
"Currently, we describe signaling enzymes with equations developed for metabolic enzymes," study author Magnus Kjærgaard explained. "Metabolic enzymes that make energy for our bodies, for example, need to process many substrates per minute. In contrast, signaling enzymes act as switches, and often only need to convert a single substrate to have an effect. Therefore, the equations developed to describe metabolic enzymes are less relevant for signaling enzymes."
The Michaelis-Menten equation has been used by biochemists for over a hundred years to show how the activity of an enzyme increases when levels of its substrate are increased. But if an enzyme is joined to its substrate, how much is present becomes irrelevant and the speed of the reaction is dependent on a connection instead. Changes in molecular structure are not usually taken into account when studying the rate of enzymatic reactions.
"Normally, the question you are trying to answer is what graph shape describes the enzyme activity. We had a much more fundamental problem," said the first author of the study Mateusz Dyla. "What should we put on the X-axis instead of concentration?"
The researchers created a model in which the link between the enzyme and its substrate could be altered. The length of a flexible connector affected the enzyme's first round of catalysis. The researchers developed an equation that can describe how an enzyme's speed changes depending on the enzyme-substrate connection. The work suggested that these connections have been underappreciated.
The connector between an enzyme and its substrate can influence reactions. Two substrates may each produce very different rates when the enzyme only connects to one at a time.
"It is like the difference between how long it takes me to eat a single hot dog, and how many hotdogs I can eat over a whole week," Magnus explained. "Over the course of a week, I will be limited by how fast I can digest the hot dogs. This is irrelevant to the time it takes to eat the first hot dog. Therefore, the two types of measurements give different results. If you want to understand kinase switches, you have to focus on the first round of catalysis."
This work could impact the development of drugs that target enzymes called kinases. "We hope that one day it will be possible to make drugs that not only target the enzyme, but also target how it is connected to its substrate," added Mateusz.
Sources: AAAS/Eurekalert! via Aarhus University, Proceedings of the National Academy of Sciences
