Uncompetitive inhibition
It is sometimes explained by supposing that the inhibitor can bind to the enzyme-substrate complex but not to the free enzyme.
This type of mechanism is rather rare,[2] and in practice uncompetitive inhibition is mainly encountered as a limiting case of inhibition in two-substrate reactions in which one substrate concentration is varied and the other is held constant at a saturating level.
This has exactly the form of the Michaelis–Menten equation, as may be seen by writing it in terms of apparent kinetic constants: in which
This is apparent when viewing a Lineweaver-Burk plot of uncompetitive enzyme inhibition: the ratio between V and Km remains the same with or without an inhibitor present.
This may be seen in any of the common ways of plotting Michaelis–Menten data, such as the Lineweaver–Burk plot, for which for uncompetitive inhibition produces a line parallel to the original enzyme-substrate plot, but with a higher intercept on the ordinate:[5][6] The unique traits of uncompetitive inhibition lead to a variety of implications for the inhibition's effects within biological and biochemical systems.
Uncompetitive inhibition is present within biological systems in a number of ways.
In fact, it often becomes clear that the traits of inhibition specific to uncompetitive inhibitors, such as their tendency to act at their best at high concentrations of substrate, are essential to some important bodily functions operating properly.
It has also been found that a number of the genes that code for human alkaline phosphatases are inhibited uncompetitively by amino acids such as leucine and phenylalanine.
[9] Additionally, uncompetitive inhibition works alongside transformation-related protein 53 to help repress the activity of cancer cells and prevent tumorigenesis in certain forms of the illness, as it inhibits glucose-6-phosphate dehydrogenase, an enzyme of the pentose phosphate pathway).
Although uncompetitive inhibition is present in various diseases within biological systems, it does not necessarily only relate to pathologies.
For example, active sites capable of uncompetitive inhibition appear to be present in membranes, as removing lipids from cell membranes and making active sites more accessible through conformational changes has been shown to invoke elements resembling the effects of uncompetitive inhibition (i.e. both
[11] This presence of uncompetitive enzymes in membranes has also been supported in a number of other studies.
For example, in studies of the protein ADP ribosylation factor, which is involved in regulating membrane activity, it was found that brefeldin A, a lactone antiviral trapped one of the protein's intermediates via uncompetitive inhibition.
In fact, brefeldin A was found to relate to the activity of the Golgi apparatus and its role in regulating movement across the cell membrane.
It is part of the mechanism by which N-methyl-D-aspartate glutamate receptors are inhibited in the brain, for example.
Specifically, this type of inhibition impacts the granule cells that make up a layer of the cerebellum.
These cells have the receptors mentioned, and their activity typically increases as ethanol is consumed.
Various uncompetitive blockers act as antagonists at the receptors and modify the process, with one example being the inhibitor memantine.
Since uncompetitive inhibitors block high concentrations of substrates very efficiently, their traits alongside the innate characteristics of the receptors themselves lead to very effective blocking of N-methyl-D-aspartate glutamate channels when they are excessively open due to massive amounts of agonists.
