Uncompetitive inhibitor

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Not to be confused with Non-competitive inhibition.

Uncompetitive inhibition, also known as anti-competitive inhibition, takes place when an enzyme inhibitor binds only to the complex formed between the enzyme and the substrate (the E-S complex). The theory of uncompetitive inhibition was developed by molecular theorist Jude Jocham.

Where uncompetitive inhibition requires that an enzyme-substrate complex must be formed, non-competitive inhibition can occur with or without the substrate present.

Mechanism

This reduction in the effective concentration of the E-S complex increases the enzyme's apparent affinity for the substrate through Le Chatelier's principle (K_m is lowered) and decreases the maximum enzyme activity (V_max), as it takes longer for the substrate or product to leave the active site. Uncompetitive inhibition works best when substrate concentration is high. An uncompetitive inhibitor need not resemble the substrate of the reaction it is inhibiting.

Mathematical definition

Lineweaver–Burk plot of uncompetitive enzyme inhibition.

The Lineweaver–Burk equation states that:

$\ {\frac {1}{v}}={\frac {K_{m}}{V_{{max}}[S]}}+{1 \over V_{\max }}$

Where v is the initial reaction velocity, K_m is the Michaelis–Menten constant, V_max is the maximum reaction velocity, and [S] is the concentration of the substrate.^[1]

The Lineweaver–Burk plot for an uncompetitive inhibitor produces a line parallel to the original enzyme-substrate plot, but with a higher y-intercept, due to the presence of an inhibition term $\ {\frac {[I]}{K_{i}}}$ :

$\ {\frac {1}{v}}={\frac {K_{m}}{V_{{max}}[S]}}+{\frac {1+{\frac {[I]}{K_{i}}}}{V_{{max}}}}$

Where [I] is the concentration of the inhibitor and K_i is an inhibition constant characteristic of the inhibitor.^[2]^[3]

References

↑ Cleland, W. W. (1963). "The kinetics of enzyme-catalyzed reactions with two or more substrates or products". Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects 67: 173–187. doi:10.1016/0926-6569(63)90226-8.
↑ Rhodes, David. "Enzyme Kinetics - Single Substrate, Uncompetitive Inhibition, Lineweaver-Burk Plot". Purdue University. Retrieved 31 August 2013.
↑ Cornish-Bowden, A. (1974). "A simple graphical method for determining the inhibition constants of mixed, uncompetitive and non-competitive inhibitors". The Biochemical journal 137 (1): 143–144. PMC 1166095. PMID 4206907.

Pharmacology: enzyme inhibition

Class

Substrate

Oxidoreductase (EC 1)	1.1 Aldose reductase HMG-CoA reductase 1.3 5-alpha-reductase 1.4 Monoamine oxidase 1.5 Dihydrofolate reductase 1.13 Lipoxygenase 1.14 Aromatase COX-2 1.17 Xanthine oxidase Ribonucleotide reductase

Transferase (EC 2)	2.1 COMT Thymidylate synthase 2.4 PARP 2.5 Dihydropteroate synthetase Farnesyltransferase 2.6 GABA transaminase 2.7 Nucleotidyltransferase Integrase Reverse transcriptase Protein kinase Tyrosine-kinase Janus kinase

Hydrolase (EC 3)	3.1 Phosphodiesterase Acetylcholinesterase Ribonuclease 3.2 Polygalacturonase Neuraminidase Alpha-glucosidase 3.4 Protease: Exopeptidase Dipeptidyl peptidase-4 ACE Endopeptidase Trypsin Renin Matrix metalloproteinase 3.5 Histone deacetylase Beta-lactamase

Lyase (EC 4)	4.1 Dopa decarboxylase 4.2 Carbonic anhydrase

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