![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Molecular Pharmacology, Vol 10, 235-247, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics
1 Department of Pharmacology and Experimental Therapeutics, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 212O5, and Laboratory of Pharmacology, Sloan-Kettering Institute for
Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
The relationship between the inhibition constant (Ki) and fractional inhibition (in particular I50) in classical steady-state enzyme kinetics has been analyzed. The analysis covers enzyme reactions with different numbers of reactants, different reaction mechanisms, and different types and mechanisms of inhibition. The assumptions are made that the product concentrations are very low and that the products have much lower affinities for the enzyme than those of the substrates. The following generalized conclusions are drawn. (a) Fractional velocity (fv) and fractional inhibition (fi) in the presence of an inhibitor (I) can be expressed by fv = 1/[1 + (I/Ki)(Ex/Et)] and fi = 1/[1 + (Ki/I)(Et/Ex)], respectively, where Et is the total amount of enzyme and Ex is the amount of the enzyme species with which the inhibitor may combine. (b) In a multisubstrate reaction, if all the substrates with which the inhibitor does not compete are at saturating concentrations, the relationship between Ki and I50 is the same as for a one-substrate reaction. (c) Inhibition of either the competitive, noncompetitive, or uncompetitive type produces a generalized relationship, Ki/I50 = Ex/Et. This relationship indicates that Ki will never be greater than I50, and that the ratio of Ki and I50 provides a simple experimental method for determination of the availability of the enzyme species for inhibitor binding on the distribution of enzyme forms in an enzyme reaction. (d) In partial noncompetitive inhibition, Kii I50 > Ki, or Ki > I50 > Kii, depending upon whether the crossover point in the Lineweaver-Burk plot is above or below the horizontal axis (where Kii and Ki[unknown] are the Ki values obtained from the intercept and slope, respectively); noncompetitive inhibition, Ki is always equal to I5O. Examples are cited of one-substrate reactions indicating that competitive, noncompetitive, or uncompetitive inhibition can be illustrated or detected by novel graphical methods different from those currently available.
Note:
ACKNOWLEDGMENTS
I am grateful to Professor Paul Talalay for
valuable suggestions and advice during the course
of these studies. I would like to thank Miss Julia
T. Hawkins for reading and checking the manuscript, and Dr. Daniel M. Byrd, III, for valuable
comments on the manuscript.
This article has been cited by other articles:
|
|
 |
|
  G. B. Lesinski, E. T. Raig, K. Guenterberg, L. Brown, M. R. Go, N. N. Shah, A. Lewis, M. Quimper, E. Hade, G. Young, et al. IFN-{alpha} and Bortezomib Overcome Bcl-2 and Mcl-1 Overexpression in Melanoma Cells by Stimulating the Extrinsic Pathway of Apoptosis Cancer Res., October 15, 2008; 68(20): 8351 - 8360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Bradshaw-Pierce, C. A. Steinhauer, D. Raben, and D. L. Gustafson Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma Mol. Cancer Ther., September 1, 2008; 7(9): 3006 - 3017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kloda and C. Czajkowski Agonist-, Antagonist-, and Benzodiazepine-Induced Structural Changes in the {alpha}1 Met113-Leu132 Region of the GABAA Receptor Mol. Pharmacol., February 1, 2007; 71(2): 483 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Sancar, S. S. Ericksen, A. M. Kucken, J. A. Teissere, and C. Czajkowski Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors Mol. Pharmacol., January 1, 2007; 71(1): 38 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Blount, A. Beasley, R. Zoraghi, K. R. Sekhar, E. P. Bessay, S. H. Francis, and J. D. Corbin Binding of Tritiated Sildenafil, Tadalafil, or Vardenafil to the Phosphodiesterase-5 Catalytic Site Displays Potency, Specificity, Heterogeneity, and cGMP Stimulation Mol. Pharmacol., July 1, 2004; 66(1): 144 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Toulokhonova, W. J. Metzler, M. R. Witmer, R. A. Copeland, and J. Marcinkeviciene Kinetic Studies on beta -Site Amyloid Precursor Protein-cleaving Enzyme (BACE). CONFIRMATION OF AN ISO-MECHANISM J. Biol. Chem., February 7, 2003; 278(7): 4582 - 4589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Kucken, J. A. Teissere, J. Seffinga-Clark, D. A. Wagner, and C. Czajkowski Structural Requirements for Imidazobenzodiazepine Binding to GABAA Receptors Mol. Pharmacol., February 1, 2003; 63(2): 289 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-C. Chou, A. Nadas, and S. Zolla-Pazner Synergy Determination Issues J. Virol., September 11, 2002; 76(20): 10577 - 10578. [Full Text] [PDF]
|
|
|
|
|
|
J. Marcinkeviciene, L. M. Kopcho, T. Yang, R. A. Copeland, B. M. Glass, A. P. Combs, N. Falahatpisheh, and L. Thompson Novel Inhibition of Porcine Pepsin by a Substituted Piperidine. PREFERENCE FOR ONE OF THE ENZYME CONFORMERS J. Biol. Chem., August 2, 2002; 277(32): 28677 - 28682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Holden and C. Czajkowski Different Residues in the GABAA Receptor alpha 1T60-alpha 1K70 Region Mediate GABA and SR-95531 Actions J. Biol. Chem., May 17, 2002; 277(21): 18785 - 18792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Pan, J. Xu, L. Mahurter, E. Bolan, M. Xu, and G. W. Pasternak Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene PNAS, November 20, 2001; 98(24): 14084 - 14089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Wagner and C. Czajkowski Structure and Dynamics of the GABA Binding Pocket: A Narrowing Cleft that Constricts during Activation J. Neurosci., January 1, 2001; 21(1): 67 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Kucken, D. A. Wagner, P. R. Ward, J. A. Teissére, A. J. Boileau, and C. Czajkowski Identification of Benzodiazepine Binding Site Residues in the gamma 2 Subunit of the gamma -Aminobutyric AcidA Receptor Mol. Pharmacol., May 1, 2000; 57(5): 932 - 939. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Boileau, A. R. Evers, A. F. Davis, and C. Czajkowski Mapping the Agonist Binding Site of the GABAA Receptor: Evidence for a beta -Strand J. Neurosci., June 15, 1999; 19(12): 4847 - 4854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. E. Goldberg, G. C. Rossi, S. R. Letchworth, J. P. Mathis, J. Ryan-Moro, L. Leventhal, W. Su, D. Emmel, E. A. Bolan, and G. W. Pasternak Pharmacological characterization of Endomorphin-1 and Endomorphin-2 in Mouse Brain J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 1007 - 1013. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Boileau, A. M. Kucken, A. R. Evers, and C. Czajkowski Molecular Dissection of Benzodiazepine Binding and Allosteric Coupling Using Chimeric gamma -Aminobutyric AcidA Receptor Subunits Mol. Pharmacol., February 1, 1998; 53(2): 295 - 303. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Boileau, J. G. Newell, and C. Czajkowski GABAA Receptor beta 2 Tyr97 and Leu99 Line the GABA-binding Site. INSIGHTS INTO MECHANISMS OF AGONIST AND ANTAGONIST ACTIONS J. Biol. Chem., January 18, 2002; 277(4): 2931 - 2937. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
