THE MECHANISM OF ENZYME-INHIBITOR-SUBSTRATE REACTIONS
Open accessAbstract
The mechanism of enzyme-inhibitor-substrate reactions has been analyzed from a theoretical standpoint and illustrated by data from the system cholinesterase-physostigmine-acetylcholine. This treatment is by no means limited to a single system but should be generally applicable to others of similar type. Competitive enzyme-inhibitor-substrate systems show the same characteristic "zones of behavior" already demonstrated for non-competitive systems by Straus and Goldstein. These zones, three in number, determine the mathematical function which relates activity of an enzyme to concentration of an added substrate or inhibitor or both. The effects of suboptimal substrate concentration in such systems have been considered, and the errors arising from various common simplifications of the descriptive equations have been pointed out. The zone behavior phenomenon has been shown to be useful in determining the number of molecules of substrate or inhibitor combining reversibly with a single enzyme center. The kinetics of competitive inhibition, dilution effect, combination of inhibitor or substrate with enzyme, and destruction of inhibitor or substrate by enzyme have been analyzed and experimentally verified, and absolute velocity constants have been determined. Theoretical conclusions have been discussed from the standpoint of their physiological significance. Specifically, it has been shown that: 1. The inhibition of cholinesterase by physostigmine is competitive. A single molecule of physostigmine or acetylcholine combines with one center of cholinesterase-n = 1; and the mechanism n = 2 has been. excluded. Numerical values of the constants for this system are as follows: K(I) = 3.11 x 10(-8)k(1) (combination) = 8.3 x 10(5)k(2) (dissociation) = 0.026 K(S) = 1.25 x 10(-3)k(3) (combination) = 260 k(4) (dissociation) = 0.32 2. No definitive value can be assigned to E, the molar concentration of enzyme centers, but in 4.54 per cent dog serum, E < 1.8 x 10(-8) (E(I)' < 0.58). The system therefore operates in (or nearly in) zone A at this concentration. 3. Competitive displacement of inhibitor by substrate and vice versa introduces considerable error in the usual 20 minute determination of the activity of an inhibited enzyme, unless properly corrected for. 4. Dissociation of the enzyme-inhibitor complex on dilution proceeds moderately slowly so that the full corrections for dilution cannot be applied unless time has been allowed for full dissociation. 5. Combination of physostigmine with cholinesterase is slow at all but large concentrations of inhibitor. 6. The destruction of physostigmine or acetylcholine by cholinesterase follows the predicted curve; k(D) for the destruction of physostigmine is found to be > 0.00182; k(D) for acetylcholine destruction is > 3500. There is no reason to assume inhibition of destruction by excess substrate or inhibitor. 7. The common assumption that enzymatic activity follows (or nearly follows) a monomolecular course is true only under limited conditions, which have been here defined. It is not valid, as a rule, for the enzymatic destruction of an inhibitor (e.g., physostigmine) and its application to such a case may lead to erroneous conclusions about the reaction mechanism.
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Alpha-terpinyl acetate competes with the substrate (AChI) for binding to AChE.
“Here, the alpha-terpinyl acetate competes with the substrate (AChI) for binding to the enzyme (Goldstein, 1944).”
From Alpha-terpinyl acetate: A natural monoterpenoid from Elettaria cardamomum as multi-target directed ligand in Alzheimer’s disease (2020) · cites this paper as Goldstein, 1944
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- Authors
- Goldstein, A.
- Affiliations
- From the Department of Pharmacology, The Harvard Medical School, Boston
- Venue
- Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 1944-07-20
- Volume
- 27
- Issue
- 6
- Pages
- 529-580
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC2238027
- OpenAlex
- W2136126162
- Cited by
- 181
- References
- 7
- Citations by year
- 2026: 3 · 2025: 4 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 4 · 2015: 2 · 2013: 2 · 2012: 2
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of General Physiology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- competitive inhibition, enzyme kinetics, cholinesterase, physostigmine, acetylcholine, enzyme-inhibitor complex, dilution effect, enzyme activity assay, velocity constant
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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