Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
The formal mechanism of linear mixed and non-competitive enzyme inhibition implies the binding of inhibitors to both the active site of the free enzyme in competition with the substrate, and to an allosteric site on the enzyme-substrate complex. However, it is evident from a review of the scientific...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2245168 |
| _version_ | 1827123320506548224 |
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| author | Alessandro Pesaresi |
| author_facet | Alessandro Pesaresi |
| author_sort | Alessandro Pesaresi |
| collection | DOAJ |
| description | The formal mechanism of linear mixed and non-competitive enzyme inhibition implies the binding of inhibitors to both the active site of the free enzyme in competition with the substrate, and to an allosteric site on the enzyme-substrate complex. However, it is evident from a review of the scientific literature that the two-site mechanism is frequently mistaken as the actual underlying mechanism of mixed inhibition. In this study, we conducted a comprehensive assessment of the mechanistic relevance of this type of inhibition using a statistical approach. By combining a statistical analysis of the inhibition cases documented in the BRENDA database with a theoretical investigation of inhibition models, we conclude that mixed inhibitors exclusively bind to the active site of enzymes. Hence ruling out any implication of allosteric sites and depriving the two-site model of any mechanistic relevance. |
| first_indexed | 2024-03-09T02:02:30Z |
| format | Article |
| id | doaj.art-2326b8298ced48eda3c7a746c5875d25 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:23:03Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-2326b8298ced48eda3c7a746c5875d252024-09-09T17:23:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2245168Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site modelAlessandro Pesaresi0Istituto di Cristallografia – Consiglio Nazionale delle Ricerche, Trieste, ItalyThe formal mechanism of linear mixed and non-competitive enzyme inhibition implies the binding of inhibitors to both the active site of the free enzyme in competition with the substrate, and to an allosteric site on the enzyme-substrate complex. However, it is evident from a review of the scientific literature that the two-site mechanism is frequently mistaken as the actual underlying mechanism of mixed inhibition. In this study, we conducted a comprehensive assessment of the mechanistic relevance of this type of inhibition using a statistical approach. By combining a statistical analysis of the inhibition cases documented in the BRENDA database with a theoretical investigation of inhibition models, we conclude that mixed inhibitors exclusively bind to the active site of enzymes. Hence ruling out any implication of allosteric sites and depriving the two-site model of any mechanistic relevance.https://www.tandfonline.com/doi/10.1080/14756366.2023.2245168Mixed inhibitionnon-competitive inhibitioninhibition mechanism |
| spellingShingle | Alessandro Pesaresi Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model Journal of Enzyme Inhibition and Medicinal Chemistry Mixed inhibition non-competitive inhibition inhibition mechanism |
| title | Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model |
| title_full | Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model |
| title_fullStr | Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model |
| title_full_unstemmed | Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model |
| title_short | Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model |
| title_sort | mixed and non competitive enzyme inhibition underlying mechanisms and mechanistic irrelevance of the formal two site model |
| topic | Mixed inhibition non-competitive inhibition inhibition mechanism |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2245168 |
| work_keys_str_mv | AT alessandropesaresi mixedandnoncompetitiveenzymeinhibitionunderlyingmechanismsandmechanisticirrelevanceoftheformaltwositemodel |