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Source: Oxford English Dictionary online
Original passage:
Time-dependent inhibition (TDI) is a term which covers any phenomenon resulting in reduction of enzyme activity with incubation time. Although TDI can arise for a number of reasons, including the formation of potent yet reversible-binding metabolites, the most important molecular mechanisms are: Generation of reactive electrophiles (typically from furan, thiophene, acetylene and alkene groups) which react with the P450 to form covalent adducts of the heme or apoprotein, inactivating the enzyme. This is often referred to as “suicide inhibition” or “mechanism based inhibition”. Here, the enzyme activity cannot be recovered by dialysis of the incubate and a 1:1 stoichiometry of the enzyme inactivation and inhibitor-enzyme adduct generation is expected. The formation of tight-binding complexes between the P450 heme and metabolites of particular chemistries, whose off-rate is so low that the enzyme activity is essentially removed from the in vitroincubation system. Alkylamine and benzodioxazole moieties are the principal functional groups involved here. This is often referred to as “quasi-irreversible” inhibition as CYP activity can be recovered by dialysis.
Source: Fowler, S., and Zhang, H. (2008) AAPS J. 10, 410-424.
Satisfactory paraphrasing:
Enzyme activity that decreases with incubation time is known as time-dependent inhibition (TDI). Two major mechanisms help explain why TDI occurs. One is “suicide inhibition” or “mechanism based inhibition” and the other is “quasi-irreversible.” With mechanism based inhibition, reactive electrophiles, usually from furan, thiophene, acetylene and alkene groups, are formed when they react with P450 to form covalent adducts of the heme or apoprotein which irreversibly inactivates the enzyme. Quasi-irreversible inhibition occurs when P450 heme and certain metabolites, usually alkylamine and benzodioxazole moities, form tight-binding complexes with low off-rates, resulting in almost no enzyme activity. In this case, dialysis can restore enzyme activity. (Fowler, Zhang, 2008).
Reference list
Fowler, S., and Zhang, H. (2008) AAPS J. 10, 410-424.
Plagiarized paraphrasing:
Activity that decreases enzyme activity with incubation time is called time-dependent inhibition (TDI). Although TDI can occur for a number of reasons, the principle molecular mechanisms are: Covalent adduct formation from the interaction of reactive electrophiles, usually from furan, thiophene, acetylene and alkene groups, with the heme or apoprotein component of P450 resulting in irreversible enzyme inhibition. Often this is called “suicide inhibition” or “mechanism based inhibition.” The enzyme activity cannot be recovered by dialysis. P450 heme and metabolites of certain chemistries form complexes whose off-rate is so low that the enzyme activity is basically removed from the in vitro incubation system. Alkylamine and benzodioxazole moities are the major functional groups involved here. Often this is called “quasi-irreversible” inhibition because CYP activity can be recovered by dialysis.
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