INDUCED SUBSTRATE INHIBITION

A term first introduced by Cleland to indicate that for ordered substrate binding mechanisms, addition of an inhibitor mimicking the first substrate may still permit binding of the second substrate. Hence, as long as the addition of the first substrate is not of the rapid equilibrium type, the presence of the inhibitor will induce substrate inhibition by the second substrate. An example of induced substrate inhibition is provided in the thymi-dylate synthase reaction where the second substrate methylene tetrahydrofolate becomes an inhibitor, but only in the presence of the inhibitor bromodeoxyuridine 5 -monophosphate. 

Few cases of induced substrate inhibition have been reported, partly because few mechanisms are truly ordered (the presence of B must keep I from dissociating in order to see the effect), and partly because the inhibitor may fail to induce the conformation change that permits addition of the second substrate. Bromodeoxyuridine 5 -monophosphate (BrdUMP) does induce substrate inhibi-... 

The negative feedback in glycolysis, induced by substrate inhibition of lumped PFK HK reaction, thus fulfills an important functional role but concomitantly opens the possibility of sustained oscillations. In particular, because glycolytic oscillations have no obvious physiological role and are only observed under rather specific experimental conditions, it is plausible that they are merely an unavoidable side effect of regulatory interactions that are optimized for other purposes. 

ISOTOPE TRAPPING STICKY SUBSTRATES Substrate-induced conformational change, INDUCED FIT MODEL SUBSTRATE INHIBITION ABORTIVE COMPLEX FORMATION LACTATE DEHYDROGENASE LEE-WILSON EQUATION... 

That the type II deiodinase represents a common enzyme for the ORD of T4 and rT3 is supported by their mutual competitive inhibition with corresponding Km and /C( values [72-74,82,83]. T3, which is not a substrate for the type II deiodinase, also does not inhibit the deiodination of T4 and rT3 in vitro. In addition to competitive substrate inhibition, other mechanisms exist for the regulation of type II enzyme activity by thyroid hormone in vivo. Experimental hypothyroidism in rats induces a large increase in type II activity in the CNS [71,82], pituitary [72,83,87] and BAT [73] at least in part by prolongation of the half-life of the enzyme [88]. Treatment of hypothyroid rats with T3 produces a rapid fall in type II deiodinase in CNS and pituitary which appears to be due to an accelerated inactivation of the enzyme [88]. 

Reduced serum folate concentrations have been demonstrated in patients with homocystinuria taking pyridoxine. The mechanism of this effect may involve removal of substrate inhibition of the enzyme, A5-methyltetrahydrofolate homocysteine methyltransferase, due to pyridoxine-induced reduction of the substrate, homocysteine (27). 

Comutagenic Action of Harman and Norharman When the reconstituted MFO system, which contained 3-MC induced cytochrome P-448, was used to study the effects of Norharman and Harman on the hydroxylation of Benzo(a)pyrene, they both showed an enhancement effect under the optimal enzymatic conditions. Norharman, however, showed a larger activity increase in Benzo(a)pyrene hydroxylation than Harman(Figure 5). It ascertains that the inhibitory effects of these carbolines on mutagenicity are not dependent on cytochrome P-448 in the sense of simple substrate inhibition. 

The membrane transfer of drugs that are substrates for a particular transporter will change when that transporter is subject to another drug that induces or inhibits its activity. For example, the action of P-glycoprotein can be inhibited by quinidine, verapamil, erythromycin, clarithromycin and the statins. Inhibition of this transporter can interfere with its ability to keep loperamide out of the brain, resulting in opioid effects in the central nervous system. Similarly,... 

The compound sparteine is a substrate of the drug-metabolizing isoenzyme CYP2D6 (Casarett et al. 2001 Zanger et al. 2004). Serum levels of sparteine may be altered by drugs or supplements that induce or inhibit CYP2D6. 

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