Inhibition of enzyme competitive

Considerable DNase but no RNase activity results if Ca-+ is replaced by Sr-+, while Fe-+ and Cu J+ cause minimal activation (3, 40). A number of heavy metal cations inhibit DNase and RNase activities competitively with Ca-+ Hg-+, Zn2+, and Cd-+ are the most potent of these (3). Studies with synthetic substrates, to be discussed below, indicate that Ca2+ is not only required for the proper binding of substrates but also that it is required for the subsequent independent hydrolytic process. Although several divalent cations can substitute for Ca2t in the binding function, as evidenced by their competitive inhibition of enzymic activity (3) and their ability to promote nucleotide binding (62), the catalytic role of Ca2+ appears to be unique. 

Besides the aforementioned competitive stq>pression of self-coupling by cross-coupling, lignin may introduce additional siq>pression effects on NEP-foimation by competitive inhibition of enzyme catalytic efficiency. Lignin contains phenolic fimctionalities in its monomeric stmcture, and these may serve as additional substrates for the HRP enzyme despite some steric huubaiKes. Such effects would lead to apparent reduction of enzyme catalytic efficiency, particularly at high lignin concentrations. 

Competitive Inhibition of enzymes. In the case of competitive inhibition, the structural analogs compete with the natural substrates for the active site of enzymes. The enzymes of nucleic acid, and protein, synthesis can also be inhibited in this way. Thus, the enzyme thymidilate synthetase is competitively inhibited by 5-fiuorodeoxyuridine, a derivative of 5-fluorouracil (Fig. 14). Thymidilate synthetase supplies d-thymidine-5 -phosphate (-thymidilate), a substance which is important to the synthesis of DNA. Inhibition of this enzyme thus brings DNA synthesis to a stop and, with it, all further development. We will discuss DNA synthesis and also thymidilate synthetase in more detail later (p. 165). 

The first member of this class, acarbose, was introduced in the early 1990s. a-Glucosidase inhibitors slow the intestinal process of carbohydrate digestion by competitive inhibition of the activity of a-glucosidase enzymes located in the brush border of the enterocytes... 

Figure 10.4 Lineweaver-Burk plot illustrating comparison of competitive inhibition with no inhibition of enzyme activity...

Reversible, non-competitive inhibition of polymerase is also afforded by a series of N-benzoyl pyrrolidines. Substitution on the benzoyl moiety with a para-trifluoromethyl group is optimal in this series. Bulky, hydrophobic groups at the 2-position of the pyrrolidine ring increase activity, and the 5-position tolerates a wide range of substituents, indicative of a solvent exposed portion of the inhibitor. Compound (+)-38, containing a 2-thienyl moiety at the 5-position, has an IC50 of 190 nM in the enzyme assay while its enantiomer is almost 100-fold less active [83]. 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

Dapsone, which was first proposed in 1941, possesses both bactericidal as weU as bacteriostatic activity with respect to Mycobacterium leprae and Mycobacterium tuberculosis. It is used to treat patients with herpetiform dermatitis. It is believed that the mechanism of its action consists of competitive inhibition of the enzyme dihydroprotease synthetase, which blocks synthesis of folic acid in microorganisms, allowing it to also be viewed as an analog of p-aminobenzoic acid. Synonyms of this drug are avosulfon, croysulfon and others. 

A) Drugs that competitively inhibit CYP enzymes cause a decrease in concentrations of the object (original) drug. 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

Mechanism of Action A fixed-combination carbapenem. Imipenem penetrates the bacterial cell membrane and binds to penicillin-binding proteins, inhibiting cell wall synthesis. Cilastatin competitively inhibits the enzyme dehydropeptidase, preventing renal metabolism of imipenem. Therapeutic Effect Produces bacterial cell death. Pharmacokinetics Readily absorbed after IM administration. Protein binding 13%-21%. Widely distributed. Metabolized in the kidneys. Primarilyexcreted in urine. Removed by hemodialysis. Half-life 1 hr (increased in impaired renal function). 

The competitive inhibition of aldolase by a number of structural analogs of D-ftuctose 1,6-diphosphate has been investigated.120 Among these analogs were 1,4-anhydro-DL-ribitol 5-phosphate, 1,4-anhydro-DL-xylitol 5-phosphate, 1,4-anhydro-D-arabinitol 5-phosphate, 2,5-anhydro-D-mannitol 1,6-diphosphate, and 2,5-anhydro-D-glucitol 1,6-diphosphate. Their respective, enzyme-inhibitor,... 

When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5 -AMP by several cyclic nucleotide phosphodiesterases (PDE Figure 2-13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20). 

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49-4). Each requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1. 

A. Effect of a competitive inhibitor on the reaction velocity (v0) versus substrate [S] plot. B. Lineweaver-Burke plot of competitive inhibition of an enzyme. 

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