Enzyme activation inhibitors

Although substrates may enhance or inhibit their own conversion, as noted in Section 10.4.1, other species may also affect enzyme activity. Inhibitors are compounds that decrease observable enzyme activity, and activators increase activity. The combination of an inhibitor or activator with an enzyme may be irreversible, reversible, or partially... 

Many other enzyme-activated inhibitors are being developed.C/d/t... 

A closely related E. coli protein is a 79-kDa multifunctional enzyme that catalyzes four different reactions of fatty acid oxidation (Chapter 17). The amino-terminal region contains the enoyl hydratase activity.32 A quite different enzyme catalyzes dehydration of thioesters of (3-hydroxyacids such as 3-hydroxydecanoyl-acyl carrier protein (see Eq. 21-2) to both form and isomerize enoyl-ACP derivatives during synthesis of unsaturated fatty acids by E. coli. Again, a glutamate side chain is the catalytic base but an imidazole group of histidine has also been implicated.33 This enzyme is inhibited irreversibly by the N-acetylcysteamine thioester of 3-decynoic acids (Eq. 13-8). This was one of the first enzyme-activated inhibitors to be studied.34... 

PLP-dependent enzymes are inhibited by a great variety of enzyme-activated inhibitors that react by several distinctly different chemical mechanisms.11 Here are a few. The naturally occurring gabaculline mimics y-aminobutyrate (Gaba) and inhibits y-aminobutyrate aminotransferase as well as other PLP-dependent enzymes. The inhibitor follows the normal catalytic pathway as far as the ketimine. There, a proton is lost from the inhibitor permitting formation of a stable benzene ring and leaving the inhibitor stuck in the active site ... 

Another enzyme-activated inhibitor is the streptomyces antibiotic D-cycloserine (oxamycin), an antitubercular drug that resembles D-alanine in structure. A potent inhibitor of alanine racemase, it also inhibits die non-PLP, ATP-dependent, D-alanyl-D-alanine synthetase which is needed in the biosynthesis of die peptidoglycan of bacterial cell walls. 

When a 2 -Cl or -F analog of UDP was used in place of the substrate an irreversible side reaction occurred by which Cl or F, inorganic pyrophosphate, and uracil were released 349 When one of these enzyme-activated inhibitors containing 3H in the 3 position was tested, the tritium was shifted to the 2 position with loss of Cl and formation of a reactive 3 -carbonyl compound (Eq. 16-24) that can undergo P elimination at each end to give an unsaturated ketone which inactivates the enzyme. This suggested that the Fe-tyrosyl radical abstracts an electron (through a... 

Enzyme-activated inhibitors 682, 864 Enzyme assay, coupled 768 Enzyme-inhibitor complex 472 Enzyme regulation 535 - 537, 539 - 553,571-581... 

Males with deficiency of the 5a-reductase isoenzyme do not develop acne, male pattern baldness, or enlarged prostates.274 The last fact was some of the impetus for development of the steroid 5a-reductase inhibitor finasteride, which is widely used to treat benign prostate enlargement 274/277/278 It is an enzyme-activated inhibitor in which the NADH reduces the C= C bond in the A ring, which is not in the same position as in the substrate. The resulting anion cannot become protonated but instead adds to the NAD+ as shown in Eq. 22-15. 

The C-17 acetylenic progesterone antagonist (nore-thyndrone) is also an enzyme activated inhibitor of the aromatase. 

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

Frerman FE, Miziorko HM, Beckmann JD. Enzyme-activated inhibitors, alternate substrates, and a dead endinhibitor of the general Acyl-CoA Dehydrogenase. J. Biol. Chem. 1980 255 1192-1198. 

PLP-dependent enzymes are inhibited by a great variety of enzyme-activated inhibitors that react by several distinctly different chemical mechanisms. ... 

Johnston, J.O. (1987). Biological characterization of 10-(2-propynyl)estr-4-ene-3,l7-dione (MDL 18,962), an enzyme-activated inhibitor of aromatase. Steroids 50, 105-120. 

Johnston, J.O., C.L. Wright, and G.W. Holbert (1995). Enzyme-activated inhibitors of steroidal hydroxylases. J. Steroid Biochem. Mol. Biol. 52, 17-34. 

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