Suicidality

Herbicidal Inhibition of Enzymes. The Hst of known en2yme inhibitors contains five principal categories group-specific reagents substrate or ground-state analogues, ie, rapidly reversible inhibitors affinity and photo-affinity labels suicide substrate, or inhibitors and transition-state, or reaction-intermediate, analogues, ie, slowly reversible inhibitors (106). 

Suicide substrate and reaction intermediate inhibitors promise the highest degree of specificity and have drawn increased attention (106). 

In order for the cyclooxygenase to function, a source of hydroperoxide (R—O—O—H) appears to be required. The hydroperoxide oxidizes a heme prosthetic group at the peroxidase active site of PGH synthase. This in turn leads to the oxidation of a tyrosine residue producing a tyrosine radical which is apparendy involved in the abstraction of the 13-pro-(5)-hydrogen of AA (25). The cyclooxygenase is inactivated during catalysis by the nonproductive breakdown of an active enzyme intermediate. This suicide inactivation occurs, on average, every 1400 catalytic turnovers. 

Anxiety disorders and insomnia represent relatively common medical problems within the general population. These problems typically recur over a person s lifetime (3,4). Epidemiological studies in the United States indicate that the lifetime prevalence for significant anxiety disorders is about 15%. Anxiety disorders are serious medical problems affecting not only quaUty of life, but additionally may indirecdy result in considerable morbidity owing to association with depression, cardiovascular disease, suicidal behavior, and substance-related disorders. 

Depression is a common psychiatric disorder. The lifetime risk of developing a depressive episode is estimated to be as high as 8—12% for men and 20—26% for women (116). Depression, one of the most widespread of all life-threatening disorders, is almost always a factor in the mote than 30,000 suicides that occur annually in the United States alone (117). 

Aluminide and sUicide cementation coatings such as TaAl on tantalum and MoSi2 on molybdenum oxidize at slow rates and possess some inherent self-repair characteristics. Fine cracks that appear and are common to these coatings can be tolerated because stable, protective oxides form within the cracks and seal them. Thermal cycling, however, accelerates faUure because of thermal expansion mismatch that ultimately dismpts the protective oxide coating. 

Active site directed P-lactam-derived inhibitors have a competitive component of inhibition, but once in the active site they form an acyl en2yme species which follows one or more of the pathways outlined in Figure 1. Compounds that foUow Route C and form a transiendy inhibited en2yme species and are subsequendy hydroly2ed to products have been termed inhibitory substrates or competitive substrates. Inhibitors that give irreversibly inactivated P-lactamase (Route A) are called suicide inactivators or irreversible inhibitors. The term progressive inhibitor has also been used. An excellent review has appeared on inhibitor interactions with P-lactamases (28). 

The efficiency of inactivation by covalent bond formation vs release of the reactive species into solution has been described by its partition ratio. The most efficient inactivators have catalytic partition ratios of 0, in which case each inhibitor molecule leads to inactivation of the enzyme. To this date, many of these inhibitors have been designed, and alternative names like suicide substrate, Trojan Horse inactivator, enzyme induced inactivator, inhibitor, and latent inactivator have been used for this class of inhibitors. A number of comprehensive reviews are available (26—32). 

NH2). The acid crystallises readily when 4g in 50mL H2O is treated with abs EtOH at 4°/ 3hrs, and is collected washed with cold abs EtOH and Et20 and dried in vac. Also recrystallises from aqueous Me2CO, Rp on Si02 TLC plates with n-BuOH-H20-AcOH (4 1 1) is 0.26. The racemate has m 238-240°. [Leukart et al. Helv Chim Acta 59 2181 1976 Eberle and Zeller Helv Chim Acta 68 1880 1985 Jansen et al. Reel Trav Chim Pays-Bas 88 819 7969.] It is a suicide inhibitor of y-cystathionase and other enzymes [Washtier and Abeles Biochemistry 16 2485 7977 Shinozuka et al. Eur J Biochem 124 377 7982]. 

A wide variety of a-tnfluoromethyl a-amino acids are readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allylic alcohols [138, 139] a-Tnfluoromethyl-subsumted a-amino acids show anubactenal and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [140] Furthermore, they are interesting candidates for peptide modification... 

Suicide Substrates —Mechanism-Based Enzyme Inactivators... 

During World War I. Haber was in charge of the German poison gas program. In April of 1915. the Germans used chlorine for the first time on the Western front, causing 5000 fatalities. Haber s wife. Clara, was aghast she pleaded with her husband to forsake poison gas. When he adamantly refused to do so. she committed suicide. 

Formation of block polymers is not limited to hydrocarbon monomers only. For example, living polystyrene initiates polymerization of methyl methacrylate and a block polymer of polystyrene and of polymethyl methacrylate results.34 However, methyl methacrylate represents a class of monomers which may be named a suicide monomer. Its polymerization can be initiated by carbanions or by an electron transfer process, the propagation reaction is rapid but eventually termination takes place. Presumably, the reactive carbanion interacts with the methyl group of the ester according to the following reaction... 

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