Suicide inactivators

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. 

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). 

Bartels I, H-J Knackmuss, W Reineke (1984) Suicide inactivation of catechol 2,3-dioxygenase from Pseudomonas putida mt-2 by 3-halocatechols. Appl Environ Microbiol 47 500-505. 

Alston TA, L Mela, HJ Bright (1977) 3-Nitropropionate, the toxic substance of Indigofera, is a suicide inactivator of succinate dehydrogenase. Proc Natl Acad USA 14 3767-3771. 

Mor, A. Reboud-Ravaux, M. Mazaleyrat, J.-P. Wakselman, M. Susceptibility of plasminogen activators to suicide inactivation. Thrombosis Res. Suppl VIII 1988, 35-44. 

Arno, M.B., Acosta, M., Del Rio, J.A., Varon, R., and Garcfa-Canovas, R, Akinetic study on the suicide inactivation of peroxidase by hydrogen peroxide, Biochim. Biophys. Acta, 1041, 43-47, 1990. 

However, an important problem arises during the peroxidative removal of phenols from aqueous solutions PX is inactivated by free radicals, as well as by oligomeric and polymeric products formed in the reaction, which attach themselves to the enzyme (Nazari and others 2007). This suicide peroxide inactivation has been shown to reduce the sensitivity and efficiency of PX. Several techniques have been introduced to reduce the extent of suicide inactivation and to improve the lifetime of the active enzyme, such as immobilization. Moreover, Nazari and others (2007) reported a mechanism to prevent and control the suicide peroxide inactivation of horseradish PX by means of the activation and stabilization effects of Ni2+ ion, which was found to be useful in processes such as phenol removal and peroxidative conversion of reducing substrates, in which a high concentration of hydrogen peroxide may lead to irreversible enzyme inactivation. 

T. A., Eisenthal, R., Harrison, R., Suicide inactivation of xanthine oxidoreductase during reduction of inorganic nitrite to nitric oxide. Biochem. J. 358 (2001), p. 325-333... 

Salach JI, Singer TP, Castagnoli N, Jr, et al. Oxidation of the neurotoxic amine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP. Biochem Biophys Res Commun 1984 125(2) 831-835. 

Tomchick, D.R., Machius, M., Cole, P.A. and Yu, Fi. (2007) Structural basis of histone demethylation by LSDl revealed by suicide inactivation. Nature Structural si Molecular Biology, 14 (6), 535-539. 

Figure 13.4 Various LSDl inhibitors. Suicide inactivators pargyline 5 and tranylcypromine 6. Histone H3 tail 21-amino acid peptide analogs 7-11 as reversible and irreversible inibitors. Noncompetitive polyamine inhibitors 12 and 13.

Mechanistic Analysis of a Suicide Inactivator of Histone Demethylase LSDl. Biochemistry, 46, 6892-6902. 

Cytochrome P-450 from rat or human liver microsome preparations is inactivated when incubated anaerobically with carbon tetrachloride in the presence of NADPH and an oxygen-scavenging system (Manno et al. 1988 1992). Inactivation involved destruction of the heme tetrapyrrolic structure, and followed pseudo first-order kinetics with fast and slow half lives of 4.0 and 29.8 minutes. When compared with rat liver microsomes, the human preparations were 6-7 times faster at metabolizing carbon tetrachloride, and only about one- eighth as susceptible to suicide inactivation (about 1 enzyme molecule lost for every 196 carbon tetrachloride molecules metabolized). 

Manno M, Ferrara R, Cazzaro S, et al. 1992. Suicidal inactivation of human cytochrome P-450 by carbon tetrachloride and halothane in vitro. Pharmacol Toxicol 70 13-18. 

Manno M, Rezzadore M, Cazzaro S. 1991. Suicidal inactivation of cytochrome P-450 by halothane and carbon tetrachloride. Institut Occup Med, Padova, Italy 329-331. 

A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation). In this type of inhibition, the effector compound (i.e., the in-... 

A special class of irreversible inhibitors is the suicide inactivators. These compounds are relatively un-reactive until they bind to the active site of a specific enzyme. A suicide inactivator undergoes the first few chemical steps of the normal enzymatic reaction, but instead of being transformed into the normal product, the... 

The preparation of extracts of plant tissue containing active DPOs can be fraught with problems. In the intact plant tissue, both enzyme and substrate are present but are thought to be compartmentalized, with the enzyme bound to membranes and the native substrate ) present in the vacuole. As soon as the tissue is disrupted, these can react together with the very real risk of a suicidal inactivation of the enzyme by its own reaction products. As a result, most isolation procedures for DPOs include additions of ascorbate and/or cysteine to prevent the formation of the reactive quinones. Assuming that the enzyme is... 

Rai GP, Zong Q, Hager LP (2000) Isolation of Directed Evolution Mutants of Chloroperoxidase Resistant to Suicide Inactivation by Primary Olefins. Israel J Chem 40 63... 

Halpert J, Naslund B, Betner I. Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro. Mol Pharmacol 1983 23 445 452. 

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