Suicide enzyme substrate

WHY DO THESE TOPICS MATTER ] In The Chemistry of... A Suicide Enzyme Substrate, we shall see how 5-fluorouracil works. Then, at the end of this chapter, we will show how the combination of several of these reactions in series, each setting up the next step like dominos falling in a row, can enable the one-pot preparation of a highly important alkaloid known as tropinone. Tropinone contains the core of several useful pharmaceuticals. 

Conjugate Additions to Activate Drugs 881 A Suicide Enzyme Substrate 883... 

We shall see examples of biochemically relevant conjugate additions in The Chemistry of... Calicheamicin ji Activation for Cleavage of DNA (see Section 19.7B) and in The Chemistry of... A Suicide Enzyme Substrate (Section 19.8). 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Suicide Enzyme Inhibitors. Snicide substrates are irreversible enzyme inhibitors that bind covalently. The reactive anchoring group is catalytically activated by the enzyme itself through the enzyme-inhibitor complex. The enzyme thus produces its own inhibitor from an originally inactive compound, and is perceived to commit suicide. To design a substrate, the catalytic mechanism of the enzyme as well as the nature of the functional gronps at the enzyme active site must be known. Conversely, successful inhibition provides valuable information about the structure and mechanism of an enzyme. Componnds that form carbanions are especially usefnl in this regard. Pyridoxal phosphate-dependent enzymes form such carbanions readily becanse... 

Mahmoudi A, Nazari K, Khosraneh M et al (2008) Can amino acids protect horseradish peroxidase against its suicide-peroxide substrate Enzyme Microb Technol 43 329-335... 

As these inhibitors owe their activity to the kcat term (i.e., the enzyme s usual mode of action) they have been designated "kcat inhibitors" by Rando (1), while Abeles and Maycock (2 ) have used the term "Suicide Enzyme Inactivators" because the enzyme, in accepting such a "booby-trapped" substrate commits suicide by its own mechanism of action. 

Compartmentation of substrate and enzyme. Enzymes can also be compartmentalised, like the hydrolytic enzymes found in the lysosome, but the release of these suicide enzymes during apoptosis is rather more of an on/off switch than a true regulation. 

Mechanism of action of S-adenosylhomoeysteine hydrolase (enzyme) and its inhibition by deoxyadenosine. (a) The enzyme uses enzyme-bound NAD+ to temporarily oxidize substrate and eventually hydrolyze it to adenosine and homocysteine. [Reproduced with permission from R. H. Abeles, Suicide enzyme inactivators. Chem. Eng. News 61(38), 55 (September 19, 1983). 1983 by the American Chemical Society.] (b) Deoxyadenosine, a suicide substrate, is also oxidized by the enzyme with the formation of a ketosugar, which undergoes decomposition, with the product dissociating from the enzyme and leaving the enzyme in the reduced state (NADH). 

Suicide substrate I An enzyme substrate that itself is not toxic but that produces a toxic metabolic product. 

Suicide substrate A chemical that forms a stable complex with an enzyme leading to its irreversible inhibition suicide compounds are chemically related to natural enzyme substrates... 

The enzyme inactivation by suicide inhibitors should be active-site directed. Not only must the inhibitor be processed by the enzyme s catalytic site, but the resulting reactive moiety should react at the active site also and not inactivate the enzyme by covalently binding amino acid residues outside the active site. Protection from inactivation by enzyme substrate or a simple competitive inhibitor is evidence for active-site directedness. Enzyme activity should also be monitored in the presence of exogenous reactive inhibitor, produced noncatal5hically, to ensure that... 

This concept of suicide substrates or enzyme inactivators has many potential implications whereby organic chemists can synthesize well-designed substrate analogues of specific enzymes. Of course, the design of new suicide enzyme inactivators involves higher and higher levels of chemical sophistication. The majority of the work done with suicide inhibitors has been on non-proteolytic enzymes, especially pyridoxal- and flavin-dependent enzymes. 

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). 

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). 

Suicide Substrates —Mechanism-Based Enzyme Inactivators... 

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