Enzymes, Coenzymes, and Their Models

Biopterin cofactor and related compounds, chemistry and biological function of 88YGK564. 

Enzyme mechanism and inhibition, reactions of cyclopropane derivatives with heterocyclic fragments of enzymes in studies of 88AG(E)537. 

Enzymes altered at their active sites, catalytic activity of 88AG(E)913. 

Ionic intermediates in enzyme-catalyzed C-C bond formation 90CRV1151. 

Pteridine-dependent monooxygenases, mechanism of oxygen activation with 88ACR101. 

---

Chelation is a feature of much research on the development and mechanism of action of catalysts. For example, enzyme chemistry is aided by the study of reactions of simpler chelates that are models of enzyme reactions. Certain enzymes, coenzymes, and vitamins possess chelate stmctures that must be involved in the mechanism of their action. The activation of many enzymes by metal ions most likely involves chelation, probably bridging the enzyme and substrate through the metal atom. Enzyme inhibition may often result from the formation by the inhibitor of a chelate with a greater stabiUty constant than that of the substrate or the enzyme for a necessary metal ion. 

Kinetic studies of reversible inhibition by substrate analogs give evidence of the mode of action of the inhibitor and the types of enzyme-inhibitor complex formed, and estimates of their dissociation constants. The complexes may be isolated and sometimes crystallized. Studies of the stabilities, optical properties, and structures of ternary complexes of enzymes, coenzymes, and substrate analog in particular, as stable models of the catalytically active ternary complexes or of the transition state for hydride transfer (61,79,109,115-117), can only be touched upon here there is direct evidence with several enzymes that the binding of coenzymes is firmer in such complexes than in their binary complexes (85,93,118), which supports the indirect, kinetic evidence already mentioned for a similar stabilization in active ternary complexes. 

Retey, J. Coenzymes B,2-Dependent Enzymes and Their Models. In Vitamin B/2 and B 12-Proteins Krautler, B.. Arigoni. D., Golding, B.T.. Eds. Wiley-VCH. Verlag GmbH Weinheim, 1998 273-288. 

The development of magnetic resonance techniques coupled with computer time averaging has made the study of enzyme structure and function by these techniques more fruitful. H NMR, 13C NMR and 19F NMR have been used successfully to determine the structure of B 12-compounds in solution. We are rapidly approaching the point where the structure and function of the B 12-coenzymes will be completely understood, and the need for the synthesis and study of simple Bi2-model compounds such as the cobaloximes (3) will be no longer necessary. However, even though studies on the chemistry of B 12-coenzymes is a necessary prerequisite to our understanding of their biochemical role, it is a wrong assumption to expect that the chemical properties of free coenzymes in aqueous solution should be duplicated in the enzymes. 

Yang and Schulz also formulated a treatment of coupled enzyme reaction kinetics that does not assume an irreversible first reaction. The validity of their theory is confirmed by a model system consisting of enoyl-CoA hydratase (EC 4.2.1.17) and 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) with 2,4-decadienoyl coenzyme A as a substrate. Unlike the conventional theory, their approach was found to be indispensible for coupled enzyme systems characterized by a first reaction with a small equilibrium constant and/or wherein the coupling enzyme concentration is higher than that of the intermediate. Equations based on their theory can allow one to calculate steady-state velocities of coupled enzyme reactions and to predict the time course of coupled enzyme reactions during the pre-steady state. 

At the same time, Snell and coworkers used model systems to achieve most of the reactions of the pyridoxal enzymes (Metzler and Snell, 1952a,b Olivard et al., 1952 Ikawa and Snell, 1954a,b Metzler et al 1954a,b Longnecker and Snell, 1957). They too developed the modern mechanisms for the series of reactions and demonstrated the role of the coenzyme as an electron sink by substituting alternative catalysts for pyridoxal phosphate. In particular, they showed that 2-hydroxy-4-nitrobenzaldehyde (Ikawa and Snell, 1954) functioned in their model systems just as did the vitamin its electronic structure is really quite similar (3). 

---