Coenzyme action

In this chapter we are concerned, not primarily with vitamins per se, but with coenzymes. Many coenzymes are modified forms of vitamins. The modifications take place in the organism after ingestion of the vitamins. Coenzymes act in concert with enzymes to catalyze biochemical reactions. Tightly bound coenzymes are sometimes referred to as prosthetic groups. A coenzyme usually functions as a major component of the active site on the enzyme, which means that understanding the mechanism of coenzyme action usually requires a complete understanding of the catalytic process. 

The area of carbon-cobalt bond cleavage reactions is of perhaps the greatest direct relevance to the mechanism of action of the B,2 coenzymes. Thus, while it is not yet clear if new organocobalt intermediates are formed (and decomposed) from substrates and the cobalt-containing moiety of adenosylcobalamin during the enzyme-catalyzed intramolecular rearrangements (see Section 4), it is clear that the activation of adenosylcobalamin, as well as the coenzymic action of methylcobalamin require that the carbon-cobalt bond of the coenzymes be cleaved. 

The vitamin action is due to the coenzymic action of (+)-biotin towards carboxylase. 

The few examples above give some idea of the variety of mechanisms of coenzyme action, an action which operates in conjunction with the activation by the enzyme macromolecule itself. The mechanism of this activation is one of the most important problems facing modem biochemistry. 

As is often the case, coenzyme biochemistry leads to unconventional organic chemistry. In this regard, coenzymes are nature s special reagents and their well-defined structures make them ideal molecules to use for developing the concept of structure-function relationship by bioorganic approaches (273). This chapter will thus be concerned with this aspect and special attention will be devoted to model design of coenzyme action. 

Enzymes often need for their activity the presence of a non-protein portion, which may be closely combined with the protein, in which case it is called a prosthetic group, or more loosely associated, in which case it is a coenzyme. Certain metals may be combined with the enzyme such as copper in ascorbic oxidase and selenium in glutathione peroxidase. Often the presence of other metals in solution, such as magnesium, are necessary for the action of particular enzymes. 

An example of a biologically important aide hyde is pyridoxal phosphate which is the active form of vitamin Bg and a coenzyme for many of the reac tions of a ammo acids In these reactions the ammo acid binds to the coenzyme by reacting with it to form an imine of the kind shown in the equation Re actions then take place at the ammo acid portion of the imine modifying the ammo acid In the last step enzyme catalyzed hydrolysis cleaves the imme to pyridoxal and the modified ammo acid... 

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. 

The catalytic action is specific and may be affected by the presence of other substances both as inhibitors and as coenzymes. Most enzymes are named in terms of the reactions they catalyze (see Chapter 1). There are three major types of enzyme reactions, namely ... 

Riboflavin was first isolated from whey in 1879 by Blyth, and the structure was determined by Kuhn and coworkers in 1933. For the structure determination, this group isolated 30 mg of pure riboflavin from the whites of about 10,000 eggs. The discovery of the actions of riboflavin in biological systems arose from the work of Otto Warburg in Germany and Hugo Theorell in Sweden, both of whom identified yellow substances bound to a yeast enzyme involved in the oxidation of pyridine nucleotides. Theorell showed that riboflavin 5 -phosphate was the source of the yellow color in this old yellow enzyme. By 1938, Warburg had identified FAD, the second common form of riboflavin, as the coenzyme in D-amino acid oxidase, another yellow protein. Riboflavin deficiencies are not at all common. Humans require only about 2 mg per day, and the vitamin is prevalent in many foods. This vitamin... 

Boyer, P. D., 1970. The Enzymes, 3rd ed. New York Academic Pre.s.s. A good reference. source for the mechanisms of action of vitamins and coenzymes. 

Formation of tire active coenzyme 5 -deoxyadeno.sylcobalamin from inactive vitamin Bjg i-s initiated by die action of flavoprotein reducta.se.s. The re.sulting Co. specie.s, dubbed a. supernucleophile, attacks the 5 -carbon of ATP in an unusual adeno.syl transfer. 

Be Pyridoxine, pyridoxal, pyridoxamine Coenzyme in transamination and decarboxylation of amino acids and glycogen phosphorylase role in steroid hormone action Disorders of amino acid metabolism, convulsions... 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Since carotenoids are isoprenoids, they share a common early pathway with other biologically important isoprenoids such as sterols, gibberellins, phytol and the terpenoid quinones (Fig. 13.3). In all cases, these compounds are derived from the C5 isoprenoid, isopentenyl diphosphate (IPP). Until a few years ago it was believed that a single pathway from the Cg precursor mevalonic acid (MVA) formed IPP, which itself was synthesised from hydroxymethylglutaryl coenzyme A (HMG CoA) by the action of HMG... 

Garlic s proven mechanisms of action include (a) inhibition of platelet function, (b) increased levels of two antioxidant enzymes, catalase and glutathione peroxidase, and (c) inhibition of thiol enzymes such as coenzyme A and HMG coenzyme A reductase. Garlic s anti-hyperlipidemic effects are believed to be in part due to the HMG coenzyme A reductase inhibition since prescription medications for hyperlipidemia have that mechanism of action (statins). It is unknown whether garlic would have the same drug interactions, side effects, and need for precautions as the statins. 

Figure 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

Many papers have been published about the enzymatic degradation of polyphenols through the action of oxidizing enzymes. Thus, various classifications have been provided for these types of biocatalytic molecules, according to their coenzyme requirements or according to the nature of the oxidizing substrate (the electron acceptor) and the reaction products (Fig. 4.1). 

One model of an ionic mechanism of action of Li+ in affective disorders has been proposed, in which the receptors for Li+ are ion channels and cation coenzyme receptor sites, and in which the presence of intracellular Li+ in excitable cells results in the displacement of exogenous Na+ and/or other intracellular cations [13]. It has been suggested that this could lead to a decrease in the release of neurotransmitters alternatively it may be that this intracellular Li+ is altering a preexisting, disease-related electrolyte imbalance [14]. A number of observations of such imbalances in affective disorders have been made depression is associated with elevated levels of intracellular Na+ [15] retention of Li+ is observed in manic-depressive patients prior to an episode of mania [ 16] and Na+/K+ activity is defective during both mania and depression [17]. 

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