Coenzyme mechanism

Vitamins are essential in mammalian physiology because their coenzyme forms are prosthetic groups or cofactors in many enzyme reactions or because they can perform certain specialized functions in the human organism. Vitamin A and its role in the visual process is an example. The biology of vitamins may be examined from the nutritional or biochemical points of view. The former is concerned with minimum daily requirements, dietary sources, bioavailability, and deficiency syndromes. The biochemist looks for structures, functional groups, conversion to coenzymes, mechanisms of action, mode of transport, and storage. Both aspects will be addressed in this chapter, though the emphasis will be on the biochemical properties of vitamins. 

Heterocycles as intermediates in enzyme-catalyzed reactions 84CSR97. Coenzymes, mechanism of action 85APO(21)1. 

The trouble with the statement you just made is that it is obviously open to disproof. There are lots of models that have taught something to the biochemists. All of the coenzyme mechanisms were discovered by work with models. That has taught the biochemists something, I hope. 

According to the proposed mechanism for biological 0x1 dation of ethanol the hydrogen that is transferred to the coenzyme comes from C 1 of ethanol Therefore the dihydropyridme ring will bear no deuterium atoms when CD3CH2OH IS oxidized because all the deuterium atoms of the alcohol are attached to C 2... 

Fatty acids are biosynthesized by way of acetyl coenzyme A The following sec tion outlines the mechanism of fatty acid biosynthesis... 

Adenosylcobalamin (coenzyme B 2) is required in a number of rearrangement reactions that occurring in humans is the methylmalonyl-Co A mutase-mediated conversion of (R)-methylmalonyl-Co A (6) to succinjl-CoA (7) (eq. 1). The mechanism of this reaction is poorly understood, although probably free radical in nature (29). The reaction is involved in the cataboHsm of valine and isoleucine. In bacterial systems, adenosylcobalamin drives many 1,2-migrations of the type exemplified by equation 1 (30). 

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. 

In oiological systems, the most frequent mechanism of oxidation is the remov of hydrogen, and conversely, the addition of hydrogen is the common method of reduc tion. Nicotinamide-adenine dinucleotide (NAD) and nicotinamide-adenine dinucleotide phosphate (NADP) are two coenzymes that assist in oxidation and reduction. These cofactors can shuttle between biochemical reac tions so that one drives another, or their oxidation can be coupled to the formation of ATP. However, stepwise release or consumption of energy requires driving forces and losses at each step such that overall efficiency suffers. 

FIGURE 14.22 Glutamate aspartate aminotransferase, an enzyme conforming to a double-displacement bisnbstrate mechanism. Glutamate aspartate aminotransferase is a pyridoxal phosphate-dependent enzyme. The pyridoxal serves as the —NH, acceptor from glntamate to form pyridoxamine. Pyridoxamine is then the amino donor to oxaloacetate to form asparate and regenerate the pyridoxal coenzyme form. (The pyridoxamine enzyme is the E form.)... 

The first two of these are mediated by 5 -deoxyadenosylcobalamin, whereas methyl transfers are effected by methylcobalamin. The mechanism of ribonucleotide reductase is discussed in Chapter 27. Methyl group transfers that employ tetrahydrofolate as a coenzyme are described later in this chapter. 

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. 

The pyruvate dehydrogenase complex (PDC) is a noncovalent assembly of three different enzymes operating in concert to catalyze successive steps in the conversion of pyruvate to acetyl-CoA. The active sites of ail three enzymes are not far removed from one another, and the product of the first enzyme is passed directly to the second enzyme and so on, without diffusion of substrates and products through the solution. The overall reaction (see A Deeper Look Reaction Mechanism of the Pyruvate Dehydrogenase Complex ) involves a total of five coenzymes thiamine pyrophosphate, coenzyme A, lipoic acid, NAD+, and FAD. 

The mechanism of the pyruvate dehydrogenase reaction is a tour de force of mechanistic chemistry, involving as it does a total of three enzymes (a) and five different coenzymes—thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD (b). 

This enzyme interconverts ribulose-5-P and ribose-5-P via an enediol intermediate (Figure 23.30). The reaction (and mechanism) is quite similar to the phosphoglucoisomerase reaction of glycolysis, which interconverts glucose-6-P and fructose-6-P. The ribose-5-P produced in this reaction is utilized in the biosynthesis of coenzymes (including N/ DH, N/ DPH, F/ D, and Big), nucleotides, and nucleic acids (DNA and RNA). The net reaction for the first four steps of the pentose phosphate pathway is... 

FIGURE 24.21 A mechanism for the methylmalonyl-CoA mntase reaction. In the first step, Co is rednced to Co dne to homolytic cleavage of the Co —C bond in cobalamin. Hydrogen atom transfer from methylmalonyl-CoA yields a methylmalonyl-CoA radical that can undergo rearrangement to form a snccinyl-CoA radical. Transfer of an H atom regenerates the coenzyme and yields snccinyl-CoA. 

In biological reactions, the situation is different from that in the laboratory. Only one substrate molecule at a time is present in the active site of the enzyme where reaction takes place, and that molecule is held in a precise position, with coenzymes and other necessary reacting groups nearby. As a result, biological radical reactions are both more controlled and more common than laboratory or industrial radical reactions. A particularly impressive example occurs in the biosynthesis of prostaglandins from arachiclonic acid, where a sequence of four radical additions take place. The reaction mechanism was discussed briefly in Section 5.3. 

Figure 19.15 Mechanism of biological aldehyde and ketone reductions by the coenzyme NADH.

Problem 21.22 Write the mechanism of the reaction shown in Figure 21.9 between coenzyme A and acetyl adenylate to give acetyl CoA. 

Lanosterol biosynthesis begins with the selective conversion of squalene to its epoxide, (35)-2,3-oxidosqualene/ catalyzed by squalene epoxidase. Molecular 02 provides the source of the epoxide oxygen atom, and NADPH is required, along with a flavin coenzyme. The proposed mechanism involves... 

Figure 29.11 MECHANISM Mechanism of the conversion of pyruvate to acetyl CoA through a multistep sequence of reactions that requires three different enzymes and four different coenzymes. The individual steps are explained in the text.

Figure 29.12 MECHANISM The citric acid cycle is an eight-step series of reactions that results in the conversion of an acetyl group into two molecules of C02 plus reduced coenzymes. Individual steps are explained in the text.

Step 1 of Figure 29.13 Carboxylation Gluconeogenesis begins with the carboxyl-afion of pyruvate to yield oxaloacetate. The reaction is catalyzed by pyruvate carboxylase and requires ATP, bicarbonate ion, and the coenzyme biotin, which acts as a carrier to transport CO2 to the enzyme active site. The mechanism is analogous to that of step 3 in fatty-acid biosynthesis (Figure 29.6), in which acetyl CoA is carboxylated to yield malonyl CoA. 

Most amino acids lose their nitrogen atom by a transamination reaction in which the -NH2 group of the amino acid changes places with the keto group of ct-ketoglutarate. The products are a new a-keto acid plus glutamate. The overall process occurs in two parts, is catalyzed by aminotransferase enzymes, and involves participation of the coenzyme pyridoxal phosphate (PLP), a derivative of pyridoxine (vitamin UJ. Different aminotransferases differ in their specificity for amino acids, but the mechanism remains the same. 

Towards the unification of coenzyme B12-dependent diol dehydratase stereochemical and model studies the bound radical mechanism. R. G. Finke, D. A. Schiraldi and B. J. Mayer, Coord. Chem. Rev., 1984, 54,1-22 (40). 

Figure 11-4. Mechanism of oxidation and reduction of nicotinamide coenzymes. There is stereospecificity about position 4 of nicotinamide when it is reduced by a substrate AHj. One of the hydrogen atoms is removed from the substrate as a hydrogen nucleus with two electrons (hydride ion, H ) and is transferred to the 4 position, where it may be attached in either the A or the B position according to the specificity determined by the particular dehydrogenase catalyzing the reaction. The remaining hydrogen of the hydrogen pair removed from the substrate remains free as a hydrogen ion.

In addition to its coenzyme role, NAD is the source of ADP-ribose for the ADP-ribosylation of proteins and polyADP-ribosylation of nucleoproteins involved in the DNA repair mechanism. 

Meganathan, R., Biosynthesis of menaquinone (vitamin Kj) and ubiquinone (coenzyme Q) a perspective on enzymatic mechanism. Vitamins Hormones, 61, 173, 2001. 

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