Vitamin coenzyme, mechanism

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. 

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. 

Thus, the experimental data presented are consistent with the intermediacy of 7T-olefin-cobalt(III) complexes. By invoking a (t-tt rearrangement mechanism, rearrangements catalyzed by the vitamin coenzyme can be generalized. 

METALLO ENZYMES AND METALLO COENZYMES — covers the preparation, analysis, and biochemical effects of enzymes and co-enzymes that contain metals such as cobalt, copper, iron, zinc, and molybdenum. Also included are items dealing with metallo proteins, metal-containing vitamins, and mechanisms by which metals are bound to various enzymes. 

Properties and Reactions.—Physicochemical studies of axial ligation of pyridine to cobalt corroles have been carried out/ and the kinetics and mechanism of cobalt-carbon bond cleavage in the alkylation of tin and mercury ions have also been studied. The mechanism of action of the vitamin coenzyme has been reviewed/ and several studies of the mechanism of cobalt-carbon bond cleavage and isomerization reactions of the model cobalt cobaloxime system have been published. ... 

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. 

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. 

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. 

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

A component of the ribotide reductase complex of enzymes, protein Ba, has been shown to contain two non-heme iron atoms per mole (77). This enzyme plays a vital, albeit indirect, role in the synthesis of DNA. Curiously, the lactic acid bacteria do not employ iron for the reduction of the 2 hydroxyl group of ribonucleotides. In these organisms this role has been assumed by the cobalt-containing vitamin Bi2 coenzyme (18). The mechanism of the reaction has been studied and has been shown to procede with retention of configuration (19). 

The precise mechanism of dimethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute effects of dimethylhydrazine exposure may involve the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Back and Thomas (1963) noted that the deaths probably involve respiratory arrest and cardiovascular collapse. The central nervous system as a target is consistent with the delayed latency in response reported for dimethylhydrazine (Back and Thomas 1963). There is some evidence that 1,1-dimethylhydrazine may act as an inhibitor of glutamic acid decarboxylase, thereby adversely affecting the aminobutyric acid shunt, and could explain the latency of central-nervous-system effects (Back and Thomas 1963). Furthermore, vitamin B6 analogues that act as coenzymes in the aminobutyric acid shunt have been shown to be effective antagonists to 1,1-dimethylhydrazine toxicity (reviewed in Back and Thomas 1963). 

This is a complex molecule, made up of an adenine nucleotide (ADP-3 -phosphate), pantothenic acid (vitamin B5), and cysteamine (2-mercaptoethylamine), but for mechanism purposes can be thought of as a simple thiol, HSCoA. Pre-eminent amongst the biochemical thioesters is the thioester of acetic acid, acetyl-coenzyme A (acetyl-CoA). This compound plays a key role in the biosynthesis and metabolism of fatty acids (see Sections 15.4 and 15.5), as well as being a building block for the biosynthesis of a wide range of natural products, such as phenols and macrolide antibiotics (see Box 10.4). 

Mechanism of Action An antihyperlipidemic, water-soluble vitamin that is a component of two coenzymes needed for tissue respiration, lipid metabolism, and glyco-genolysis. Inhibits synthesis of VLDLs, Therapeutic Effect Reduces total, LDL, and VLDL cholesterol levels and triglyceride levels increases HDL cholesterol concentration. 

Pyridoxal phosphate is the coenzyme for the enzymic processes of transamination, racemization and decarboxylation of amino-acids, and for several other processes, such as the dehydration of serine and the synthesis of tryptophan that involve amino-acids (Braunstein, 1960). Pyridoxal itself is one of the three active forms of vitamin B6 (Rosenberg, 1945), and its biochemistry was established by 1939, in considerable part by the work of A. E. Braunstein and coworkers in Moscow (Braunstein and Kritzmann, 1947a,b,c Konikova et al 1947). Further, the requirement for the coenzyme by many of the enzymes of amino-acid metabolism had been confirmed by 1945. In addition, at that time, E. E. Snell demonstrated a model reaction (1) for transamination between pyridoxal [1] and glutamic acid, work which certainly carried with it the implication of mechanism (Snell, 1945). 

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). 

All aminotransferases have the same prosthetic group and the same reaction mechanism. The prosthetic group is pyridoxal phosphate (PLP), the coenzyme form of pyridoxine, or vitamin B6. We encountered pyridoxal phosphate in Chapter 15, as a coenzyme in the glycogen phosphorylase reaction, but its role in that reaction is not representative of its usual coenzyme function. Its primary role in cells is in the metabolism of molecules with amino groups. 

The body maintains an antioxidant network consisting of vitamins A, C, and E, antioxidant enzymes, and a group of related compounds called coenzyme Q, for which the general formula is shown. The n represents the number of times that a particular group is repeated it can be 6, 8, or 10. The coenzyme Q molecules are also called ubiquinones, because they are so ubiquitous in the body. Antioxidants are molecules that are easily oxidized and so react readily with radicals before the radicals can react with other compounds in the body. A variety of intricate mechanisms... 

In general, less is known about the mechanisms of action of the lipid-soluble vitamins than about the coenzymes derived from water-soluble vitamins. The structures and functions of vitamins D, K, E, and A are discussed briefly. 

Frequently enzymes act in concert with small molecules, coenzymes or cofactors, which are essential to the function of the amino acid side chains of the enzyme. Coenzymes or cofactors are distinguished from substrates by the fact that they function as catalysts. They are also distinguishable from inhibitors or activators in that they participate directly in the catalyzed reaction. Chapter 10, Vitamins and Coenzymes, starts with a description of the relationship of water-soluble vitamins to their coenzymes. Next, the functions and mechanisms of action of coenzymes are explained. In the concluding sections of this chapter, the roles of metal cofactors and lipid-soluble vitamins in enzymatic catalysis are briefly discussed. 

Model reactions have contributed significantly to our understanding of biological processes. Both pyridoxal phosphate (vitamin B6) and Bi2-coenzymes have proved useful in mechanism studies. Methyl transfer reactions to various metals are of environmental significance. In 1968 it was shown that methylcobalamin could transfer a methyl carbanion to mercury(II) salts in aqueous solutions. Recent research on interaction between B12-coenzymes and platinum salts has shown that charged Ptn salts labilize the Co—-C bond. Secondly, the B12-coenzymes are unstable in the presence of platinum salts this observation correlates with the fact that patients who have received cw-platin develop pernicious anemia. 

Some non-enzymatic antioxidants play a key role in these defense mechanisms. These are often vitamins (A, C, E, K), minerals (zinc, selenium), caretenoids, organosulfur compounds, allyl sulfide, indoles, antioxidant cofactors (coenzyme Qio)> and polyphenols (flavonoids and phenolic acids) [1,37]. Further, there is good evidence that bilirubin and uric acid can act as antioxidants to help neutralize certain free radicals [38]. Alpha-carotene, lycopene, lutein, and zeaxanthine [39] can be considered subgroups of carotenoids [40] that are effective antioxidant compounds. 

Areas of biomimetic chemistry relating to enzyme systems that function both with and without the benefit of coenzymes are included. Special emphasis has been placed on the following subjects vitamin Bi2 and flavins oxygen binding and activation bioorganic mechanisms and nitrogen and small molecule fixation. 

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