Vitamin coenzymes from

Riboflavin (vitamin Bj) is chemically specified as a 7,8-dimethyl-10-(T-D-ribityl) isoalloxazine (Eignre 19.22). It is a precnrsor of certain essential coenzymes, such as flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) in these forms vitamin Bj is involved in redox reactions, such as hydroxylations, oxidative carboxylations, dioxygenations, and the reduction of oxygen to hydrogen peroxide. It is also involved in the biosynthesis of niacin-containing coenzymes from tryptophan. 

Table 2.3 Role and distribution for some vitamin and non-vitamin coenzymes (adapted from http //en.wikipedia. org/wi ki/C oenzyme).

Nutritionally, humans derive their pyridoxal coenzyme from vitamin B6. Most symptoms of vitamin Be deficiency apparently result from the involvement of the coenzyme in the biosynthesis of neurotransmitters and the niacin group of NAD and NADPH rather than from amino acid deficiency. 

Whereas plants and certain microorganisms can generate all required coenzymes from CO2 or simple organic precursors, animals must obtain precursors (designated as vitamins) for a major fraction of their coenzymes from nutritional sources. Still, most vitamins must be converted into the actual coenzymes by reactions catalyzed by animal enzymes. The structures and biosynthetic pathways of some coenzymes are characterized by extraordinary complexity. Enzymes for coenzyme biosynthesis have frequently low catalytic rates, and some of them catalyze reactions with highly unusual mechanisms. 

Whereas tetrahydrobiopterin is biosynthesized from GTP via just three enzyme-catalyzed steps (2), some coenzyme biosynthetic pathways are characterized by enormous complexity. Thus, the biosynthesis of vitamin B12 requires five enzymes for the biosynthesis of the precursor uroporhyrinogen III (16) from succinyl-CoA (10) and glycine (11) that is then converted into vitamin B12 via the sequential action of about 20 enzymes (3). Additional enzymes are involved in the synthesis of the building blocks aminopropanol and dimethylbenzimidazole (4, 5). Vitamin B12 from nutritional sources must then be converted to coenzyme B12 by mammalian enzymes. Ultimately, however, coenzyme B12 is used in humans by only two enzymes, albeit of vital importance, which are involved in fatty acid and amino acid metabolism (6). Notably, because plants do not generate corrinoids, animals depend on bacteria for their supply of vitamin B12 (which may be obtained in recycled form via nutrients such as milk and meat) (7). 

Cofactors that are small organic molecules are called coenzymes. Often derived from vitamins, coenzymes can be either tightly or loosely bound to the enzyme. If tightly bound, they are called prosthetic groups. Loosely associated coenzymes are more like cosubstrates because they bind to and are released from the enzyme just as substrates and products are. The use of the same coenzyme by a variety of enzymes and their source in vitamins sets coenzymes apart from normal substrates, however. Enzymes that use the same coenzyme are usually mechanistically similar. In Chapter 9, we will examine the mechanistic importance of cofactors to enzyme activity. A more detailed discussion of coenzyme vitamins can be found in Section 8.6. 

No I all cofaclyrs are derived from vitamins, Coenzyme Q, lipoic acid, dolichol phosphate, biopterin, heme, and molybdopterin are cofactors that are synthesized in the body from simple organic compounds. Heme and molybdopterin are relatively complex, from a nutritional point of view, because they require metal ions as part of their structure. 

Hypervitaminosis Riboflavin. The combination of regulated active transport and conversion to the coenzyme forms prevents hypervitaminosis problems with this vitamin. Toxicities from the water-soluble riboflavin phosphate have not been reported. There are... 

Animals and plants cannot synthesize vitamin B12. In fact, only a few microorganisms can synthesize it. Humans must obtain all their vitamin B12 from their diet, particularly from meat. Because vitamin B12 is needed in only very small amounts, deficiencies caused by consumption of insufficient amounts of the vitamin are rare, but have been found in vegetarians who eat no animal products. Deficiencies are most commonly caused by an inability to absorb the vitamin in the intestine. The deficiency causes pernicious anemia. The following are examples of enzyme-catalyzed reactions that require coenzyme B12 ... 

Since the coenzyme from vitamin is required in two distinct enzyme reactions, i.e., remethylation of homocystine and catabolism of methylmalonic acid, the fundamental defect must involve a step in converting to its coenzymes. Formation of both deoxyadenosyl B and methyl B requires a prior reductive step catalyzed by cobalamin reductase, which appears to be the defective enzyme in this variant (Hogervorst et al., 2002) (Fig. 20.4). 

Yeast extract Substance from yeast containing vitamins, coenzymes, and nucleosides used to enrich media. 

Riboflavin in its coenzyme forms (FMN and FAD) plays key metabolic roles in biological oxidation-reduction reactions involving carbohydrates, amino acids and lipids, and in energy production via the respiratory chain. These coenzymes also act in cellular metabolism of other water-soluble vitamins through the production and activation of folate and pyridoxine (vitamin Bg) to their respective coenzyme forms and in the synthesis of niacin (vitamin B3) from tryptophan. In addition, some neurotransmitters and other amines require FAD for their metabolism. Recently, Chocano-Bedoya et al. (2011) suggested a possible benefit of high intakes of riboflavin (about 2.5 mg/ day) from food sources on the reduction of incidence of premenstrual syndrome. 

Riboflavin is delivered in form of free vitamin, or as its coenzymes, i.e. flavin mononucleotide (FMN) and adenine dinucleotide (FAD), which occurs mainly as a prosthetic group of flavoproteins. Release of coenzymes from flavoproteins by acidification in stomach and proteolysis, both gastric and intestinal, must precede the absorption. This hydrolysis also releases several percentages of covalently bound FAD from 8a-(peptidyl)riboflavins (Chia et al. 1978). Free riboflavin is physiologically preferred form of absorbed vitamin B2 (Daniel et al. 1983). The upper small intestine enzymes which catalyse reversible reactions of conversion nucleotides into riboflavin are located in the brush-border membrane of enterocytes (Figure 36.1). 

Our own involvement in this area of research came about in an indirect way. A major interest in the laboratory had been the role of vitamin Bja in methyl group transfer from N -methyl-H4-folate to homocysteine to yield methionine, a problem that was an extension of studies on the isolation of the vitamin coenzyme while in Horace A. Barker s laboratory in 1958. When the exciting report by Clark and Marcker appeared showing that W-formylmethionine-tRNA (fMet-rRNA) was the initiator or protein synthesis, it was a natural extension of our work to examine the formation of fMet-tRNA, since this reaction also involved both a one-carbon transfer from a reduced folate derivative and the amino acid methionine. Herbert Dickerman, a postdoctoral fellow in the laboratory at that time, was able to purify the transformylase enzyme from E. coU extracts that catalyzed eqn. (1) ... 

Animals do not synthesize pantothenic acid. However, they, like yeasts and bacteria, convert the exogenous vitamin derived from the diet to coenzyme A (CoA) and acyl-carrier protein (ACP), the two metabolically active forms. The reaction pathway is shown in Eigirre 6. 

The adenine nucleotide for the coenzymes is provided by ATP. Niacin (also called vitamin B3) is the portion of the coenzyme that the body cannot synthesize and must acquire through the diet. (Humans can synthesize a small amount of vitamin B3 from the amino acid tryptophan but not enough to meet the body s metabolic needs.)... 

Animals (and also some yeasts and bacteria) do not synthesise pantothenic acid as they only convert exogenous vitamin obtained from food into both metabolically active forms, coenzyme A and ACP. Exogenous coenzyme A is first hydrolysed to pantothenic acid and pantetheine (via d -phosphopantetheine) exogenous (R)-panthenol (5-72) is oxidised to pantothenic acid. 

Abrams, R., and S. Duraiswami Deoxycytidylate formation from C5rtidylate without glycosidic cleavage in Lactobacillus leichmannii extracts containing vitamin coenzyme. Biochem. Biophys. Research Commun. 18, 409 (1965). 

Naturally occurring compounds with carbon-metal bonds are very rare The best example of such an organometallic compound is coenzyme Bi2 which has a carbon-cobalt ct bond (Figure 14 4) Pernicious anemia results from a coenzyme B12 deficiency and can be treated by adding sources of cobalt to the diet One source of cobalt IS vitamin B12 a compound structurally related to but not identical with coen zyme B12... 

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. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

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... 

Pantothenic acid is found in extracts from nearly all plants, bacteria, and animals, and the name derives from the Greek pantos, meaning everywhere. It is required in the diet of all vertebrates, but some microorganisms produce it in the rumens of animals such as cattle and sheep. This vitamin is widely distributed in foods common to the human diet, and deficiencies are only observed in cases of severe malnutrition. The eminent German-born biochemist Fritz Lipmann was the first to show that a coenzyme was required to facilitate biological acetylation reactions. (The A in... 

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