Vitamins cofactor forms

Vitamin K (phylloquinone) and similar substances with modified side chains are involved in carboxylating glutamate residues of coagulation factors in the liver (see p. 290). The form that acts as a cofactor for carboxylase is derived from the vitamin by enzymatic reduction. Vitamin K antagonists (e. g., coumarin derivatives) inhibit this reduction and consequently carboxylation as well. This fact is used to inhibit blood coagulation in prophylactic treatment against thrombosis. Vitamin K deficiency occurs only rarely, as the vitamin is formed by bacteria of the intestinal flora. 

Coenzyme B12 is the cofactor form of vitamin B 2, which is unique among all the vitamins in that it contains not only a complex organic molecule but an essential trace element, cobalt. The complex corrin ring system of vitamin B12 (colored blue in Fig. 2), to which cobalt (as Co3+) is coordinated, is chemically related to the porphyrin ring system of heme and heme proteins (see Fig. 5-1). A fifth coordination position of cobalt is filled by dimethylbenzimidazole ribonucleotide (shaded yellow), bound covalently by its 3 -phosphate group to a side chain of the corrin ring, through aminoisopropanol. 

The terms cofactor, coenzymes, and prosthetic group are used to describe the nonprotein moieties of the enzyme active center. The distinction between these terms is not sharp. Some of the cofactors are derivatives of vitamins that form either covalent or noncovalent linkages at or near the active site of the enzyme, and some are metal ions. If a cofactor (coenzyme) is tightly bound to the protein moiety (the apoenzyme), it is often referred to as a prosthetic group. A coenzyme that is easily removed from the holoenzyme, leaving behind the apoenzyme, is often regarded as a second substrate. 

Folate Is a generic term referring to a family of related compounds. All of these compounds represent modifications of the simplest form of the vitamin, folic acid (pteroylglutamic add, PlcGlu). Folic add does not occur in nature in appreciable amounts, though it is readily assimilated by the body and converted to the active cofactor forms of the vitamin. Folic acid is the form of the vitamin used in folate supplements. Folates are modified by reduction and by a poly glutamyl chain or tail. The reduced folates include dlhydrofolate and tetrahydrofolate. 

Folate deficiency can result in an overall decline in the concentrations of all the cofactor forms of folate in the cell Vitamin Bjt deficiency can result in a decline in the concentration of tetrahydrofolale and an increase in that of 5-methyhHifolate. Both deficiencies would be expected to result in impairment of the catabolism of histidine. 

Vitamin Bu is unique among all the vitamins in that it is the largest and most complex and because it contains a metal ion. 1 hismetal ion is cobalt. Cobalt occurs in three oxidation states Co, Co, and Co. The medicinal forms of the vitamin are cyanocobalamin and hydnoxocobalamin. In cyanocobalamin, a molecule of Cyanide is complexed to the Co atom. Cyanocobalamin is readily converted in the body to the cofactor forms methylcobalamin and 5-deoxyadenosylcobalamin. Methylcobalamin contains cobalt in the Co slate, where it acts as a cofactor for methionine synthase. 5 Deoxyadenosylcobalamin, which contains cobalt in the Co state, is the cofactor for methylmalonyl-CoA mutase. Vitamin Btj is also a cofactor for leucine aminomutase, anen7yme used in leucine metabolism (Poston, 1984). This enzyme appears not to have a vital function in metabolism. No more... 

The structure of vitamin appears in Figure 9,21. The X indicates the point of attachment of the cyanide group in cyanocobalamin, the hydroxyj group in hy drostocobalamin, and the methyl and deoxyadenosyl groups in the cofactor forms of the vitamin. 

Parent amino acid Modified form Vitamin cofactor... 

Some vitamins undergo a rather unique transformation prior to becoming ftmctional. They are covalently attached to specific enzymes. Biotin, for example, is covalently boimd to the biotin-requiring enzymes. Pantothenic acid, in a modified form, is covalently bound to fatty acid synthase. Riboflavin, following conversion to the cofactor form, is bound to succinate dehydrogenase, as well as to a few other enzymes requiring riboflavin-based cofactors. 

The concentration of free pantothenic acid in the liver is about 15 xM that in the heart is about tenfold greater (Robishaw and Neely, 1985). The concentration of the cofactor form of the vitamin, coenzyme A, is higher in the mitochondrion than in the cytosol. In the Ever, cytosolic coenzyme A is about 0.06 mM, and mitochondrial coenzjmie A, about 2.6 mM. In the liver, about 70% of coenzyme A is mitochondrial, whereas in the heart about 95% is mitochondrial (Tahiliani and Neely, 1987). These values might be compared with that for carnitine, another molecule used in the handling of fatty acids. Please consult the Carnitine section in Chapter Four. About half of the coenzjrme A in liver occurs as the long-chain fatty acyl-coenzyme A derivative. The concentration of fatty acid s)mthase in the cytoplasm is quite low, about 0.01 pM. Hence, the concentration of the 4 -phospho-pantetheine cofactor is much lower than that of coenzyme A. The pantothenic acid boimd to this enzyme does not make a significant contribution to our dietary vitamin. 

Vitamin B12 contains cobalt in a corrin ring that resembles a porphyrin. In the cofactor forms of the vitamin, an adenosyl moiety or methyl group is attached to the cobalt, forming adenosylcobalamin or methylcobalamin (Figure 7-17). 

The answer is b. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121—138. Wilson, pp 287—320.) All the vitamins listed except lipoamide contain at least one phosphate in their cofactor form. Thiamine (vitamin... 

GABA-T utilizes pyridoxal as the cofactor in the transamination reaction (Fig. 12-7A). Pyridoxal 5-phosphate (Vitamin B6, the cofactor) forms a Schiff base with GABA s NH2 group. The adjacent C-H bond has its proton abstracted by the enzyme reprotonation results in the tautomeric Schiff base, which on hydrolysis affords succinic semialdehyde and pyridoxamine. The pyridoxamine then forms a Schiff base with the carbonyl of a-ketoglutarate, reversing the steps, whereby hydrolysis of the tautomeric base yields l-glutamic acid, and the pyridoxamine, which has given up its NH2 function, reverts to the cofactor aldehyde form to repeat the cycle. 

A broad range of enzymic reactions of amino acids is mediated by pyridoxal phosphate (PLP), the cofactor form of vitamin Bg. The general mechanism of action of this cofactor was suggested independently by Braunstein and Shemyakin (16) and by Snell (17), and although a great deal of experimental work has been achieved since the Braunstein-Snell hypothesis was put forward, it still holds good today. 

The major sales form of vitamin B6 is the hydrochlorid salt of the primary alcohol pyridoxine. Another vitamin B6 form introduced in the market is the dihydrochlo-rid salt of pyridoxamine. Both vitamin B6 forms are commercially produced via various straightforward chemical synthesis routes. The biologically active cofactor is the aldehyde pyridoxal-5 -phosphate, which is derived in human or animals from the vitamin B6 forms by oxidation or transamination before or after 5 phosphorylation by pyridoxal kinases. 

C,7H2oN406 376.368 Widely distributed, but occurs naturally in free form only in the retina, in whey and in urine. Main forms occurring in tissues and cells are flavine mononucleotide and flavine-adenine dinucleotide. Colour additive in food. Used as adsorption indicator in titrimetric detn. of Ag. Nutrient supplement. Vitamin cofactor. Orange needles. Sol. EtOH spar. sol. H2O. Mp 280° dec. [ ]d -9.8 (H2O). [ ]d -125 (20A NaOH). pAa, 1.9 pA,2 10.2 (25°). Green fluor. in soln. X ax 220 265 365 455 (H2O). 

D(S)-Methylmalonyl-CoA L(/ )-Methylmalonyl-CoA SuccInyl-CoA The racemase enzyme acts by moving the a-hydrogen on D-methylmalonyl-CoA and the mutase by movement of the CoA carboxyl group. The mutase enzyme requires a cofactor form of vitamin B12, 5 -deoxyadenosylcobalamin... 

Flavoprotein enzymes contain flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD) as prosthetic groups. FMN and FAD are formed in the body from the vitamin riboflavin (Chapter 45). FMN and FAD are usually tighdy—but not covalendy—bound to their respecdve apoenzyme proteins. Metalloflavopro-teins contain one or more metals as essential cofactors. 

Four of the B vitamins are essential in the citric acid cycle and therefore in energy-yielding metabolism (1) riboflavin, in the form of flavin adenine dinucleotide (FAD), a cofactor in the a-ketoglutarate dehydrogenase complex and in succinate dehydrogenase (2) niacin, in the form of nicotinamide adenine dinucleotide (NAD),... 

Peptidyl hydroxyprohne and hydroxylysine are formed by hydroxylation of peptidyl proline or lysine in reactions catalyzed by mixed-function oxidases that require vitamin C as cofactor. The nutritional disease scurvy reflects impaired hydroxylation due to a deficiency of vitamin C. 

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

In 1958 Barker (20) isolated a red, heat stable, light labile, cofactor which was required for the metabolism of glutamate in cell-extracts of Clostridium tetanomorphum. Subsequently this cofactor was crystallized. X-ray crystallography identified Barker s cofactor as the coenzyme form of Vitamin B12 (15, 21). 

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

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