Plasma and Leukocyte Concentrations of Ascorbate

The plasma concentration of vitamin C falls relatively rapidly during depletion studies, to undetectably low levels within 4 weeks of initiating a vitamin C-free diet, although clinical signs of scurvy may not develop for a further 3 to Table 13.2 Plasma and Leukocyte Ascorbate Concentrations as Criteria of Vitamin C Nutritional Status Table 13.2 Plasma and Leukocyte Ascorbate Concentrations as Criteria of Vitamin C Nutritional Status 4 months and tissue concentrations of the vitamin may be as...

Metabolic Consequences of Biotin Deficiency

The activities of biotin-dependent carboxylases fall in deficiency, resulting in impaired gluconeogenesis, with accumulation of lactate, pyruvate, and alanine, and impaired lipogenesis, with accumulation of acetyl CoA, resulting in ketosis. There are also changes in the fatty acid composition of membrane lipids. A variety of abnormal organic acids are excreted by both biotin-deficient patients and experimental animals (as shown in Table 11.1). There is accumulation of the apoenzymes of...

Toxicity of Vitamin A

Vitamin A is both acutely and chronically toxic. Acutely, large doses of vitamin A (in excess of 300 mg in a single dose to adults) cause nausea, vomiting, and headache, with increased pressure in the cerebrospinal fluid - signs that disappear within a few days. After a very large dose, there may also be drowsiness and malaise, with itching and exfoliation of the skin extremely high doses can prove fatal. Single doses of 60 mg of retinol are given to children in developing countries as a...

Toxicity of Vitamin D

Intoxication with vitamin D causes weakness, nausea, loss of appetite, headache, abdominal pains, cramps, and diarrhea. More seriously, it also causes hypercalcemia, with plasma concentrations of calcium between 2.75 to 4.5 mmol per L, compared with the normal range of 2.2 to 2.5 mmol per L. At plasma concentrations of calcium above 3.75 mmol per L, vascular smooth muscle may contract abnormally, leading to hypertension and hypertensive encephalopathy. Hypercalciuria may also result in the...

Metabolic Functions Of Vitamin E

The best-established function of vitamin E is as a lipid-soluble antioxidant in plasma lipoproteins and cell membranes. Many of the antioxidant actions are unspecific, and a number of synthetic antioxidants have a vitamin E-sparing effect. There is considerable overlap between the antioxidant roles of vitamin E and selenium (Section 4.3.2). A number of studies have shown that a-tocopherol has a role in modulation of gene expression and regulation of cell proliferation (Section 4.3.3),...

Vitamin B6 and the Premenstrual Syndrome

Studies during the 1960s showing that vitamin B6 supplements were effective in overcoming some of the side effects of (high-dose) oral contraceptives have led to the use of vitamin B6 in treatment of the premenstrual syndrome - the condition of nervousness, irritability, emotional disturbance, headache, and or depression suffered by many women for up to 10 days before menstruation. Twelve placebo-controlled, double-blind trials of vitamin B6 in the premenstrual syndrome were reviewed by...

Yyyy

Oh oh oh I I I ch2- ch ch ch ch2oh I Figure 7.2. Products of riboflavin metabolism. Relative molecular masses (Mr) riboflavin, 376.4 lumiflavin, 256.3 8- and 7-carboxylumichrome, 296.2 and lumichrome, 242.2. flavokinase. There is some evidence that 8-hydroxymethylriboflavin may have biological activity it is not known whether or not it is involved in the formation of 8-a-amino acid covalent links in proteins. Significant amounts of both of these hydroxylated derivatives and their onward...

Biosynthesis of Pantothenic Acid

Plants and microorganisms are capable of the de novo synthesis of pantothenic acid from oxo-isovalerate and aspartate, by the pathway shown in Figure 12.3 animals are reliant on a preformed source of pantothenic acid. Oxo-isovalerate may be formed by the transamination of valine it is also the immediate precursor of valine biosynthesis and an intermediate in the synthesis of leucine (both are essential amino acids in mammals). Oxo-iso-valerate undergoes a hydroxymethyl transfer reaction, in...

Drug Induced Pellagra

The antituberculosis drug isoniazid ( so-nicotinic acid hydrazide) can cause pellagra by forming a biologically inactive complex with pyridoxal phosphate, the metabolically active form of vitamin B6, and hence reducing the activity of kynureninase (Section 8.3.3.2). This isoniazid-induced pellagra responds to the administration of niacin supplements. However, isoniazid may also cause peripheral neuropathy, which responds to vitamin B6 and not niacin, and therefore it became usual to give...

Vitamin E Tocopherols and Tocotrienols

For a long time, it was considered that, unlike the other vitamins, vitamin E had no specific functions rather it was the major lipid-soluble, radical-trapping antioxidant in membranes. Many of its functions can be met by synthetic antioxidants however, some of the effects of vitamin E deficiency in experimental animals, including testicular atrophy and necrotizing myopathy, do not respond to synthetic antioxidants. The antioxidant roles of vitamin E and the trace element selenium are closely...

Inactivation and Excretion of Calcitriol

Most vitamin D is excreted in the bile less than 5 is excreted as water-soluble metabolites in urine. Some 2 to 3 of the vitamin D in bile is cholecalciferol, calcidiol, and calcitriol, but most is a variety of polar metabolites and their glucuronide conjugates. In most tissues, the major pathway for inactivation of calcitriol is by way of 24-hydroxylation to calcitetrol, then onward oxidation byway of the 24-oxo-derivative, 23-hydroxylation, and oxidation to calcitroic acid (see Figure 3.3)....

Antioxidant Functions of Vitamin E

Vitamin E functions as a lipid antioxidant both in vitro and in vivo a number of synthetic antioxidants will prevent or cure most of the signs of vitamin E deficiency in experimental animals. Polyunsaturated fatty acids undergo oxidative attack by hydroxyl radicals and superoxide to yield alkylperoxyl (alkyl-dioxyl) radicals, which perpetuate a chain reaction in the lipid-withpotentially disastrous consequences for cells. Similar oxidative radical damage can occur to proteins (especially in a...

Hydroxylation of Cholecalciferol

There are two separate cytochrome P450-dependent mixed-function oxidases in the liver that catalyze the 25-hydroxylation of cholecalciferol (see Figure 3.3). The activity of both enzymes is higher in tissue from vitamin D-deficient animals, and there is some evidence that calcitriol either inhibits or represses them. The mitochondrial enzyme (CYP27A), which has a Km of 10-5 M, catalyzes the hydroxylation of cholecalciferol twice as fast ergocalciferol. It also acts on a number of C-27 steroids...

Vitamin E Deficiency in Experimental Animals

Vitamin E deficiency in experimental animals results in a number of different conditions, with considerable differences between different species in their susceptibility to different signs of deficiency. As shown in Table 4.2, some of the lesions can be prevented or cured by the administration of synthetic an-tioxidants, and others respond to supplements of selenium. Vitamin E-deficient female animals suffer death and resorption of the fetuses. This was the basis of the original biological...

Vitamin C Ascorbic Acid

Vitamin C is a vitamin for only a limited number of vertebrate species humans and the other primates, the guinea pig, bats, the passeriform birds, and most fishes. Most insects and invertebrates are also incapable of ascorbate synthesis. Ascorbate is synthesized as an intermediate in the gulonolactone pathway of glucose metabolism in those vertebrate species for which ascorbate is a vitamin, one enzyme of the pathway, gulonolactone oxidase, is absent. The vitamin C deficiency disease, scurvy,...

Digestion and Absorption of Folates

Within the intestinal lumen, folate conjugates are hydrolyzed by glutamate carboxypeptidase (pteroylpolyglutamate hydrolase, also known as conjugase), a zinc-dependent enzyme of the pancreatic juice, bile, mucosal brush border, and lysosomes of enterocytes and other cells. In the rat, conjugase is mainly a pancreatic enzyme, acting in the intestinal lumen, whereas in human beings the conjugase of the mucosal brush border and enterocytes is more important. Conjugase is a general poly-y-glutamyl...

Retinol and Retinaldehyde in the Visual Cycle

Binding of retinaldehyde to the protein opsin in the rods, and related proteins in the cones, of the retina gives a highly sensitive signal transduction and amplification system, such that a single photon results in a measurable change in the current across the outer section membrane, and hence the propagation of a nerve impulse. In the outer segment of rod cells, opsin may constitute more than 90 of the total protein it is present at a concentration of approximately 3 mmol per L. Photoexcited...

The Methionine Load Test

The metabolism of methionine, shown in Figure 9.5, includes two pyridoxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionine synthetase is little affected by vitamin B6 deficiency, presumably because it has a high affinity for its cofactor, and possibly also a slow rate of turnover. However, cystathionase activity falls in vitamin B6 deficiency, and there is an increase in the tissue content of inactive apoenzyme. The result of this is that in vitamin B6...

Biotinidase

Proteolysis of biotin-containing enzymes releases biocytin, either as free biotinyl-lysine or as a variety of small biocytin-containing peptides the e-amino lysine link of biocytin is not a substrate for peptidases. Biocytin is hydrolyzed by biotinidase, which acts on free or peptide-incorporated biocytin to release biotin, but has no general peptidase or esterase activity. Biotinidase is most active toward free biocytin, but it will also release biotin from biocytin-containing peptides. The...

The Vitamins

The vitamins are a disparate group of compounds they have little in common either chemically or in their metabolic functions. Nutritionally, they form a cohesive group of organic compounds that are required in the diet in small amounts (micrograms or milligrams per day) for the maintenance of normal health and metabolic integrity. They are thus differentiated from the essential minerals and trace elements (which are inorganic) and from essential amino and fatty acids, which are required in...

Biotin in Regulation of the Cell Cycle

Biotin is essential for cell proliferation. Peripheral blood mononuclear cells appear to take up biotin by a system that is distinct from the sodium-dependent multivitamin transporter that is responsible for intestinal and renal uptake of biotin (Section 11.1). In response to mitogenic stimuli the uptake of biotin increases several-fold, with no change in the activity of the sodium-dependent transporter. At the same time, there is an increase in the rate of expression of methylcrotonyl CoA,...

Leucine Aminomutase

Leucine aminomutase catalyzes isomerization of leucine and -leucine. As with methylmalonyl CoA mutase, the reaction involves cleavage of the Co-C bond to form the 5' -deoxyadenosyl radical, which then removes hydrogen from the f -carbon of leucine (or the a - carbon of f -leucine), followed by migration of the amino group and attack by the product radical on deoxyadenosine. In addition to adenosylcobalamin, the reaction is pyridoxal phosphate-dependent (Section 9.3.1) presumably, migration of...

Pyridoxal Phosphate in Amino Acid Metabolism

The various reactions of pyridoxal phosphate in amino acid metabolism shown in Table 9.1 all depend on the same chemical principle - the ability to stabilize amino acid carbanions and to labilize bonds about the a-carbon, by pyridoxal phosphate internal aldimine (Schiff base) R C COO pyridoxamine phosphate O Figure 9.2. Reactions of pyridoxal phosphate-dependent enzymes with amino acids. reaction of the a-amino group of the substrate with the carbonyl group of the coenzyme. The ring nitrogen of...

Interconversion of Substituted Folates

Methylene-, methenyl-, and 10-formyl-tetrahydrofolates are freely interconvertible. The two activities involved - methylene-tetrahydrofolate dehydrogenase and methenyl-tetrahydrofolate cyclohydrolase - form a trifunctional enzyme with 10-formyl-tetrahydrofolate synthetase (Paukert et al., 1976). This means that single-carbon fragments entering the folate pool in any form other than as methyl-tetrahydrofolate can be readily available for any of the biosyn-thetic reactions shown in Figure 10.4....

Drug Induced Vitamin B6 Deficiency

Vitamin B6 deficiency may result from the prolonged administration of drugs that are carbonyl-trapping reagents, and hence can form biologically inactive adducts with pyridoxal and pyridoxal phosphate. Such compounds include penicillamine, the antituberculosis drug isoniazid, and the anti-Parkinsonian drugs Benserazide and Carbidopa. Such drug-induced vitamin B6 deficiency frequently manifests as the tryptophan-niacin deficiency disease pellagra (Section 8.5.6). As discussed in Section 8.3,...

Bibliography

Achkar CC, Derguini F, Blumberg B, Langston A, Levin AA, Speck J, Evans RM, Bolado J Jr., Nakanishi K, Buck J, et al. (1996) 4-Oxoretinol, a new natural ligand and transac-tivator of the retinoic acid receptors. Proceedings of the National Academy of Sciences of the USA 93, 4879-84. Adams PW, Wynn V, Folkard J, and Seed M (1976) Influence of oral contraceptives, pyri-doxine (vitamin B6) and tryptophan on carbohydrate metabolism. Lancet (i), 759-64. Adiga PR (1994) Riboflavin carrier protein in...

Absorption and Metabolism of Carotenoids

Carotenoids are absorbed passively, dissolved in lipid micelles various studies have estimated the biological availability and absorption of dietary carotene as between 5 to 60 , depending on the nature of the food, whether it is cooked or raw, and the amount of fat in the meal. In addition, much of the carotene in foods is present as crystals that may not dissolve to any significant extent in intestinal contents (Parker, 1989 1996 Parker etal., 1999 Hickenbottom et al., 2002 Ribaya-Mercado,...

The Pellagragenic Effect of Excess Dietary Leucine

Pellagra was a major problem in parts of India where jowar (Sorghum vulgare) is the dietary staple, despite the fact that the tryptophan content of sorghum proteins is higher than that of maize, the cereal traditionally associated with endemic pellagra. The intake of tryptophan and niacin was as great among people whose dietary staple was jowar as that of rice eaters, yet pellagra was common among jowar eaters and not in rice-eating communities, suggesting that the relatively high content of...

Niacin

Niacin is unusual among the vitamins in that it was discovered as a chemical compound, nicotinic acid produced by the oxidation of nicotine, in 1867 -long before there was any suspicion that it might have a role in nutrition. Its metabolic function as part of what was then called coenzyme II nicotinamide adenine dinucleotide phosphate (NADP) was discovered in 1935, again before its nutritional significance was known. It is not strictly correct to regard niacin as a vitamin. Its metabolic role...

Vitamin K Vitamers

As shown in Figure 5.1, compounds with vitamin K activity have a 2-methyl-1,4-naphthoquinone ring. There are two naturally occurring vitamers phylloquinone (from plants) has a phytyl side chain, whereas the menaquinones (from bacteria) have a polyisoprenyl side chain, with up to 15 isoprenyl units (most commonly 6 to 10), shown by menaquinone-w. Bacteria also form a variety of Figure 5.1. Vitamin K vitamers and the vitamin K antagonists dicoumarol and warfarin. Relative molecular masses (Mr)...

Photosynthesis of Cholecalciferol in the Skin

Cholecalciferol Synthesis

Cholecalciferol is formed nonenzymically in the skin by UV irradiation of 7-dehydrocholesterol, as shown in Figure 3.2. 7-Dehydrocholesterol is an HO v calciol (cholecalciferol) Figure 3.2. Synthesis of calciol from 7-dehydrocholesterol in the skin. intermediate in the synthesis of cholesterol that accumulates in the skin, but not other tissues. It is synthesized in the sebaceous glands, secreted onto the surface of the skin, and then absorbed into the epidermis. It is found throughout the...

Phytoestrogens

A number of compounds shown in Figure 14.12 that occur in plant foods as glycosides and other conjugates have weak estrogenic antiestrogenic actions, and are collectively known as phytoestrogens. They all have two hydroxyl groups that are the same distance apart as the hydroxyl groups of estradiol and can bind to estrogen receptors. The amounts of phytoestrogens produced increase in response to microbial and insect attack, suggesting that they have antibacterial or antifungal actions in the...

Fatty Liver and Kidney Syndrome in Biotin Deficient Chicks

Birds are especially sensitive to biotin deficiency, at least partly because their intestinal flora make little or no contribution to biotin intake. This is of considerable commercial importance with intensively reared poultry. In adult birds, biotin deficiency does not affect egg production, but does reduce the amount of biotin in the eggs, thus impairing embryonic development. In severe deficiency, the hatchability of the eggs can fall to near zero. In young chicks, biotin deficiency is...

Inhibition of Nitrosamine Formation by Ascorbate

In addition to dietary sources, a significant amount of nitrate is formed en-dogenously by the metabolism of nitric oxide - 1 mg per kg of body weight per day (about the same as the average dietary intake), increasing 20-fold in response to inflammation and immune stimulation. There is considerable secretion of nitrate in saliva, and up to 20 of this may be reduced to nitrite by oral bacteria. Under the acidic conditions of the stomach, nitrite can react with amines in foods to form...

The Role of Tetrahydrobiopterin in Nitric Oxide Synthase

Nitric oxide ( NO) was discovered as the endothelium-derived relaxation factor. It is produced in the central nervous system, lungs, macrophages, and vascular endothelial cells in response to a variety of stimuli. It initiates a cGMP signaling cascade. In smooth muscle, nitric oxide activates a cytosolic guanylate cyclase by reacting with a heme-containing regulatory subunit and causing a conformational change. This results in smooth muscle relaxation and hence vasodilatation as a result of...

The Role of Pyridoxal Phosphate in Steroid Hormone Action and Gene Expression

Steroid hormones act by binding to, and activating, nuclear receptors that then bind to hormone response elements on DNA, increasing (or sometimes decreasing) the transcription of specific genes. Early studies showed that pyridoxal phosphate reacts with a lysine residue in the steroid receptor protein and extracts the steroid-receptor complex from tight nuclear binding. The specificity for pyridoxal phosphate, but not pyridoxal, and the low physiological concentration at which the effect can be...

Metabolism and Excretion of Ascorbate

Ascorbic Acid Role Catecholemines

The major fate of ascorbic acid in human metabolism is excretion in the urine, either unchanged or as dehydroascorbate and diketogulonate. Both ascorbate and dehydroascorbate are filtered at the glomerulus, then reabsorbed, by a sodium-independent process. Reabsorbed dehydroascorbate is reduced to ascorbate in the kidneys. At plasma concentrations above about 85 mol per L, the renal transport systemis saturated, and ascorbate is excreted quantitatively with increasing intake. Ascorbate...

Quinone Catalysts in Mammalian Enzymes

Mammalian copper-dependent oxidases, including plasma amine oxidases (the semicarbazide-sensitive, chlorgyline-resistant, amine oxidases, not the flavin-dependent monoamine oxidases) and lysyl oxidase (which is involved in the cross-linking of collagen and elastin) have long been known to contain a reactive carbonyl group that is essential for activity. Although this was originally assumed to be pyridoxal phosphate, there is no evidence for its presence in these enzymes, and the apoenzymes...

Folate and Other Pterins and Vitamin B12

Folic acid functions in the transfer of one-carbon fragments in a wide variety of biosynthetic and catabolic reactions it is therefore metabolically closely related to vitamin B12, which also functions in one-carbon transfer. Deficiency of either vitamin has similar clinical effects, and it seems likely that the main effects of vitamin B12 deficiency are exerted by effects on folate metabolism. The pterins include the redox cofactors biopterin and molybdopterin, as well as various insect...

Vitamin B6

Vitamin B6 has a central role in the metabolism of amino acids in transaminase reactions (and hence the interconversion and catabolism of amino acids and the synthesis of nonessential amino acids), in decarboxylation to yield biologically active amines, and in a variety of elimination and replacement reactions. It is also the cofactor for glycogen phosphorylase and a variety of other enzymes. In addition, pyridoxal phosphate, the metabolically active vitamer, has a role in the modulation of...

Utilization of One Carbon Substituted Folates

Thymidylate Synthetase

As shown in Figure 10.4, 10-formyl-tetrahydrofolate and methylene-tetra-hydrofolate are donors of one-carbon fragments in a number of biosynthetic reactions, including the synthesis of purines, pyrimidines, porphyrins, and Figure 10.8. Synthesis of thymidine monophosphate. Thymidylate synthetase, EC 2.1.1.45 and dihydrofolate reductase, EC 1.5.1.3. THF, tetrahydrofolate. Figure 10.8. Synthesis of thymidine monophosphate. Thymidylate synthetase, EC 2.1.1.45 and dihydrofolate reductase, EC...

Transamination of Amino Acids Aminotransferase Reactions

Hydrolysis of the a-carbon-amino bond of the ketimine results in the release of the oxo-acid corresponding to the amino acid substrate, leaving pyridoxamine phosphate at the catalytic site of the enzyme. In this case, there is no reformation of the internal Schiff base to the reactive lysine residue. This is the half-reaction of transamination. The process is completed by reaction of pyridoxamine phosphate with a second oxo-acid substrate, forming an intermediate ketimine, then by the reverse...

Thiamin Diphosphate in the Oxidative Decarboxylation of Oxoacids

The reaction of the pyruvate dehydrogenase complex is shown in Figure 6.2 the reactions of the 2-oxoglutarate and branched-chain oxo-acid dehydrogenase complexes follow the same sequence, and the multienzyme complexes are similar. Thiamin binds the oxo-acid substrate, decarboxylating it to an active aldehyde intermediate. This is then transferred to enzyme-bound lipoamide, reducing the disulfide bridge of the lipoamide and forming a thioester. The resultant acyl group is transferred to coenzyme...

Dietary Folate Equivalents

The folate in foods consists of a mixture of the different one-carbon substituted derivatives, with varying numbers of conjugated glutamyl residues. The biological availability of these vitamers differs and is consistently lower than that of free folic acid (pteroyl monoglutamate), which is the compound that Figure 10.1. Folate vitamers, the folate antagonist methotrexate, molybdopterin, and tetrahydrobiopterin. Relative molecular masses (Mr) tetrahydrofolic acid, 445.4 methotrexate, 454.5 and...

Toxicity of Vitamin B6

Animal studies have shown that vitamin B6 is neurotoxic, causing peripheral neuropathy, with ataxia, muscle weakness, and loss of balance in dogs given 200 mg ofpyridoxine per kg of body weight for 40 to 75 days, and the development of a swaying gait and ataxia within 9 days at a dose of300 mg per kg body weight (Phillips et al., 1978 Krinke et al., 1980). At the lower dose of 50 mg per kg of body weight, there are no clinical signs of toxicity, but histologically there is loss of myelin in...

The Possible Essentiality of Inositol

There is no evidence that inositol is a dietary essential, because it is synthesized by all eukaryotic cells. Infants may have a higher requirement than can be met by endogenous synthesis, and dietary inositol is a growth factor for the newborn mouse. In female gerbils, inositol is a dietary essential, and deficiency Figure 14.6. Formation of inositol trisphosphate and diacylglycerol. Phosphatidylinos-itol kinase, EC 2.7.1.67 and hormone-sensitive phospholipase, EC 3.1.4.3. Figure 14.6....

The Role of Biotin in Carboxylation Reactions

The reactive intermediate is 1-ALcarboxy-biotin (see Figure 11.1) bound to a lysine residue of the enzyme as biocytin, which is formed from enzyme-bound biocytin by reaction with bicarbonate. The biotin-dependent carboxylases catalyze a two-step reaction 1. enzyme-biotin + ATP + HCO3- enzyme-biotin-COOH + ADP + Pi 2. enzyme-biotin- COOH + acceptor enzyme-biotin + acceptor-COOH. In the bacterial biotin-dependent decarboxylases, reaction 2 proceeds from right to left, followed by decomposition of...

Marginal Compounds and Phytonutrients

In addition to the established vitamins, a number of organic compounds have clear metabolic functions they can be synthesized in the body, but it is possible that under some circumstances (as in premature infants and patients maintained on long-term total parenteral nutrition) endogenous synthesis may not be adequate to meet requirements. These compounds include biopterin (Section 10.4), carnitine (Section 14.1), choline (Section 14.2), creatine (Section 14.3), inositol (Section 14.4),...

Enzyme Induction by Biotin

Biotin acts to induce glucokinase, phosphofructokinase, and pyruvate kinase (key enzymes of glycolysis), phosphoenolpyruvate carboxykinase (a key enzyme of gluconeogenesis), and holocarboxylase synthetase, acting via a cell-surface receptor linked to formation of cGMP and increased activity of RNA polymerase. The activity of holocarboxylase synthetase (Section 11.2.2) falls in experimental biotin deficiency and increases with a parallel increase in mRNA during repletion (Chauhan and...

Biotin Vitamin H

Biotin Protein Ligase

Biotin was originally discovered as part of the complex called bios, which promoted the growth of yeast, and separately, as vitamin H, the protective or curative factor in egg white injury - the disease caused by diets containing large amounts of uncooked egg white. The glycoprotein avidin in egg white binds biotin with high affinity. This has been exploited to provide a variety of extremely sensitive assay systems. Dietary deficiency of biotin sufficient to cause clinical signs is extremely...

Pantothenic Acid

Pantothenic acid has a central role in energy-yielding metabolism as the functional moiety of coenzyme A (CoA), in the biosynthesis of fatty acids as the prosthetic group of acyl carrier protein, and through its role in CoA in the mitochondrial elongation of fatty acids the biosynthesis of steroids, porphyrins, and acetylcholine and other acyl transfer reactions, including postsynthetic acylation of proteins. Perhaps 4 of all known enzymes utilize CoA derivatives. CoA is also bound by disulfide...

Pharmacological Uses of Vitamin D

Multiple sclerosis is less common among people living at high altitude, where UV exposure is greater. Patients with multiple sclerosis have poor vitamin D status and low bone density, although this could be a result of the disease rather than a cause. Calcitriol prevents the development of experimental autoimmune encephalomyelitis in mice, a widely accepted model of multiple sclerosis, and it has been suggested that vitamin D supplements may protect genetically susceptible people from...

Pharmacological Uses of Vitamin A Retinoids and Carotenoids

2.5.2.1 Retinoids in Cancer Prevention and Treatment Since the discovery of vitamin A, the observation that the main effects of deficiency are hyperplasia and loss of differentiation of squamous epithelium has raised speculation that the vitamin may be associated with carcinogenesis. Either deficiency may be a risk factor for cancer or increased intake may be protective. Deficient animals develop more spontaneous tumors and are more sensitive to chemical carcinogens, whereas liver reserves of...

Criteria of Vitamin Adequacy and the Stages of Development of Deficiency

For any nutrient, there is a range of intakes between that which is clearly inadequate, leading to clinical deficiency disease, and that which is so much in excess of the body's metabolic capacity that there may be signs of toxicity. Between these two extremes is a level of intake that is adequate for normal health and the maintenance of metabolic integrity, and a series of more precisely definable levels of intake that are adequate to meet specific criteria and may be used to determine...

Neurological Degeneration in Vitamin B2 Deficiency

Vitamin B12 deficiency is accompanied by neurological degeneration in about two-thirds of cases - either peripheral neuropathy or subacute combined degeneration of the spinal cord. Folic acid deficiency is only rarely associated with similar neurological damage. Subacute combined degeneration of the spinal cord is from demyelination of the corticospinal tracts and posterior columns of the spinal cord, leading to gait ataxia and loss of position sense and vibratory sense. Peripheral neuropathy...

The Tryptophan Load Test

The tryptophan load test for vitamin B6 nutritional status (the ability to metabolize a test dose of tryptophan) is one of the oldest metabolic tests for functional vitamin nutritional status. It was developed as a result of observation of the excretion of an abnormal-colored compound, later identified as the tryptophan metabolite xanthurenic acid. Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new...

Other Functions of Calcitriol

Calcitriol receptors have been identified in a variety of tissues in some of these, the effect of calcitriol is to induce the synthesis of calbindin-D in others, it is regulation of cell proliferation and differentiation. Calbindin-D9k has been identified in both the placenta and yolk sac of rats and mice, and increases in the later stages of gestation when there is considerable fetal uptake of calcium for mineralization of the skeleton. In both birds and mammals, calcitriol is also required...

The Possible Essentiality of Taurine

Taurine is a dietary essential in the cat, which is an obligate carnivore with a limited capacity for taurine synthesis from cysteine. On a taurine-free diet, neither supplementary methionine nor cysteine will maintain normal plasma concentrations of taurine, because cats have an alternative pathway of cysteine metabolism reaction with mevalonic acid to yield felinine which is excreted in the urine. The activity of cysteine sulfinic acid decarboxylase in cat liver is very low. It is not known...

The Neuronal Function of Thiamin Triphosphate

Pentose Phosphate Pathway

Early studies showed that the development of neurological abnormalities in thiamin deficiency did not follow the same time course as the impairment of pyruvate and 2-oxoglutarate dehydrogenase or transketolase activities. The brain regions in which metabolic disturbances are most marked were not those that are vulnerable to anatomical lesions. These studies suggested a function for thiamin in the nervous system other than its coenzyme role. Thiamin triphosphate is formed in brain and skeletal...

Oxidation and Reduction of Ascorbate

As shown in Figure 13.3, oxidation of ascorbic acid, for example, by the reduction of superoxide to hydrogen peroxide or Fe3 to Fe2 , and similar reduction of other transition metal ions, proceeds by a one-electron process, forming the monodehydroascorbate radical. The radical rapidly disproportionates into ascorbate and dehydroascorbate. Most tissues also have both nicotinamide adenine dinucleotide phosphate NADPH and reductases, which reduce the radical back to ascorbate. Ascorbate is thus an...

Assessment of Vitamin Nutritional Status

The same criteria used to define requirements can also be used to assess vitamin nutritional status. Although vitamin deficiencies give rise to more-or-less clearly defined signs and symptoms, diagnosis is not always easy, so biochemical assessment is frequently needed to confirm a presumptive diagnosis. Furthermore, whereas experimental studies may involve feeding diets deficient in one nutrient, but otherwise complete, it is unlikely that under normal conditions an individual would have such...

Impaired Glucose Tolerance

Impaired glucose tolerance is common in pregnancy and may be severe enough to be classified as diabetes mellitus so-called gestational diabetes , which usually resolves on parturition. A number of studies have shown that supplements of 100 mg of vitamin B6 per day result in improved glucose tolerance Rose et al., 1975 . As discussed in Section 9.5.4.2, estrogen metabolites inhibit kynureninase, and they also lead to reduced activity of kynurenine hydroxylase. As a result, in pregnancy or in...

Stimulation of Intestinal Calcium and Phosphate Absorption

Early studies showed that, after the administration of 3H cholecalciferol or ergocalciferol to vitamin D-deficient animals, there is marked accumulation of 3H calcitriol in the nuclei of intestinal mucosal cells. Physiological doses of vitamin D cause an increase in the intestinal absorption of calcium in deficient animals the response is faster alter the administration of calcidiol and faster still after calcitriol. There are two separate responses of intestinal mucosal cells to calcitriol a...

The Role of Calcitriol in Bone Metabolism

In addition to the role of bone mineral as a structural component of bone, it can be regarded as a major reserve of calcium for the body. In an adult, the skeleton contains 25 mol of calcium, whereas the total extracellular fluids contain only about 25 mmol. Parathyroid hormone, calcitonin, and calcitriol regulate the intestinal absorption and renal excretion of calcium, and the mobilization and deposition of bone calcium, maintaining the plasma concentration in a narrow range between 2.2 to...

Antihypertensive Actions of Vitamin B6

Vitamin B6 depletion leads to the development of hypertension in experimental animals, which is normalized within 24 hours by repletion with the vitamin. Four mechanisms, which are not mutually exclusive, have been proposed to account for this Dakshinamurti and Lal, 1992 Dakshinamurti, 2001 1. Central effects on blood pressure regulation as a result of decreased synthesis of brain GABA and serotonin 5-hydroxytryptamine . Glutamate decarboxylase activity in the nervous system is especially...

Nonnutritional Rickets and Osteomalacia

Induction of cytochrome P450 enzymes by barbiturates and other anticonvulsants can result in increased catabolism of calcidiol, and hence secondary, drug-induced osteomalacia. The antituberculosis drug isoniazid inhibits cholecalciferol 25-hydroxylase, and again prolonged administration can cause osteomalacia. Three conditions associated with defective 1-hydroxylation of calcidiol can all be treated by the administration of either calcitriol itself or 1a-hydroxycholecalciferol, which is a...

Vitamin B2 Riboflavin

Riboflavin Fad

Riboflavin has a central role as a redox coenzyme in energy-yielding metabolism and a more recently discovered role as the prosthetic group of the cryptochromes in the eye - the blue-sensitive pigments that are responsible for day-length sensitivity and the setting of circadian rhythms. Dietary deficiency is relatively widespread, yet is apparently never fatal there is not even a clearly characteristic riboflavin deficiency disease. In addition to intestinal bacterial synthesis of the vitamin,...

Nongenomic Actions of Retinoids

In addition to its genomic functions, retinoic acid also has a number of non-genomic functions. It enhances the stability of keratin mRNA, leading to increased synthesis of this protein Crowe, 1993 . Retinoic acid acts also as an effector in response to transmembrane signaling by retinoylation of target proteins. In the synthesis of most glycoproteins containing mannose, the intermediate carrier of the mannosyl moiety is the polyene dolichol phosphate. However, in some systems, retinyl...