Markers of DNA Oxidative Damage

There is increased formation of 8-hydroxyguanine (a marker of oxidative radical damage) in DNA during (short-term) vitamin C depletion (Fraga et al., 1991). In addition, the rate of removal of 8-hydroxyguanine from DNA by excision repair, and thus the urinary excretion of 8-hydroxyguanine, is affected by vitamin C status (Cooke et al., 1998). These results suggest that measurement of 8-hydroxyguanine in DNA, or its urinary excretion, may provide a way of estimating requirements to meet a...

Vitamin K Deficiency

Vitamin K deficiency results in prolonged prothrombin time, and eventually hemorrhagic disease, as a result of the impairment of synthesis of the vitamin K-dependent blood clotting proteins. Although osteocalcin synthesis is similarly impaired, the effects on blood clotting predominate, and effects of vitamin K deficiency on bone mineralization can only be demonstrated in experimental animals if they are transfused with preformed blood clotting factors. Otherwise, they suffer fatal hemorrhage...

Urinary Excretion of Vitamin B6 and 4Pyridoxic Acid

Some biologically active vitamin B6 is excreted in the urine, and a number of studies have assessed nutritional status by microbiological measurement of this excretion it is difficult to interpret the results in terms of underlying nutritional status rather than as a reflection of recent intake, although the excretion does fall in deficiency (Sauberlich et al., 1972, 1974). A possibly important source of error here is that minor renal damage, resulting in albuminuria, will result in a...

Folate Requirements

At the time that the U.K. and European Union reference intakes of folate shown in Table 10.3 were being discussed, the results of intervention trials for the prevention of neural tube defects (Section 10.9.4) were only just becoming available. At that time, there was no information concerning the effects of folate status onhyperhomocysteinemia (Section 10.3.4.2). The U.S. Canadian report (Institute of Medicine, 1998) notes specifically that protective effects with respect to neural tube defects...

Pernicious Anemia

Pernicious anemia is the megaloblastic anemia due specifically to vitamin B12 deficiency, in which there is also spinal cord degeneration and peripheral neuropathy. It is a disease of later life. Only about 10 of patients are under age 40 by the age of 60, about 1 of the population is affected, rising to 2 to 5 of people over age 65, as a result of atrophic gastritis and thus impaired absorption of vitamin B12 (Section 10.7.1). Early studies suggested that folate supplements exacerbate or...

Functions of Vitamin E in Cell Signaling

Both in vitro and in vivo a-tocopherol inhibits platelet aggregation in response to agonists such as arachidonic acid and phorbol ester the effect seems to be mediated by a protein kinase C mechanism. In cultured cells, a-tocopherol lowers protein kinase C activity, apparently by activating diacylglycerol ki-nase and phosphoprotein phosphatase, and hence initiating the dephospho-rylation and inactivation of protein kinase C (Steiner, 1999 Freedman and Keaney, 2001). Inhibition of protein kinase...

The Formation and Turnover of ACP

Although fatty acid f-oxidation is catalyzed by a series of intramitochon-drial enzymes, and the fatty acyl chain is carried by CoA, fatty acid synthesis is catalyzed by a cytosolic-multienzyme complex in which the growing fatty acyl chain is bound by thioester linkage to an enzyme-bound 4 -phospho-pantetheine residue. This component of the fatty acid synthetase complex is ACP. Apo-ACP is activated by a transferase, holo-ACP synthetase, which transfers 4'-phosphopantetheine from CoA to the...

Oxoglutarate Linked Iron Containing Hydroxylases

As shown in Table 13.1, a number of iron-containing hydroxylases share an unusual reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of 2-oxoglutarate. Proline and lysine hydroxylases are required for the postsynthetic modification of collagen, and proline hydroxylase also for the postsynthetic modification of osteocalcin (Section 5.3.3) and other proteins. Aspartate f -hydroxylase is required for the postsynthetic modification of protein C, the vitamin...

The dUMP Suppression Test

The ability of deoxyuridine to suppress the incorporation of 3H thymidine into DNA in rapidly dividing cells (Section 10.3.3.3) can also be used to give an index of functional folate nutritional status. Bone marrow biopsy samples provide the best source, and this has been generally a research tool rather than a screening test however, transformed lymphocytes can also be used. The dUMP suppression test is probably the most sensitive index of folate depletion abnormalities are apparent within 5...

Pantothenic Acid Deficiency in Experimental Animals

Pantothenic acid deficiency in black and brown rats leads to a loss of fur color - at one time, pantothenic acid was known as the antigray hair factor. There is no evidence that the normal graying of hair with age is related to pantothenic acid nutrition, nor that pantothenic acid supplements have any effect on hair color. In pantothenic acid-deficient rats, tissue CoA is depleted, affecting mainly the peroxisomal oxidation of fatty acids, which is mainly concerned with detoxication...

Assessment Of Vitamin D Status

Before gross anatomical deformities are apparent in vitamin D-deficient children, bone density is lower than normal, and this can be detected by radiography. This preclinical condition is known as radiological rickets. At an earlier stage of deficiency, there is a marked elevation of plasma alkaline phosphatase released by osteoclastic activity the reference range for alkaline phosphatase in children is 75 to 250 units per L. For many years, this stage of biochemical rickets was used as a means...

Vitamin C in Cardiovascular Disease

Vitamin C deficiency is associated with an increased risk of atherosclerosis, but there is little evidence of protective effects at intakes greater than needed to meet requirements (Jacob, 1998). A systematic review (Ness et al., 1996) found limited evidence of benefits of high intakes of vitamin C in reducing the incidence of stroke, but inconsistent evidence with respect to coronary heart disease. Scorbutic guinea pigs develop hypercholesterolemia, which may lead to the development of...

Assessment of Vitamin A Nutritional Status

An early sign of vitamin A deficiency is impaired dark adaptation - an increase in the time taken to adapt to seeing in dim light. The apparatus required is not suitable for use in field studies, or for use with children (the group most at risk from deficiency), and the dark adaptation test is largely of historical interest. Balance, color vision, and the senses of taste and smell are also affected in early deficiency, but none of these provides a sensitive or specific test of status. Liver...

Bacterial Biosynthesis of Vitamin B2

Vitamin B12 is synthesized only by bacteria and possibly some algae. There are no plant sources of the vitamin, and no plant enzymes are known to require vitamin B12 as a coenzyme. A number of reports have suggested that vitamin B12 occurs in some algae, but this may be the result of bacterial contamination of the water in which they were grown. Nori, made from the edible seaweed Porphyra tenera, has been reported to contain biologically active cobalamin when it is fresh but, on drying, there...

Upper Levels of Intake

Even large intakes of phylloquinone have no apparent toxic effects, although they may be dangerous in patients receiving anticoagulant therapy (Section 5.4). Menadione and its water-soluble derivatives are potentially toxic in excess and have been reported to cause hemolytic anemia, hyperbilirubinemia, central nervous system toxicity, and methemoglobinemia in the newborn. Table 5.1 Reference Intakes of Vitamin K ( g day) Table 5.1 Reference Intakes of Vitamin K ( g day) FAO, Food and...

Carnitine as an Ergogenic

By extrapolation from the muscle weakness and fatigue seen in children with genetic defects of carnitine biosynthesis or metabolism, it has been assumedthat supplementary carnitine mayhave aperformance-enhancing or ergogenic action, and supplements are commonly taken by athletes and bodybuilders. There is little evidence that supplements have any effect on muscle work output. Although supplements increase plasma carnitine, they do not significantly increase the muscle content (Brass, 2000)....

Carcinoid Syndrome

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as...

Tissue Uptake and Metabolism of Folate

Methyl-tetrahydrofolate from the intestinal mucosa circulates bound to albumin and is the main vitamer for uptake by extrahepatic tissues. Small amounts of other one-carbon substituted folates also circulate (about 10 to 15 of plasma folate is 10-formyl-tetrahydrofolate) and are also available for tissue uptake. There are two mechanisms for tissue uptake of folate 1. The reduced folate transporter is a transmembrane protein with a high affinity for methyl-tetrahydrofolate and a low affinity for...

The Formation of CoA from Pantothenic Acid

CoA functions as the carrier of fatty acids, as thioesters, in mitochondrial p-oxidation. The resultant two-carbon fragments, as acetyl CoA, then undergo oxidation in the citric acid cycle. CoA also functions as a carrier in the transfer of fatty acyl groups in a variety of biosynthetic and catabolic reactions, including steroidogenesis long-chain fatty acid synthesis from palmitate in mitochondria and endoplasmic reticulum monounsaturation of palmitoyl CoA to palmitoleyl CoA (C16 1 9) and...

Tissue and Whole Blood Concentrations of Nicotinamide Nucleotides

Measurement of liver and other tissue concentrations of NAD(P) gives a precise estimate of niacin nutritional status and seems to be the most sensitive indicator in experimental animals. Measurement of the whole blood concentration of NAD(P) may serve the samepurpose there is a good correlation between blood and liver concentrations of nicotinamide nucleotides in experimental animals. The sensitivity of the method is such that reproducible determinations can be carried out on finger-prick...

Muscle Pyridoxal Phosphate

Some 80 of the body's total vitamin B6 is as pyridoxal phosphate in muscle, and some 80 of this is associated with glycogen phosphorylase. This does not seem to function as a reserve of the vitamin and is not released from the muscle in deficiency. Muscle pyridoxal phosphate is released into the circulation (as pyridoxal) in starvation as muscle glycogen reserves are exhausted and there is less requirement for glycogen phosphorylase activity. Under these conditions, it is potentially available...

Methionine Synthetase

As shown in Figure 10.9, the overall reaction of methionine synthetase is the transfer of the methyl group from methyl-tetrahydrofolate to homocysteine. However, the enzyme also requires S-adenosyl methionine and a flavoprotein reducing system in addition to the cobalamin prosthetic group. A common polymorphism of methionine synthetase, in which aspartate919 is replaced by glycine, is associated with elevated plasma homocysteine in some cases, although it is less important than...

Calcidiol 1aHydroxylase

The active metabolite of vitamin D, calcitriol, is formed in the proximal tubules of the kidneys from calcidiol. There are three cytochrome P450-dependent enzymes in kidneys that catalyze 1-hydroxylation of calcidiol CYP27A and CYP27 in mitochondria and a microsomal 1 a -hydroxylase, which is ferredoxin-dependent. It is likely that the microsomal enzyme is the most important its synthesis is induced by cAMP in response to parathyroid hormone (Section 3.2.8.2) and repressed by calcitriol (Omdahl...

Pro and Antioxidant Roles of Ascorbate

Ascorbate can act as a radical-trapping antioxidant, reacting with superoxide and a proton to yield hydrogen peroxide, or with the hydroxy radical to yield water. In each case, the product is monodehydroascorbate. The antioxidant activity of ascorbate is variable. From consideration of the chemistry involved, itwouldbe expectedthat, overall, 2 moles ofperoxyl radical would be trapped per mole of ascorbate, because of the reaction of 2 moles of monodehydroascorbate to regenerate ascorbate and...

Plasma and Erythrocyte Concentrations of Folate and Vitamin B2

Measurement of plasma concentrations of the two vitamins is probably the method of choice, and a number of simple and reliable radioligand binding assays have been developed, some of which permit simultaneous determination of both vitamins. Nevertheless, there are a number of problems involved in radioligand binding assays, especially for folate. In some centers, microbiological determination of plasma or whole blood folates is the preferred technique. The ligand binding assays that are...

Vitamin KDependent Proteins in Blood Clotting

The formation of blood clots is the result of the conversion of the soluble protein fibrinogen into fibrin, an insoluble network of fibers. This is achieved by specific proteolysis of fibrinogen at two arginine-glycine junctions, removing two pairs of small peptides (fibrinopeptides), catalyzed by thrombin. The resultant fibrin monomer aggregates into the insoluble fibrin polymer, which undergoes further covalent cross-linkage, catalyzed by a transamidase, the so-called fibrin-stabilizing...

Vitamins

More information - www.cambridge.org 9780521803885 Nutritional Biochemistry of the Vitamins The vitamins are a chemically disparate group of compounds whose only common feature is that they are dietary essentials that are required in small amounts for the normal functioning of the body and maintenance of metabolic integrity. Metabol-ically, they have diverse functions, such as coenzymes, hormones, antioxidants, mediators of cell signaling, and regulators of cell and tissue growth and...

Bacterial Biosynthesis of Menaquinones

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikimic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic...

Biosynthesis and Metabolism of Carnitine

Carnitine is synthesized from lysine and methionine by the pathway shown in Figure 14.2 (Vaz and Wanders, 2002). The synthesis of carnitine involves the stepwise methylation of a protein-incorporated lysine residue at the expense of methionine to yield a trimethyllysine residue. Free trimethyllysine is then released by proteolysis. It is not clear whether there is a specific precursor protein for carnitine synthesis, because trimethyllysine occurs in a number of proteins, including actin,...

Vitamin A Retinoids and Carotenoids

Vitamin A deficiency is a serious problem of public health nutrition, second only to protein-energy malnutrition worldwide, and is probably the most important cause of preventable blindness among children in developing countries. Marginal deficiency is a significant factor in childhood susceptibility to infection, and hence morbidity and mortality, in developing countries even in developed countries, vitamin A (along with iron) is the nutrient most likely to be supplied in marginal amounts. In...

Preface

In the preface to the first edition of this book, I wrote that one stimulus to write it had been teaching a course on nutritional biochemistry, in which my students had raised questions for which I had to search for answers. In the intervening decade, they have continued to stimulate me to try to answer what are often extremely searching questions. I hope that the extent to which helping them through the often conflicting literature has clarified my thoughts is apparent to future students who...

The Role of Ascorbate in Iron Absorption and Metabolism

Nonheme iron is absorbed as Fe2+, and not as Fe3+ ascorbic acid in the intestinal lumen will both maintain iron in the reduced state and also chelate it, thus increasing absorption. A dose of 25 mg of vitamin C taken together with a semisynthetic meal increases the absorption of iron 65 , whereas a 1-g dose gives a nine-fold increase (Hallberg, 1982). This is an effect of ascorbic acid present together with the test meal neither intravenous administration of vitamin C nor supplements several...

Cellular Retinoid Binding Proteins CRBPs and CRABPs

There are five intracellular retinoid binding proteins that show considerable sequence homology not only with each other, but also with a variety of other intracellular binding proteins for hydrophobic metabolites, including the intracellular fatty acid binding protein (Li and Norris, 1996 Noy, 2000 Vogel et al., 2001). The two cellular retinol binding proteins bind all-trans- and 13-ci's-retinol, but not 9-cis- or 11-cis-retinol, or retinoic acid. They also bind retinaldehyde, although there...

Upper Levels of Folate Intake

There are two potential problems associated with widespread enrichment of foods with folic acid or the indiscriminate use of folic acid supplements 1. Intakes of folic acid in excess of about 5,000 g per day antagonize the anticonvulsants used in treatment of epilepsy, leading to an increase in fit frequency (Section 10.9.6). Table 10.4 Reference Intakes of Vitamin Bi2 ( g day) Table 10.4 Reference Intakes of Vitamin Bi2 ( g day) EU, European Union FAO, Food and Agriculture Organization WHO,...

Metabolic Functions Of Thiamin

The studies of Peters in the 1920s and 1930s (Peters, 1963) established the coenzyme role of thiamin in the oxidative decarboxylation of pyruvate. Thiamin diphosphate is the coenzyme for three multienzyme complexes in mammalian mitochondria that are involved in the oxidative decarboxylation of oxo-acids pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase in central Figure 6.2. Reaction of the pyruvate dehydrogenase (EC 1.2.4.1) complex. CoASH, free coenzyme A. Figure 6.2. Reaction of the...

Biotin Deficiency In Pregnancy

Biotin deficiency in experimental animals is teratogenic, and a number of the resultant birth defects resemble human birth defects. Up to half of pregnant women have elevated excretion of 3-hydroxy-isovaleric acid (Section 11.4), which responds to supplements of biotin, in the first trimester, suggesting that marginal status may be common in early pregnancy and may be a factor in the etiology of some birth defects. This may be the result of increased catabolism of biotin as a result of steroid...

Assessment Of Vitamin E Nutritional Status

The most commonly used index of vitamin E nutritional status is the plasma concentration of a-tocopherol because it is transported in plasma lipoproteins, it is best expressed per mole of cholesterol or per milligram of total plasma lipids (Horwitt et al., 1972 Winbauer et al., 1999). The reference range is Table 4.3 Indices of Vitamin E Nutritional Status Plasma tocopherol, xmol L < 12 12-16 Plasma tocopherol, imol g plasma < 1.1 1.1-1.86 Plasma tocopherol, mmol mol < 2.2 2.2-2.25...

Coenzyme Saturation of Transaminases

A number of studies have measured the activation of plasma transaminases by pyridoxal phosphate added in vitro however, it is difficult to interpret the results, because plasma transaminases arise largely accidentally, as a result of cell turnover, and the amount released will depend on tissue damage. Furthermore, there is a considerable amount of pyridoxal phosphate in plasma, largely associated with serum albumin, and the extent to which plasma transaminases are saturated will depend largely...

The Schilling Test for Vitamin B2 Absorption

The absorption of vitamin B12 can be determined by the Schilling test. An oral dose of 57Co or 58Co vitamin B12 is given with a parenteral flushing dose of 1 mg of nonradioactive vitamin, and the urinary excretion of radioactivity is followed as an index of absorption of the oral material. Normal subjects excrete 16 to 45 of the radioactivity over 24 hours, whereas patients lacking intrinsic factor or with antiintrinsic factor antibodies excrete less than 5 . The test can be repeated, giving...

No2 h2o

Reactions of a - and y-tocopherol with peroxynitrite. y-tocopheryl orthoquinorie (y-tocored) Figure 4.6. Reactions of a - and y-tocopherol with peroxynitrite. therefore causing increased oxidative damage to lipids, especially in the absence of coantioxidants such as ascorbate or ubiquinone (Upston et al., 1999 Carret al., 2000). 4.3.1.2 Reaction of Tocopherol with Peroxynitrite Nitric oxide can react with superoxide to yield peroxynitrite, which, although not a radical, can react...

Biosynthesis of Thiamin

There are differences in the pathways of thiamin biosynthesis between prokaryotes and eukaryotes, and also between organisms that are aerobes and facultative anaerobes. Some organisms are completely autotrophic for thiamin, whereas others require the presence of either preformed pyrimidine or thiazole in the culture medium, and indeed some require both. The pyrimidine moiety is not synthesized by the usual pathway for pyrimidine synthesis, but arises from amino-imidazole ribonucleotide, an...

Assessment Of Vitamin K Nutritional Status

The usual method of assessing vitamin K nutritional status, or monitoring the efficacy of anticoagulant therapy, is a functional test of blood clotting, and hence the ability to synthesize the vitamin K-dependent clotting factors. The standard assay measures the time taken for the formation of a fibrin clot in citrated plasma after the addition of calcium ions and thromboplastin to activate the extrinsic clotting system - the prothrombin time. The normal prothrombin time is 11 to 13 seconds...

Calcidiol 24Hydroxylase

Both calcidiol and calcitriol are substrates for 24-hydroxylation, catalyzed by a cytochrome P450-dependent enzyme in kidneys, intestinal mucosa, cartilage, and other tissues that contain calcitriol receptors. This enzyme is induced by calcitriol the activities of calcidiol 1-hydroxylase and 24-hydroxylase in the kidney are subject to regulation in opposite directions, so that decreased requirement for, and synthesis of, calcitriol results in increased formation of 24-hydroxycalcidiol. Kidney...

Pharmacological Uses of Vitamin E

Although vitamin E deficiency causes infertility in experimental animals (Section 4.4.1), there is no evidence that deficiency has any similar effects onhuman fertility. It is a considerable leap of logic from the effects of gross depletion in experimental animals to the popular, and unfounded, claims for vitamin E in enhancing human fertility and virility. There are no established pharmacological uses of vitamin E except for the protection ofpreterminfants exposed to highpartialpressure...

Ch3

D-a-tocopherol 2R, 4'R, 8'R (RRR)-a-tocopherol D-a-tocopherol 2R, 4'R, 8'R (RRR)-a-tocopherol L-a-tocopherol 2S, 4'R, 8'R (SRR)-a-tocopherol Figure 4.2. Stereochemistry of -tocopherol. L-a-tocopherol 2S, 4'R, 8'R (SRR)-a-tocopherol Figure 4.2. Stereochemistry of -tocopherol. 0.4 x mg p-tocopherol + 0.3 x mg y-tocopherol + 0.01 x mg -tocopherol + 0.3 x mg a-tocotrienol + 0.05 x mg p-tocotrienol + 0.01 x mg y-tocotrienol (Holland etal., 1991). As shown in Figure 4.2, the tocopherols have three...

Assay of Vitamin C

Because it is a potent reducing agent, vitamin C is commonly determined by titrimetric orpotentiometric redoxmethods. Suchmethods underestimate the amount of the vitamin present because dehydroascorbate - which has vitamin activity- is formed by atmospheric oxidation of ascorbate in the sample, especially under neutral conditions, and is not detected by redox assay methods. Vitamin C can also be determined colorimetrically, alter oxidation to dehydroascorbate, by reaction with...

Cell Differentiation Proliferation and Apoptosis

Not only is calcitriol an important determinant for the differentiation of osteo-clastprecursor cells, it also directs the differentiation and maturation of normal and leukemic cells into monocytes, and potentiates apoptosis induced by 9-ds-retinoic acid, although it does not induce apoptosis itself. This suggests the possibility of what has been called maturation therapy for leukemia rather than conventional chemotherapy (James et al., 1999). Calcitriol induces terminal differentiation of skin...

Stimulation of Enzyme Activity by Ascorbate In Vitro

Over the years, a number of enzymes have been assumed to be ascorbate-dependent, because their activity is stimulated in vitro by the addition of ascorbate to the incubation medium. In general, these reactions are not ascorbate-dependent ascorbate is one of a variety of reducing reagents that enhance the reaction. Ascorbate is also frequently added to the incubation medium to remove hydrogen peroxide formed during a variety of reactions. Again, a number of reducing agents have the same action,...

Bacterial Synthesis of Biotin

Biotin is synthesized in microorganisms from pimelate by the pathway shown in Figure 11.3 (Marquet et al., 2001 Schneider and Lindqvist, 2001). The first committed stepis the condensation of pimeloyl CoA with alanine, with release of the carboxyl group of alanine, catalyzed by keto-aminopelargonic acid synthase. It is a pyridoxal phosphate-dependent reaction, similar to the condensation of succinyl CoA and glycine to form S -aminolevulinic acid in porphyrin synthesis. There is a considerable...

Methods of Analysis and Units of Activity

Historically, the vitamins, like hormones, presented chemists with a considerable challenge. They are present in foods, tissues, and body fluids in very small amounts, of the order of moles, nmoles, or even pmoles per kilogram, and cannot readily be extracted from the multiplicity of other compounds that might interfere in chemical analyses. Being organic, they are not susceptible to determination by elemental analysis as are the minerals. In addition, for several vitamins, there are multiple...

Vitamin B6 Requirements Estimated from Depletion Repletion Studies

Early studies of vitamin B6 requirements used the development of abnormalities of tryptophan or methionine metabolism during depletion, and normalization during repletion with graded intakes of the vitamin. Although tryptophan and methionine load tests are unreliable as indices of vitamin B6 status in epidemiological studies (Section 9.5.4 and Section 9.5.5), under the controlled conditions of depletion repletion studies they do give a useful indication of the state of vitamin B6 nutrition....

Sources of Substituted Folates

The major point of entry for one-carbon fragments into substituted folates is methylene-tetrahydrofolate, which is formed by the catabolism of glycine, serine, and choline. 10.3.1.1 Serine Hydroxymethyltransferase Serinehydroxymethyltrans-ferase is a pyridoxal phosphate-dependent aldolase that catalyzes the cleavage of serine to glycine and methylene-tetrahydrofolate (as shown in Figure 10.5). Serine is the major source of one-carbon substituted folates for biosynthetic reactions. At times of...

Regulation of Vitamin D Metabolism

The main physiological function of vitamin D is in the control of calcium homeostasis, and vitamin D metabolism is regulated largely by the state of calcium balance. The main regulation of vitamin D metabolism is by control of the activities of calcidiol 1-hydroxylase and 24-hydroxylase, and hence the fate of calcidiol. In general, factors that increase the activity of one of the hydroxylases simultaneously reduce the activity of the other. Although plasma calcitriol is relatively constant...

Allyl Sulfur Compounds

Members of the allium family (onions, garlic, and leeks) contain cysteine sulfoxide derivatives (allyl sulfur compounds), such as allicin and alliin (see Figure 14.9). When the plant cells are damaged, the enzyme alliinase is released from vacuoles and catalyzes the formation of thiosulfinates and thiols, including the lachrymator thiopropanal S-oxide. Their function in the plant is presumably to provide protection against attack by pests. h2o ch ch2 s s ch2 ch ch2 Figure 14.9. Allyl sulfur...

Drug Induced Vitamin B2 Deficiency

It was noted in Section 10.8.1 that nitrous oxide causes inhibition ofmethionine synthetase, as a result of irreversible oxidation of the cobalt of methylcobal-amin. Patients with hitherto undiagnosed vitamin B12 deficiency can develop neurological signs after surgery when nitrous oxide is used as the anesthetic agent. There are a number of reports of neurological damage because of vitamin B12 depletion among people occupationally exposed to nitrous oxide (especially dental surgeons). The...

Biosynthesis and Metabolism of Choline

Phosphatidylcholine can be synthesized by the pathway shown in Figure 14.3. Decarboxylation of phosphatidylserine to phosphatidylethanolamine (cephalin) is followed by methylation in which S-adenosylmethionine is the methyl donor to yield successively the relatively rare mono- and dimethyl derivatives, then phosphatidylcholine. Sequential removal of the fatty acids by phospholipase action results in the formation of lysolecithin (glycerophosphorylcholine), then hydrolysis to release choline....

Pyrroloquinoline Quinone PQQ and Tryptophan Tryptophylquinone TTQ

PQQ and TTQ (see Figure 9.6) are the cofactors for a number of dehydrogenases in gram-negative microorganisms. They can undergo reversible reduction to pyrroloquinoline quinone (PQQ) topaquinone (TPQ) pyrroloquinoline quinone (PQQ) topaquinone (TPQ) lysyl tyrosylquinone (LTQ) tryptophanyl tryptophylquinorie (TTQ) lysyl tyrosylquinone (LTQ) tryptophanyl tryptophylquinorie (TTQ) the semiquinone and quinol, and can therefore function as electron transport cofactors in redox reactions. PQQ is...

International Units and Retinol Equivalents

The obsolete International Unit (iu) of vitamin A activity was based on biological assay of the ability of the test compound to support growth in deficient animals (1 iu 10.47 nmol of retinol 0.3 fg of free retinol or 0.344 fg of retinyl acetate). 13-Q's-retinol has 75 of the biological activity of all-frans-retinol, and retinaldehyde has 90 . Food composition tables give total preformed vitamin A as the sum of all-frans-retinol + 0.75 x 13-ds-retinol + 0.9 x retinaldehyde (Holland et al.,...

Absorption and Metabolism of Retinol and Retinoic Acid

About 70 to 90 of dietary retinol is absorbed, and, even at high intakes, this falls only slightly. Retinyl esters are hydrolyzed by pancreatic lipase and carboxyl ester lipase in lipid micelles in the intestinal lumen, and also by one or more retinyl ester hydrolases in the intestinal mucosal brush border membrane. At physiological levels of intake, retinol uptake into enterocytes is by facilitated diffusion from the lipid micelles. When the transport protein in the intestinal mucosal brush...

Thiamin Deficiency

Thiamin deficiency can result in three distinct syndromes a chronic peripheral neuritis, beriberi, which may or may not be associated with heart failure and edema acute pernicious (fulminating) beriberi (shoshin beriberi), in which heart failure and metabolic abnormalities predominate, with little evidence of peripheral neuritis and Wernicke's encephalopathy with Korsakoff's psychosis, a thiamin-responsive condition associated especially with alcoholism and narcotic abuse. In general, a...

Osteocalcin and Matrix Gla Protein

Treatment with warfarin or other anticoagulants during pregnancy can lead to bone abnormalities in the fetus, the so-calledfetal warfarin syndrome, which is because of impaired synthesis of osteocalcin - a small calcium binding protein containing three y-carboxyglutamate residues found in bone matrix and dentine. It also contains a hydroxyproline residue, and thus undergoes both vitamin K- and vitamin C-dependent posttranslational modifications (Section 13.4.3). It is the most abundant of the...

Upper Levels of Niacin Intake

Nicotinic acid (but not nicotinamide) causes a marked vasodilatation, with flushing, burning, and itching of the skin. Very large single doses of nicotinic acid may cause sufficient vasodilatation to lead to hypotension after the administration of 1 to 3 g of nicotinic acid daily for several days, the effect wears off to a considerable extent. A number of nicotinoyl esters have been developed to permit sensitive patients to benefit from the hypolipidemic effect of nicotinic acid without the...

Tissue Uptake of Vitamin C

Ascorbate and dehydroascorbate are taken up into tissues by separate mechanisms, and there is little or no competition between them (Welch et al., 1995) 1. Ascorbate enters cells byway of sodium-dependent transporters. 2. Dehydroascorbate enters cells byway of the (insulin-dependent) glucose transporters (GLUT), and is reduced to ascorbate intracellularly. The relative importance of uptake of dehydroascorbate and dehydroascor-bate by tissues is unclear. It has been suggested that normal...

Human Pantothenic Acid Deficiency The Burning Foot Syndrome

In the 1940s, prisoners of war in the Far East who were severely malnourished showed, among other signs and symptoms of vitamin deficiency diseases, a new condition of paresthesia and severe pain in the feet and toes, which was called the burning foot syndrome or nutritional melalgia. Although it was tentatively attributed to pantothenic acid deficiency, no specific trials of pantothenic acid were conducted rather the subjects were given yeast extract and other rich sources of all vitamins as...

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...

Photo Addition Reaction Of Riboflavin

Riboflavin Methylene Reductase Mechanism

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

Cholecalciferol Calcitriol

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

Monodehydroascorbate

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

Visual Cycle Retinal Retinol

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

Pyridoxamine Glutamine 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 Of Vitamins

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

Quinolinate Phosphoribosyl Transferase

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

Amide Anion

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...