Chapter 29 Vitamins and Minerals
Another difference between these two classes of vitamins is their intestinal absorption. Water-soluble vitamins are readily absorbed, but the absorption of fat-soluble vitamins depends on mixed bile salt micelles. Therefore deficiencies of fat-soluble vitamins are most likely to occur in patients with fat malabsorption. Supplements of these vitamins are most effective when they are taken with a fatty meal.
Most water-soluble vitamins are transported in the blood as such, but fat-soluble vitamins are transported either as constituents of lipoproteins or bound to specific plasma proteins. Finally, renal excretion of excess water-soluble vitamins is unproblematic, whereas fat-soluble vitamins must be metabolized to water-soluble products before they can be excreted. Therefore fat-soluble vitamins are more likely to accumulate in the body and cause toxicity.
Minerals are inorganic nutrients. The macrominerals sodium, potassium, calcium, magnesium, phosphate, and chloride are components of the body fluids and the inorganic matrix of bone. They are required in quantities of more than 100 mg/day. The microminerals, or trace minerals, are required in only small quantities and serve specialized biochemical functions.
The recommended daily allowance (RDA) of each nutrient, more recently labeled as dietary reference intake (DRI), is published by the Food and Nutrition Board of the National Academy of Sciences in the United States and by similar agencies in other countries. The DRI defines not a minimal requirement but a dietary intake that meets the requirements of 97% to 98% of healthy individuals in a category.
Table 29.1 summarizes the DRIs for adult men and women. Actual requirements depend also on age, body weight, diet, and physiological status. Increases in dietary intake of many nutrients are recommended during pregnancy and lactation.
Table 29.1 Dietary Reference Intakes for Vitamins and Minerals
Nutrient | 70-kg Man | 55-kg Woman |
---|---|---|
Water-Soluble Vitamins | ||
Niacin | 16 mg | 14 mg |
Riboflavin | 1.3 mg | 1.1 mg |
Thiamin | 1.2 mg | 1.1 mg |
Pyridoxine (B6) | 1.3 mg | 1.3 mg |
Pantothenic acid | 5 mg | 5 mg |
Biotin | 30 μg | 30 μg |
Ascorbic acid | 90 mg | 75 mg |
Folic acid | 400 μg | 400 μg |
Cobalamin (B12) | 2.4 μg | 2.4 μg |
Fat-Soluble Vitamins | ||
Vitamin A | 900 μg | 700 μg |
Vitamin D | 5 μg | 5 μg |
Vitamin K | 120 μg | 90 μg |
Vitamin E | 15 mg | 15 mg |
Macrominerals | ||
Sodium | 1.5 g | 1.5 g |
Potassium | 4.7 g | 4.7 g |
Calcium | 1 g | 1 g |
Magnesium | 420 mg | 320 mg |
Chloride | 2.3 g | 2.3 g |
Phosphate | 700 mg | 700 mg |
Microminerals | ||
Iron | 8 mg | 18 mg |
Copper | 900 μg | 900 μg |
Zinc | 11 mg | 8 mg |
Manganese | 2.3 mg | 1.8 mg |
Molybdenum | 45 μg | 45 μg |
Chromium | 35 μg | 25 μg |
Selenium | 55 μg | 55 μg |
Iodide | 150 μg | 150 μg |
Fluoride | 4 mg | 3 mg |
Riboflavin is a precursor of flavin mononucleotide and flavin adenine dinucleotide
Riboflavin (vitamin B2) consists of a dimethylisoalloxazine ring covalently bound to the sugar alcohol ribitol (Fig. 29.1). Riboflavin is the dietary precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), the prosthetic groups of the flavoproteins (from Latin flavus meaning “yellow”). Both riboflavin and the flavin coenzymes are yellow in their reduced form, with an absorption band at 450 nm. Although riboflavin and its derivatives are heat stable, they are rapidly degraded to inactive products on exposure to visible light. Therefore riboflavin deficiency can occur in infants receiving phototherapy for hyperbilirubinemia (see Chapter 27), when riboflavin as well as bilirubin is destroyed by light in the skin.

Figure 29.1 Synthesis of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) from dietary riboflavin.
Dietary riboflavin is absorbed by an energy-dependent transporter in the upper small intestine and transported to the tissues, where it is converted to the coenzyme forms FMN and FAD. The excess is excreted in the urine or metabolized by microsomal enzymes in the liver.
Good sources of riboflavin include liver, yeast, eggs, meat, enriched bread and cereals, and milk. Riboflavin deficiency usually occurs along with other vitamin deficiencies and is most common in alcoholics. Symptoms include glossitis (magenta tongue), angular stomatitis, sore throat, and a moist (seborrheic) dermatitis of the scrotum and nose. This deficiency may be accompanied by a normochromic normocytic anemia.
Dietary status can be assessed by fluorometric or microbiological determination of urinary riboflavin. Alternatively, the activity of erythrocyte glutathione reductase (see Chapter 22) is determined in freshly lysed red blood cells before and after the addition of its coenzyme FAD. In riboflavin deficiency, the apoenzyme is not completely saturated with its coenzyme; therefore, the enzymatic activity is increased by added FAD.
Niacin is a precursor of NAD and NADP
The term niacin, originally applied to nicotinic acid, is often used as a generic term for the vitamin-active pyridine derivatives nicotinic acid and nicotinamide:
In both the human body and dietary sources, niacin is present as a constituent of NAD and NADP. The dietary coenzymes are hydrolyzed in the gastrointestinal tract, and free nicotinic acid and nicotinamide are absorbed in the small intestine. After their transport to the tissues, the vitamin forms are incorporated into the coenzymes (Fig. 29.2). Excess niacin is readily excreted by the kidneys.

Figure 29.2 Synthesis of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). PRPP, 5-Phosphoribosyl-1-pyrophosphate.
NAD and NADP can be synthesized from dietary tryptophan, but the pathway is inefficient. Sixty milligrams of tryptophan, which is nutritionally essential itself, is required for the synthesis of 1 mg of niacin. Also, the pathway of endogenous niacin synthesis requires riboflavin, thiamine, and pyridoxine and therefore is impaired in patients with multiple vitamin deficiencies. Most people get about equal amounts of their niacin requirement from dietary tryptophan and from niacin. Good sources of niacin include yeast, meat, liver, peanuts and other legume seeds, and enriched cereals.
CLINICAL EXAMPLE 29.1: Pellagra
Niacin deficiency, known as pellagra (the name is Italian and means “rough skin”), is seen only in people on a diet low in both niacin and tryptophan. It is often associated with maize-based diets. Maize protein is low in tryptophan, and the niacin, which is actually present in moderate amount, is poorly absorbed because it is tightly bound to other constituents of the grain.
Early deficiency signs include weakness, lassitude, anorexia, indigestion, and a glossitis similar to that in riboflavin deficiency. The signs of severe deficiency are dermatitis, diarrhea, and dementia. The dermatitis presents as a symmetrical erythematous rash on sun-exposed parts of the skin. Diarrhea is caused by widespread inflammation of mucosal surfaces. The mental changes, which initially are quite vague, can progress to a profound encephalopathy with confusion, memory loss, and overt organic psychosis. In severe cases, mental deterioration can become irreversible. Pellagra was widespread in the southern United States during the early years of the twentieth century but now is limited to poverty-stricken regions of the world.
Thiamin deficiency causes weakness and amnesia
Dietary thiamin is readily absorbed and transported to the tissues, where it is phosphorylated to its coenzyme form thiamin pyrophosphate (TPP) in an ATP-dependent reaction:
About 30 mg of the vitamin is present in the body, 80% of this in the form of TPP.
The TPP-dependent reactions are aldehyde transfers in which the aldehyde is bound covalently to one of the carbons in the thiazole (sulfur-and-nitrogen) ring of the coenzyme. One reaction type, the oxidative decarboxylation of α-ketoacids, is catalyzed by mitochondrial multienzyme complexes. Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase (see Chapter 21), branched-chain α-ketoacid dehydrogenase, and α-ketobutyrate dehydrogenase (see Chapter 26) all use the same thiamin-dependent catalytic mechanism.
A different reaction type is encountered in the cytoplasmic transketolase reaction (see Chapter 22) in which TPP transfers a glycolaldehyde from one monosaccharide to another. In general, the major catabolic, energy-producing pathways are most dependent on TPP.
CLINICAL EXAMPLE 29.2: Beriberi
Mild thiamin deficiency leads to gastrointestinal complaints, weakness, and a burning sensation in the feet. Moderate deficiency is characterized by peripheral neuropathy, mental abnormalities, and ataxia. Full-blown deficiency, known as beriberi, manifests with severe muscle weakness and muscle wasting, delirium, ophthalmoplegia (paralysis of the eye muscles), and memory loss. This is accompanied by peripheral vasodilation and increased venous return to the heart. Myocardial contractility is impaired, and death can result from high-output cardiac failure.
Beriberi became a health problem in parts of Asia at the end of the nineteenth century when the milling and polishing of rice were introduced in these countries. The thiamin in rice is present in the outer layers of the grain, which are removed by polishing; therefore, beriberi became the scourge of poor people who had to subsist mainly on rice.
CLINICAL EXAMPLE 29.3: Wernicke-Korsakoff Syndrome
Today, thiamin deficiency is most common in alcoholics who have poor intestinal absorption in addition to inadequate dietary intake. The combination of thiamin deficiency and alcohol toxicity causes Wernicke-Korsakoff syndrome. The acute stage, known as Wernicke encephalopathy, is characterized by mental derangements and delirium, ataxia (motor incoordination), and paralysis of the eye muscles.
Wernicke encephalopathy requires immediate treatment with thiamin injections to prevent development of the chronic stage, known as Korsakoff psychosis. Patients with Korsakoff psychosis suffer from a severely debilitating anterograde amnesia. They can remember events from the distant past, and their immediate recall is intact, but they cannot transcribe information from short-term to long-term memory.
Korsakoff psychosis is the most common form of amnesia in most countries. The amnesia is attributed to focal lesions in the periventricular areas of the thalamus and hypothalamus, the periaqueductal gray of the midbrain, and the mammillary bodies. The frequent confabulation that distinguishes Korsakoff psychosis from other forms of anterograde amnesia is attributed to concomitant damage in the frontal lobes.
Vitamin B6 plays a key role in amino acid metabolism
Vitamin B6 is the generic name for the dietary precursors of the coenzyme pyridoxal phosphate (PLP). They include pyridoxine, pyridoxal, and pyridoxamine as well as their phosphorylated derivatives (Fig. 29.3).

Figure 29.3 Molecular forms of vitamin B6. All vitamin forms can be converted to the coenzyme form pyridoxal phosphate in the human body.
The phosphate is removed by intestinal alkaline phosphatase, and the dephosphorylated forms are absorbed. The total body content of PLP is only 25 mg in adults, and pyridoxal and PLP are the major circulating forms of the vitamin. Synthesis of the coenzyme form is described in Figure 29.4.
Several dozen enzymes of amino acid metabolism contain PLP as a tightly bound prosthetic group. In these reactions, the aldehyde group of PLP forms an aldimine derivative with the amino group of the amino acid. The aldimine is stabilized by an intramolecular hydrogen bond with the phenolic hydroxyl group (Fig. 29.5).

Figure 29.5 In reactions of amino acid metabolism, pyridoxal phosphate forms an aldimine (Schiff base) derivative with the amino group of the amino acid. The further path of the reaction depends on the catalytic specificity of the enzyme.
Liver, fish, whole grains, nuts, legumes, egg yolk, and yeast are good sources of vitamin B6. Serious deficiency is rare, but when it occurs it is characterized by peripheral neuropathy, stomatitis, glossitis, irritability, psychiatric symptoms, and, especially in children, epileptic seizures. Some of the neurological derangements may result from impaired activity of the PLP-dependent enzyme glutamate decarboxylase, which forms the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (see Chapter 16).
Vitamin B6 deficiency is most common in alcoholics, in whom it contributes to sideroblastic anemia, peripheral neuropathy, and seizures. Some drugs, including the tuberculostatic isoniazid and the metal chelator penicillamine, can precipitate vitamin B6 deficiency by reacting nonenzymatically with the aldehyde group of pyridoxal or PLP:
Unlike the other water-soluble vitamins, vitamin B6 is toxic in high doses. The daily consumption of more than 500 mg of pyridoxine for several months leads to peripheral sensory neuropathy. Doses of 100 to 150 mg/day are used for the symptomatic treatment of carpal tunnel syndrome, a painful nerve entrapment syndrome. The “therapeutic” effect of pyridoxine probably is unrelated to its vitamin function but is related to its toxicity on peripheral nerves.
Pantothenic acid is a building block of coenzyme A
Pantothenic acid consists of pantoic acid and β-alanine:
Pantothenic acid functions as a constituent of coenzyme A (CoA) and of the phosphopantetheine group in the fatty acid synthase complex (see Chapter 23). The structure and biosynthesis of CoA are summarized in Figure 29.6.

Figure 29.6 Structure of coenzyme A. Pantothenic acid is the only nutritionally essential component of this coenzyme.
Pantothenic acid deficiency has never been observed under ordinary conditions, and an isolated deficiency in humans could be induced only under rigorously controlled experimental conditions. An amount of 5 mg/day is recommended as “safe and adequate intake.” This amount is readily supplied by most ordinary diets.
Biotin is a coenzyme in carboxylation reactions
Biotin is the prosthetic group of pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and other ATP-dependent carboxylases. These multisubunit enzymes contain biotin covalently bound to the ε-amino group of a lysine residue. In the reaction, biotin functions as a carrier of a bicarbonate-derived carboxyl group:
Yeast, liver, eggs, peanuts, milk, chocolate, and fish are good sources of biotin, and intestinal bacteria make a sizeable contribution. Humans need only 30 μg of biotin per day, and the only way to induce biotin deficiency is to eat at least 20 raw egg whites per day. Egg white contains the protein avidin, so called because it binds biotin avidly, preventing its intestinal absorption.
Folic acid deficiency causes megaloblastic anemia
Folic acid consists of pteroic acid (pteridine + para-aminobenzoic acid [PABA]) and one to seven γ-linked glutamate residues. Dietary polyglutamate forms of folic acid are hydrolyzed to pteroyl monoglutamate in the intestinal lumen:
The monoglutamate is absorbed and reduced to the active coenzyme form tetrahydrofolate (THF) by dihydrofolate reductase in the intestinal mucosa. The monoglutamate conjugate of methyl-THF is the major circulating form of THF, but intracellular THF is present in the form of polyglutamate conjugates.
THF is a carrier of one-carbon units, which are bound to one or both of the nitrogen atoms N-5 and N-10 (Fig. 29.8):

Figure 29.8 Tetrahydrofolate (THF) as a carrier of one-carbon units. FIGLU, Formiminoglutamate (formed during histidine degradation).
CLINICAL EXAMPLE 29.4: Biotinidase Deficiency
The proteolytic degradation of biotin-containing enzymes, both in the intestinal lumen and in the tissues, produces the biotin-lysine conjugate biocytin (Fig. 29.7). Biotin is released from biocytin by biotinidase. Biotinidase deficiency causes nondietary biotin deficiency. Affected infants present with hypotonia, seizures, optic atrophy, dermatitis, and conjunctivitis. This condition can be cured easily with biotin supplements. Biotinidase deficiency is often included in newborn screening programs, along with other treatable congenital diseases. It can be diagnosed by enzyme assay in fresh serum or, as a screening test, on a strip of blood-soaked filter paper.
Folate deficiency leads to impaired DNA replication in dividing cells because of reduced synthesis of purine nucleotides and thymine. In the bone marrow, hemoglobin is synthesized normally and the cytoplasm grows at a normal rate, but cell division is delayed. Therefore the production of mature cells slows down, and the cells that are formed are oversized. The result is called megaloblastic anemia or macrocytic anemia. Megaloblasts are oversized erythrocyte precursors in the bone marrow, and macrocytes are oversized erythrocytes in the blood.
Good dietary sources include yeast, liver, some fruits, and green vegetables (from Latin folium meaning “leaf”). However, folate is heat labile, and losses during food processing can be extensive. The RDA is 400 μg, and total body stores are 5 to 10 mg. Low levels of serum folate are often encountered in late pregnancy, and megaloblastic anemia can be precipitated by pregnancy. Alcoholism and intestinal malabsorption syndromes can also cause folate deficiency.
Folate levels can be determined in serum and erythrocytes. In subacute deficiency, the serum “folate” (actually methyl-THF) declines within days, followed much later by a decrease of red blood cell folate. Deficiency signs appear only when the intracellular stores are depleted.
CLINICAL EXAMPLE 29.5: Sulfonamides
Unlike humans, most bacteria make their own folate from pteridine and PABA (Fig. 29.9). Therefore their growth can be inhibited with drugs that block folate synthesis. The sulfonamides are structural analogs of PABA that inhibit the synthesis of pteroic acid in bacteria. Although they do not kill the bacteria immediately, they prevent their growth. They are bacteriostatic, not bactericidal.

Figure 29.9 Pharmacological inhibition of tetrahydrofolate synthesis in bacteria. PABA, Para-aminobenzoic acid.
Trimethoprim is an inhibitor of bacterial but not human dihydrofolate reductase. It is frequently combined with the sulfonamide sulfamethoxazole for treatment of bacterial infections.
CLINICAL EXAMPLE 29.6: Prevention of Neural Tube Defects
Neural tube defects are among the most serious birth defects. They include anencephaly (absence of the brain) and spina bifida (incomplete closure of the lumbar spine). Although the reasons for these rather common malformations (1:400 births) are not well understood, folate supplements are known to be effective in their prevention. The current recommendation is that all women who might become pregnant should consume at least 400 μg of folic acid per day. Because many women failed to heed this advice, the United States instituted compulsory fortification of flour and other grain products with folic acid in 1998, and most other countries followed. It is estimated that this program has reduced the incidence of neural tube defects by 46%.

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