Vitamins are organic molecules that function in a wide variety of capacities within the body. The most prominent function of the vitamins is to serve as cofactors (coenzymes) for enzymatic reactions. The distinguishing feature of the vitamins is that they generally cannot be synthesized by mammalian cells and, therefore, must be supplied in the diet. The vitamins are of 2 distinct types, water soluble and fat soluble.

The minerals that are considered of dietary significance are those that are necessary to support biochemical reactions by serving both functional and structural roles as well as those serving as electrolytes. The use of the term dietary mineral is considered archaic since the intent of the term mineral is to describe ions not actual minerals. The body requires both quantity elements and trace elements. The quantity elements are sodium, magnesium, phosphorous, sulfur, chlorine, potassium, and calcium. The essential trace elements are manganese, iron, cobalt, nickel, copper, zinc, selenium, molybdenum, and iodine. Additional trace elements (although not considered essential) are boron, chromium, fluoride, and silicon.

Water-Soluble Vitamins

Thiamin: Vitamin B₁

Thiamin (also written thiamine) is also known as vitamin B₁. Thiamin is derived from a substituted pyrimidine and a thiazole, which are coupled by a methylene bridge. Thiamin is rapidly converted to its active form, thiamin pyrophosphate (TPP), in the brain and liver by the enzyme thiamin diphosphotransferase (Figure 8-1).

TPP is necessary as a cofactor for a number of dehydrogenases, including pyruvate dehydrogenase (PDH) and α-ketoglutarate (2-oxoglutarate) dehydrogenase (α-KGDH). Both of these enzymes are critical to the functioning of the TCA (tricarboxylic acid) cycle (see Chapter 16). Additional important TPP-requiring enzymes are transketolase of the pentose phosphate pathway (see Chapter 15) and branched-chain α-keto acid dehydrogenase (BCKD) involved in the catabolism of the branched-chain amino acids (see Chapter 30). The enzymes, PDH, α-KGDH, and BCKD are known as the tender loving care for Nancy (TLCFN) enzymes reflective of their requirement for thiamin, lipoic acid, coenzyme A, FAD, and NAD.

Riboflavin: Vitamin B₂

Riboflavin is also known as vitamin B₂. Riboflavin is the precursor for the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Synthesis of these 2 cofactors occurs in a 2-step process. FMN is synthesized from riboflavin via the ATP-dependent enzyme riboflavin kinase (RFK). FMN is then converted to FAD via the attachment of AMP (derived from ATP) through the action of FAD pyrophosphorylase, which is also known as FMN adenylyltransferase (FMNAT) (Figure 8-2).

The enzymes that require FMN or FAD as cofactors are termed flavoproteins. Several flavoproteins also contain metal ions and are termed metalloflavoproteins. Both classes of enzyme are involved in a wide range of redox reactions, for example, succinate dehydrogenase (of the TCA cycle, see Chapter 16) and xanthine oxidase (of purine nucleotide catabolism, see Chapter 32).

Riboflavin deficiencies are rare in the United States due to the presence of adequate amounts of the vitamin in eggs, milk, meat, and cereals. Riboflavin deficiency is often seen in chronic alcoholics due to their poor dietary habits. Symptoms associated with riboflavin deficiency include itching and burning eyes, angular stomatitis and cheilosis (cracks and sores in the mouth and lips), bloodshot eyes, glossitis (inflammation of the tongue leading to purplish discoloration), seborrhea (dandruff, flaking skin on scalp and face), trembling, sluggishness, and photophobia (excessive light sensitivity). Riboflavin decomposes when exposed to visible light. This characteristic can lead to riboflavin deficiencies in newborns treated for hyperbilirubinemia by phototherapy.

Niacin: Vitamin B₃

Niacin (nicotinic acid and nicotinamide) is also known as vitamin B₃. Both nicotinic acid and nicotinamide can serve as the dietary source of vitamin B₃. Niacin is required for the synthesis of the active forms of vitamin B₃, nicotinamide adenine dinucleotide (NAD⁺), and nicotinamide adenine dinucleotide phosphate (NADP⁺). Both NAD⁺ and NADP⁺ function as cofactors for several hundred different redox enzymes (Figure 8-3).

Also, synthesis of niacin from tryptophan requires vitamins B₁, B₂, and B₆ which would be limiting on a marginal diet.

A diet deficient in niacin (as well as tryptophan) leads to glossitis of the tongue (inflammation of the tongue leading to purplish discoloration), dermatitis, weight loss, diarrhea, depression, and dementia. The severe symptoms, depression, dermatitis, and diarrhea (known as the 3 Ds), are associated with the condition termed pellagra. Several physiological conditions (eg, Hartnup disorder: see Clinical Box 30-1) as well as certain drug therapies (eg, isoniazid) can lead to niacin deficiency. In Hartnup disease, tryptophan absorption from the gut is impaired.

The major action of nicotinic acid in this capacity is a reduction in fatty acid mobilization from adipose tissue. Although nicotinic acid therapy lowers blood cholesterol, it also causes a depletion of glycogen stores and fat reserves in skeletal and cardiac muscle. Additionally, there is an elevation in blood glucose and uric acid production. For these reasons, nicotinic acid therapy is not recommended for diabetics or persons who suffer from gout.

Pantothenic Acid: Vitamin B₅

Pantothenic acid is also known as vitamin B₅. Pantothenic acid is formed from β-alanine and pantoic acid. Pantothenate is required for synthesis of coenzyme A (CoA) and is a component of the acyl carrier protein (ACP) domain of fatty acid synthase (FAS). In the synthesis of CoA from pantothenate there are 5 reaction steps, Pantothenate is phosphorylated on the hydroxyl group via the action of pantothenate kinase. The reactive sulfhydryl group is added from cysteine via the action of phosphopantothenoylcysteine synthetase. After 3 more reactions, the molecule is decarboxylated and then the adenosine-5′-diphosphate (ADP) from ATP is added, forming the fully functional coenzyme A. Pantothenate is required for the metabolism of carbohydrate via the TCA cycle and all fats and proteins. At least 70 enzymes have been identified as requiring CoA or ACP derivatives for their function (Figure 8-4).

Deficiency of pantothenic acid is extremely rare due to its widespread distribution in whole grain cereals, legumes, and meat. Symptoms specific to pantothenate deficiency are difficult to assess since they are subtle and resemble those of other vitamin B deficiencies. These symptoms include painful and burning feet, skin abnormalities, retarded growth, dizzy spells, digestive disturbances, vomiting, restlessness, stomach stress, and muscle cramps.

Vitamin B₆

Pyridoxal, pyridoxamine, and pyridoxine are collectively known as vitamin B₆. All 3 compounds are efficiently converted to the biologically active form of vitamin B₆, pyridoxal phosphate (PLP). This conversion is catalyzed by the ATP-requiring enzyme, pyridoxal kinase. Pyridoxal kinase requires zinc for full activity, thus making it a metalloenzyme (Figure 8-5).

Pyridoxal phosphate functions as a cofactor in enzymes involved in transamination reactions required for the synthesis and catabolism of the amino acids as well as in glycogenolysis as a cofactor for glycogen phosphorylase and as a cofactor for the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Deficiencies of vitamin B₆ are rare and usually related to an overall deficiency of all the B-complex vitamins. Isoniazid (see niacin deficiencies earlier) and penicillamine (used to treat rheumatoid arthritis and cystinurias) are 2 drugs that complex with pyridoxal and PLP resulting in a deficiency in this vitamin. Deficiencies in pyridoxal kinase result in reduced synthesis of PLP and are associated with seizure disorders related to a reduction in the synthesis of GABA. Other symptoms that may appear with deficiency of vitamin B₆ include nervousness, insomnia, skin eruptions, loss of muscular control, anemia, mouth disorders, muscular weakness, dermatitis, arm and leg cramps, loss of hair, slow learning, and water retention.

Biotin: Vitamin H

Biotin is the cofactor required of enzymes that are involved in carboxylation reactions, for example, acetyl-CoA carboxylase (ACC) (see Chapter 19) and pyruvate carboxylase (see Chapter 13). Biotin is found in numerous foods and is also synthesized by intestinal bacteria and as such deficiencies of the vitamin are rare. Deficiencies are generally seen only after long antibiotic therapies, which deplete the intestinal microbiota or following excessive consumption of raw eggs. The latter is due to the affinity of the egg white protein, avidin, for biotin, preventing intestinal absorption of the vitamin. Symptoms that may appear if biotin is deficient are extreme exhaustion, drowsiness, muscle pain, loss of appetite, depression, and grayish skin color (Figure 8-6).

Cobalamin: Vitamin B₁₂

Cobalamin is more commonly known as vitamin B₁₂. Vitamin B₁₂ is synthesized exclusively by microorganisms and is found in the liver of animals bound to protein as methycobalamin or 5′-deoxyadenosylcobalamin. The vitamin must be hydrolyzed from protein in order to be active. Hydrolysis occurs in the stomach by gastric acids or the intestines by trypsin digestion following consumption of animal meat. Following release from protein, vitamin B₁₂ is bound by intrinsic factor, a protein secreted by parietal cells of the stomach, and carried to the ileum where it is absorbed. Following absorption, the vitamin is transported to the liver in the blood bound to transcobalamin II (Figure 8-7).

During the catabolism of fatty acids with an odd number of carbon atoms and the amino acids valine, isoleucine, and threonine the resultant propionyl-CoA is converted to succinyl-CoA for oxidation in the TCA cycle. One of the enzymes in this pathway, methylmalonyl-CoA mutase, requires vitamin B₁₂ as a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA. The 5′-deoxyadenosine derivative of cobalamin is required for this reaction. The second reaction requiring vitamin B₁₂ catalyzes the conversion of homocysteine to methionine and is catalyzed by methionine synthase (also called homocysteine methyltransferase). This reaction results in the transfer of the methyl group from N⁵-methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate (THF) and methylcobalamin during the process of the conversion (Figure 8-8).

Folic Acid

Folic acid is a conjugated molecule consisting of a pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid. Folic acid itself is then generated through the conjugation of glutamic acid residues to pteroic acid. Folic acid is obtained primarily from yeasts and leafy vegetables as well as animal liver. Animals cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folate intake in the diet. Folate itself is not biologically active, but in derivatives of the THF form, it participates in a number of one-carbon transfer reactions. THF, and the various derivatives, are formed from dihydrofolate (DHF) which is generated within the liver (Figure 8-9).

When stored in the liver or ingested, folic acid exists in a polyglutamate form. Intestinal mucosal cells remove some of the glutamate residues through the action of the lysosomal enzyme, conjugase. The removal of glutamate residues makes folate less negatively charged and therefore, more capable of passing through the basal lamina membrane of the epithelial cells of the intestine and into the bloodstream. Folic acid is reduced within cells (principally the liver where it is stored) to tetrahydrofolate (THF also H₄ folate) through the action of DHF reductase (DHFR), an NADPH-requiring enzyme.

The function of THF derivatives is to carry and transfer various forms of one-carbon units during biosynthetic reactions. The one-carbon units are methyl, methylene, methenyl, formyl, and formimino groups. These one-carbon transfer reactions are required in the biosynthesis of serine, methionine, glycine, choline, and the purine nucleotides and dTMP. The ability to acquire choline and amino acids from the diet and to salvage the purine nucleotides makes the role of N⁵,N¹⁰-methylene-THF in dTMP synthesis the most metabolically significant function for this vitamin (see Clinical Box 8-3). The role of vitamin B₁₂ and N⁵-methyl-THF in the conversion of homocysteine to methionine also can have a significant impact on the ability of cells to regenerate needed THF (Figure 8-10).

Ascorbic Acid: Vitamin C

Ascorbic acid is more commonly known as vitamin C. Ascorbic acid is derived from glucose via the uronic acid pathway, however, the enzyme L-gulonolactone oxidase, responsible for the conversion of gulonolactone to ascorbic acid, is absent in humans making ascorbic acid required in the diet (Figure 8-11).

The active form of vitamin C is ascorbic acid itself. The main function of ascorbate is as a reducing agent in a number of different reactions. Ascorbate is the cofactor for Cu⁺-dependent monooxygenases and Fe²⁺-dependent dioxygenases. Ascorbate has the potential to reduce cytochromes a and c of the respiratory chain as well as molecular oxygen.

Vitamin C is, therefore, required for the maintenance of normal connective tissue as well as for wound healing since synthesis of connective tissue is the first event in wound tissue remodeling (see Clinical Box 8-4). Vitamin C also is necessary for bone remodeling due to the presence of collagen in the organic matrix of bones.

Ascorbic acid also serves as a reducing agent and an antioxidant. When functioning as an antioxidant, ascorbic acid itself becomes oxidized to semidehydroascorbate and then dehydroascorbate. Semidehydroascorbate is reconverted to ascorbate in the cytosol by cytochrome b₅ reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH.

Several other metabolic reactions require vitamin C as a cofactor. These include the catabolism of tyrosine and the synthesis of epinephrine from tyrosine and the synthesis of the bile acids. It is also believed that vitamin C is involved in the process of steroidogenesis since the adrenal cortex contains high levels of vitamin C, which are depleted upon adrenocorticotropic hormone (ACTH) stimulation of the gland.

Fat-Soluble Vitamins

Vitamin A

The chemical compounds known as the retinoids constitute the biologically active forms of vitamin A. The principal retinoids are retinol, retinal (retinaldehyde), and retinoic acid. These molecules can be acquired in the diet preformed only from foods of animal origin. Vitamin A can also be derived from a family of compounds called the carotenoids. The carotenoids that are found in plants and constitute the major precursors to vitamin A are α-, β-, and γ-carotene. The carotenes consist of 2 molecules of retinaldehyde linked at their aldehyde ends (Figure 8-12).

Ingested β-carotene is cleaved in the lumen of the intestine by carotene dioxygenase to yield free retinaldehyde. Retinaldehyde is reduced to retinol within intestinal enterocytes by retinaldehyde reductase, an NADPH-requiring enzyme. Retinol is esterified to palmitic acid and delivered to the blood via chylomicrons. The uptake of chylomicron remnants by the liver results in delivery of retinol to this organ for storage as a lipid ester. Transport of retinol from the liver to extrahepatic tissues occurs by binding of hydrolyzed retinol to apo-retinol-binding protein (RBP). The retinol-RBP complex is then transported to the cell surface within the Golgi and secreted. Within extrahepatic tissues, retinol is bound to cellular retinol-binding protein (CRBP). Plasma transport of retinoic acid is accomplished by binding to albumin.

Gene Control Exerted by Retinoic Acid

Within cells, retinoic acid (as well as the related compound 9-cis-retinoic acid) bind to specific receptor proteins that are members of the nuclear receptor family of hormone receptors. Following binding, the receptor-retinoic acid complex interacts with specific sequences in several genes involved in growth and differentiation and affects expression of these genes. In this capacity, retinoic acid is considered a hormone of the steroid/thyroid hormone superfamily of proteins. The retinoic acid receptors are abbreviated RAR and the related retinoid X receptors (RXRs) bind 9-cis-retinoic acid. Several genes, whose patterns of expression are altered by retinoic acid, are involved in the earliest processes of embryogenesis including the differentiation of the 3 germ layers, organogenesis, and limb development. To date, there are at least 130 genes that have been shown to be directly regulated (either positive or negative) via interaction with RAR or RXR.

Vision and the Role of Vitamin A

Photoreception in the eye is the function of 2 specialized cell types located in the retina; the rod and cone cells. Both rod and cone cells contain a photoreceptor pigment in their membranes. The photosensitive compound of most mammalian eyes is a protein called opsin to which is covalently coupled an aldehyde of vitamin A. The opsin of rod cells is called scotopsin. The photoreceptor of rod cells is specifically called rhodopsin or visual purple. This compound is a complex between scotopsin and the 11-cis-retinal (also called 11-cis-retinene) form of vitamin A. Rhodopsin is a serpentine receptor embedded in the membrane of the rod cell. Coupling of 11-cis-retinal occurs at 3 of the transmembrane domains of rhodopsin. Within the membrane of visual cells, rhodopsin is coupled to a specific G-protein called transducin (Figure 8-13).

When the rhodopsin is exposed to light, it is bleached releasing the 11-cis-retinal from opsin. Absorption of photons by 11-cis-retinal triggers a series of conformational changes on the way to conversion to all-trans-retinal. One important conformational intermediate is metarhodopsin II. The release of opsin results in a conformational change in the photoreceptor. This conformational change activates transducin, leading to an increased GTP binding by the α-subunit of transducin. Binding of GTP releases the α-subunit from the inhibitory β- and γ-subunits. The GTP-activated α-subunit in turn activates an associated phosphodiesterase; an enzyme that hydrolyzes cyclic-GMP (cGMP) to GMP. Cyclic GMP is required to maintain the Na⁺ channels of the rod cell in the open conformation. The drop in cGMP concentration results in complete closure of the Na⁺ channels. Metarhodopsin II appears to be responsible for initiating the closure of the channels. The hyperpolarization causes the closure of calcium channels in the plasma membrane of the rod cell and since calcium ions are required for the release of glutamate from pre-synaptic vesicles, the release of glutamate is inhibited. The loss of glutamate release results less activation of the glutamate receptor on bipolar cells with the consequences that these cells become depolarized and no longer release the inhibitory neurotransmitter, GABA. The result is that the optic nerve become disinhibited in the dark so that we can see with the limited light available at night (see Clinical Box 8-5).

Vitamin D

Vitamin D is a steroid hormone that functions to regulate specific gene expression following interaction with its intracellular receptor. The biologically active form of the hormone is 1,25-dihydroxy vitamin D₃ [1,25-(OH)₂D₃], also termed calcitriol. Calcitriol functions primarily to regulate calcium and phosphorous homeostasis (see Clinical Box 8-6).

Active calcitriol is derived from ergosterol (produced in plants) and from 7-dehydrocholesterol. 7-dehydrocholesterol is an intermediate in the synthesis of cholesterol (see Chapter 26) that accumulates in the skin. Upon exposure to ultraviolet (UV) light from the sun and following thermal isomerization, 7-dehydrocholesterol is nonenzymatically converted to pre-vitamin D₃, which then enters the bloodstream and is taken up by the liver where it undergoes the first of 2 activating hydroxylation reactions. Ergocalciferol (vitamin D₂) is formed by UV irradiation of ergosterol (Figures 8-14).

Vitamin D₂ and D₃ are processed to D₂-calcitriol and D₃-calcitriol, respectively, by the same enzymatic pathways in the body. Cholecalciferol (or ergocalciferol) are absorbed from the intestine and transported to the liver bound to a specific vitamin D–binding protein. In the liver, cholecalciferol is hydroxylated at the 25 position by a specific D₃-25-hydroxylase generating 25-hydroxy-D₃ [25-(OH)D₃], which is the major circulating form of vitamin D (see Figure 8-15). Conversion of 25-(OH)D₃ to its biologically active form, calcitriol, occurs through the activity of a specific D₃-1-hydroxylase present in the proximal convoluted tubules of the kidneys, and in bone and placenta. 25-(OH)D₃ can also be hydroxylated at the 24 position by a specific D₃-24-hydroxylase in the kidneys, intestine, placenta, and cartilage.

PTH is released in response to low serum calcium and induces the production of calcitriol. In contrast, reduced levels of PTH stimulate synthesis of the inactive 24,25-(OH)₂D₃. In the intestinal epithelium, calcitriol functions as a steroid hormone in inducing the expression of calbindinD_28K, a protein involved in intestinal calcium absorption. The steroid hormone action of vitamin D occurs via the action of calcitriol binding to a specific intracellular receptor that is a member of the nuclear receptor family of hormone receptors called the vitamin D receptor (VDR).

The increased absorption of calcium ions requires concomitant absorption of a negatively charged counter ion to maintain electrical neutrality. The predominant counter ion is phosphate. When plasma calcium levels fall, the major sites of action of calcitriol and PTH are bone, where they stimulate bone resorption, and the kidneys, where they inhibit calcium excretion by stimulating reabsorption by the distal tubules.

Vitamin E

Vitamin E is a mixture of several related compounds known as tocopherols and tocotrienols. The tocopherols are the major sources of vitamin E in the US diet. The tocopherols differ by the number and position of methyl (–CH₃–) groups present on the ring system of the chemical structure. The different tocopherols are designated α-, β-, γ-, and δ-tocopherol. Most vitamin E in US diets is in the form of γ-tocopherol from soybean, canola, corn, and other vegetable oils. All 4 tocopherols are able to act as free radical scavengers thus, they all have potent antioxidant properties. Vitamin E is absorbed from the intestines packaged in chylomicrons. It is delivered to the tissues via chylomicron transport and then to the liver through chylomicron remnant uptake. The liver can export vitamin E in very-low-density lipoproteins (VLDLs). Within the liver α-tocopherol transfer protein preferentially transfers α-tocopherol to VLDLs, thus α-tocopherol is the most abundant tocopherol in nonhepatic (liver) tissues. Due to its lipophilic nature, vitamin E accumulates in cellular membranes, fat deposits, and other circulating lipoproteins. The major site of vitamin E storage is in adipose tissue (Figure 8-16).

Stay updated, free articles. Join our Telegram channel

Join