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.

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.

Good sources include yeast, lean pork, and legume seeds. Thiamin deficiency can be evaluated by determination of transketolase activity in whole blood or erythrocytes, both before and after the addition of TPP. Alternatively, the plasma levels of lactate and pyruvate can be determined after an oral glucose load. These acids accumulate in persons with thiamin deficiency because pyruvate dehydrogenase requires TPP for its activity.

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.

Figure 29.4 Metabolism of vitamin B₆.

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).

Dermatitis, glossitis, and sideroblastic anemia are other abnormalities in vitamin B₆ deficiency. Sideroblastic anemia is a microcytic hypochromic anemia, similar to iron deficiency anemia but in the presence of normal serum iron. It is most likely caused by reduced activity of the PLP-dependent aminolevulinic acid (ALA) synthase in the bone marrow and the resulting impairment in heme biosynthesis. Without heme, iron cannot be used for hemoglobin synthesis but accumulates in erythroblasts in the bone marrow. These iron-loaded erythroblasts are called sideroblasts.

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.

Figure 29.7 Recycling of biotin. These reactions are required both for the utilization of dietary biotin and for the recycling of biotin during the degradation of biotin-containing carboxylase enzymes in the tissues.

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.

Vitamin B₁₂ requires intrinsic factor for its absorption

Vitamin B₁₂, or cobalamin, is chemically the most complex of all vitamins (Fig. 29.10). It is also the rarest of all vitamins. B₁₂

Stay updated, free articles. Join our Telegram channel

Join