Fundamentals of Biochemistry - A. A. Anisimov 1986

Vitamins
Water-Soluble Vitamins

Vitamin B₁ (antineuritic, thiamine). Thiamine, or 4-methyl-5-β-hydroxyethyl-N-thiazolium, is usually synthesized as a hydrochloride or hydrobromide salt. The Biosynthesis of thiamine proceeds from pyrimidine and thiazole derivatives through their preliminary phosphorylation followed by their Condensation into a single molecule via a pyrophosphorylase reaction (i.e., the elimination of H₄P₂O₇). The biosynthesis of thiazole itself has not yet been sufficiently studied. The coenzyme form, namely thiamine pyrophosphate, or Thiamine diphosphate (TDP), is formed via the direct transfer of a pyrophosphate group from ATP to thiamine.

Vitamin B₁ deficiency (beriberi, B₁-deficiency polyneuritis) begins with such precursor symptoms as loss of appetite and general lethargy, followed by weakness in the legs and numbness. Nausea and persistent constipation appear, accompanied by shortness of breath and palpitations upon the slightest physical exertion. Signs of Nervous system damage progressively increase—Skin sensitivity decreases, and paralysis and spasms of the extremities, most commonly the lower ones, develop. Marked weight loss and emaciation are observed. Edema frequently occurs. Autopsies of humans and animals that died from beriberi reveal significant structural alterations in the Central Nervous System and peripheral nerves. Both plant-based foods as well as meat, fish, and dairy products serve as sources of vitamin B₁.

Legumes—such as beans, green and dry peas, lentils, and soybeans—are particularly rich in it. The requirement for vitamin B₁ is 0.6 mg per 4.19x10³ kJ (1000 kcal) of the daily dietary intake.

The Role of vitamin B₁ in METABOLISM is primarily determined by its coenzyme Functions. The phosphorylated form of this vitamin, thiamine diphosphate, serves as the non-protein moiety of A number of Enzymes.

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Thiamine diphosphate participates in the decarboxylation reactions of α-keto acids, as well as in the Cleavage and synthesis of α-hydroxy ketones (e.g., ketosugars), i.e., in Reactions Involving the synthesis and cleavage of carbon-carbon bonds located in the immediate vicinity of a carbonyl group.

Thiamine-dependent enzymes include, for example, Pyruvate decarboxylase and transketolase (see Section 3.4). It was previously assumed that vitamin B₁ deficiency was primarily associated with the excessive accumulation of pyruvate in the Blood and Tissues due to the inhibition of its decarboxylation. However, it has now been established that this process occurs only in isolated tissues under conditions of severe deficiency. Another mechanism is more likely: the blocking of the transketolase reaction in the Pentose Phosphate Pathway, leading to a sharp deceleration in The formation of NADPH and ribose-5'-phosphate, which significantly affects many metabolic processes.

Along with these data, information on the high biological activity of non-coenzyme derivatives of vitamin B₁ has accumulated over the past twenty years. Two distinct directions have clearly emerged here: the possible involvement of various phosphoric esters of vitamin B₁ in the active transfer of energy-rich phosphate groups, and the potential role of thiamine in oxidation-reduction processes.

Vitamin B₂ (riboflavin). In addition to riboflavin itself (6,7-dimethyl-9-D-ribitylisoalloxazine), natural sources contain its coenzyme derivatives: flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These Coenzyme forms of vitamin B₂ quantitatively predominate in most animal and plant tissues, as well as in microbial Cells. Biogenesis is of a very complex nature, with guanosine serving as the initial compound. The synthesis of riboflavin is carried out by green plants, most Bacteria, and Fungi.

Vitamin B₂ deficiency (ariboflavinosis) in humans is characterized by inflammatory conditions of the oral mucosa; visual impairment—initially manifested as rapid eye fatigue, photophobia, a burning sensation in the eyes, and inflammation of the eye mucosa and eyelids, followed by involvement of the cornea. Along with this, patients exhibit anemia and lesions of the facial, ear, and chest skin. Vitamin B₂ is essential for normal fetal development. Due to the bacterial biosynthesis of riboflavin in the gastrointestinal tract, ruminant animals do not require Dietary intake of riboflavin.

Humans obtain the largest amount of riboflavin (65–70%) from dairy and meat products and bread, while 30–35% comes from vegetables and fruits. The daily requirement for vitamin B₂ is 2 mg for adults and 1–2 mg for children. Riboflavin absorbed in the intestine undergoes phosphorylation. In the process, two coenzyme forms are produced—FMN and FAD. All Flavoproteins studied are oxidation-reduction enzymes that perform the function of hydrogen transport during tissue Respiration (see Section 7.3.1).

Vitamin β₃ (pantothenic acid). Chemically, natural pantothenic acid consists of D-α,γ-dihydroxy-β,β-dimethylbutyric acid and β-Alanine residues linked together by an amide bond.

Pantothenic acid is synthesized by green plants and microorganisms from α-ketoisovaleric acid via ketopantoic acid, followed by pantoic acid, to which β-alanine is attached. The latter is formed via the decarboxylation of aspartic acid or through Transamination from malonic semialdehyde.

Derivatives of pantothenic acid are known: its amide (pantothenamide) and panthenol, formed by the reduction of the COOH group of pantothenic acid to an alcohol group. The most important derivatives of pantothenic acid are coenzyme A—in the form of which this acid performs its specific metabolic function—and the acyl carrier protein (ACP). Pantothenic acid deficiency in humans and animals manifests as growth retardation, weight loss, damage to the skin and fur, and Hair loss; as well as degenerative Changes in the myelin Sheath of the Spinal Cord, posterior roots, and sciatic nerve. These are associated with motor incoordination, a high-stepping ("goose") gait, and paralysis; and Disorders of the gastrointestinal tract, reproductive Organs, and Adrenal Glands.

Pantothenic acid is exceptionally widely distributed in nature. It is synthesized by green plants and microorganisms: Yeasts, many bacteria (including the intestinal microflora of mammals), and fungi. Animal tissues are incapable of synthesizing pantothenic acid, but they synthesize CoA from it. Pantothenic acid is present in virtually all foods of animal or plant origin. Its content is particularly high in animal Liver, Kidneys, egg yolk, caviar, and meat. Among vegetables, cauliflower, potatoes, and tomatoes are richer in pantothenic acid. The concentration of pantothenic acid is extremely high in royal jelly and brewer's Yeast. The human daily requirement for pantothenic acid is 10 mg. Pantothenic acid enters the Human and Animal Organism with food. In addition, pantothenic acid is synthesized by the intestinal microflora, particularly E. coli, in the gut of mammals and humans.

Vitamin B₅ (antipellagric, nicotinamide, PP, nicotinic acid, niacin). In nature, Vitamin PP occurs in two forms—as nicotinic acid and nicotinamide. Nicotinic acid is pyridine-3-carboxylic acid, and nicotinamide is its amide. The Conversion of Tryptophan to nicotinic acid mononucleotide occurs in humans and animals. In green plants and microorganisms, aspartate and triose derivatives serve as the initial compounds in the biogenesis of vitamin PP.

Vitamin PP deficiency causes pellagra (from Italian *pelle agra* — rough skin). The leading symptom of the disease is dermatitis. The skin turns red, becomes rough, and develops blisters and cracks; ulcerations remain at the sites of ruptured blisters. These changes affect exposed areas of the body subject to solar radiation. Another group of symptoms includes severe disorders of the Digestive System. Pellagra also leads to nervous system disorders extending to mental illness.

Plants and most microorganisms synthesize nicotinic acid and do not require its exogenous intake. It is most abundant in dried brewer's yeast and compressed baker's yeast. Significant amounts of nicotinic acid are found in cereal products. The daily requirement for vitamin PP is 6.5 mg per 4.19×10³ kJ (1000 kcal). Nicotinic acid and nicotinamide are Components of the Coenzymes NAD and NADP and, together with apoenzymes, catalyze oxidation-reduction reactions of cellular metabolism and Photosynthesis (see Section 6.5.1).

Vitamin B₆ (antidermatitic, pyridoxine, pyridoxal, pyridoxamine).

Vitamin B₆ deficiency manifests as suppression of red blood Cell production, dermatitis, inflammatory skin conditions, growth retardation in animals, and impaired Tryptophan Metabolism. Vitamin B₆ is synthesized by numerous species of microorganisms and green plants from Glycolysis products: glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, or pyruvate. The specific pathways of synthesis have not been sufficiently studied. The intestinal microflora of ruminant animals actively synthesize vitamin B₆. The human intestinal microflora also synthesizes this vitamin, though in insufficient quantities. The richest sources of vitamin B₆ are dried brewer's yeast, meat, fish, whole grains, and especially cereal bran. In animals, it is abundant in liver, Heart, and Kidney tissues. The daily requirement for vitamin B₆ is 2 mg for adults, provided that the diet supplies at least 100 g of protein. The biological activity of B₆ Vitamins is associated with their conversion within the organism into coenzyme forms—pyridoxal-5-phosphate and pyridoxamine-5-phosphate.

Pyridoxamine phosphate functions as a coenzyme in reactions involving the transformation of carbonyl compounds, for example, in the formation of 3,6-dideoxyhexoses that are components of Antigens localized On the surface of bacterial cells. The biochemical functions of Pyridoxal phosphate are: 1) transport—participation in The Active Transport of Certain Amino Acids across cell membranes; 2) catalytic—functioning as a coenzyme in a wide range of enzymatic reactions (transamination, decarboxylation, Amino Acid Racemization, etc.) catalyzed by pyridoxal phosphate-containing or "pyridoxal" enzymes; 3) regulatory function regarding the turnover rate of pyridoxal enzymes—prolonging the half-life in tissues of certain pyridoxal apoenzymes upon their saturation with pyridoxal phosphate, which increases the stability of apoenzymes against thermal Denaturation and the action of specific proteinases.

Vitamin B_c (anti-anemic factor, Folic acid, folacin, pteroylglutamic acid). Folic acid is the principal representative of a broad group of related compounds united under the general name folacin. All these compounds contain pteridine heterocycles and a p-aminobenzoic acid residue to which glutamic acid molecules are attached via a peptide linkage, with their number ranging from 1 to 7.

The starting product for pteridine biosynthesis is guanosine triphosphate (GTP). The ring opens with the release of the C-8 atom of the purine as formate. This is followed by a rearrangement that incorporates a portion of the ribose into the ring Structure. The addition of p-aminobenzoic acid yields dihydropteroic acid, which is then converted into dihydrofolic acid with the participation of ATP and glutamic acid (as an amino group source).

Folic acid is metabolically inactive, but it serves as a precursor for coenzymes involved in metabolic processes. The active coenzyme form of folacin is reduced folic acid with four hydrogen atoms attached at positions 5, 6, 7, and 8 of its pteridine ring—namely 5,6,7,8-tetrahydrofolic acid (THFA), or tetrahydropteroylglutamic acid. It has the following formula:

The glutamic acid residues are linked by an amide bond formed between the a-carboxyl and y-carboxyl groups. One-carbon residues are fixed, activated, transformed, and subsequently transferred to a substrate at the Active Site of THFA (the ethylenediamine grouping).

THFA participates in transfer reactions of one-carbon residues with varying degrees of oxidation (excluding CO₂): —CH₃

thehenyl group). Consequently, THFA plays a crucial role in the Synthesis of Purines and Pyrimidines. The primary precursors for one-carbon residues are Serine and Histidine (—CH—NH groups).

N^5,10-Methylene-THFA, formed via serine and reduced to methyl-THFA, serves as the primary source of the methyl group in the synthesis of Methionine, thymine, and Other Compounds produced through the methylation of specific groups. The utilization of formate as the sole carbon source by certain bacteria also occurs with the participation of pterin coenzymes.

In The Human Body, folacin is closely linked to hemopoiesis (blood formation) and acts as an anti-anemic factor. It was originally discovered as a growth factor for lactic acid bacteria found in spinach leaves, hence the name folic acid (from the Latin folium, meaning leaf). Folacin stimulates not only erythropoiesis but also leukopoiesis.

Folates (folic acids) are widely distributed in nature. Most microorganisms, as well as lower and higher plants, are capable of synthesizing folates. However, folates are not synthesized in the tissues of mammals and birds. Only trace amounts of pteroylmonoglutamic acid are found in PLANT AND ANIMAL tissues, where the majority of folates exist as di-, tri-, and polyglutamates. The predominant form of folates in bacteria is pteroyltriglutamic acid, whereas in yeast, it is heptaglutamate. Primary dietary sources of folates include lettuce, spinach, cabbage, carrots, tomatoes, and green onions. Among animal products, liver, kidneys, egg yolk, and cheese are particularly rich in folates. The daily requirement of folic acid for an adult is 100—200 mcg.

Vitamin B₁₂ (cobalamin). Cobalamins is a group name for compounds exhibiting B₁₂ vitamin activity. The central core of the vitamin B₁₂ molecule is a cyclic corrin system structurally resembling Porphyrins (differing in that two pyrrole rings are tightly condensed with each other rather than connected via a methylene bridge). All bonds, except for two, are coordination bonds. One of these is formed between Co above the plane of the corrin ring and 5,6-dimethylbenzimidazole, which is linked to ribose-3'-phosphate via a glycosidic bond. Below the plane of the corrin ring lies a 5'-deoxyadenosine residue attached to cobalt. In the presence of anions, particularly cyanide, Co is oxidized to the trivalent state, and the 5'-deoxyadenosine is replaced by the attacking anion. Thus, cyanocobalamin is not the native vitamin, but a modified form typically obtained during the isolation process of the vitamin.

Vitamin B₁₂ is synthesized by actinomycetes, which construct the corrin portion of the molecule from uroporphyrinogen III. Seven methyl groups are derived from S-adenosylmethionine. Riboflavin is an obligate intermediate in the biosynthesis of vitamin B₁₂. The final stages of synthesis involve the phosphorylation of 5'-deoxyadenosylcobamide and condensation with GTP. This is followed by the release of GMP, the cleavage of phosphate, and the formation of coenzyme B₁₂.

Hypo- and avitaminosis B₁₂ in humans can develop due to both exogenous vitamin deficiency (dietary) and various endogenous conditions. There are two forms of endogenous avitaminosis: gastrogenic and enterogenic. Gastrogenic avitaminosis is caused by the absence or deficiency of the "intrinsic factor," which leads to impaired utilization of dietary vitamin B₁₂.

Castle's intrinsic factor is produced in The Stomach; it is a heat-labile, non-dialyzable glycoprotein (transcorrin). It specifically binds vitamin B₁₂ to form a complex. Vitamin B₁₂ is absorbed in the intestine exclusively in this transcorrin-bound form. Gastrogenic B₁₂ avitaminosis underlies Addison-Biermer disease (synonyms: pernicious anemia, malignant anemia). The disease is characterized by disorders of the hematopoietic, nervous, digestive, and cardiovascular systems.

Enterogenic vitamin B₁₂ deficiency develops As a result of impaired absorption of vitamin B₁₂ in the intestine (e.g., due to the presence of the broad tapeworm or significant destruction of the vitamin by pathological intestinal microflora).

To designate the coenzyme forms of cobalamins, terms such as coenzyme B₁₂, cobamide coenzymes, or cobalamin coenzymes are used. These are methylcobalamin and 5'-deoxyadenosylcobalamin (with the latter predominating).

Cobamide coenzymes participate in Two Types of reactions: Methyl group transfer (methylcobalamin) and isomerization of the type

where X is the transferred group (5'-deoxyadenosylcobalamin).

In methyl transfer reactions, B₁₂-dependent enzymes function downstream of enzymes containing tetrahydrofolic acid: the CH₃ group from methyltetrahydrofolic acid is first transferred to cobalamin. B₁₂-dependent enzymes also participate in Methane synthesis by anaerobic bacteria, as well as in The transfer of CH₃ groups from methylcorrinoids to Hg, As, Se, and Te, resulting in the formation of toxic compounds such as methylmercury, dimethylmercury, etc. The range of reactions and the set of active coenzyme forms in microorganisms are more diverse than in animals. For microorganisms, 14 cobamide coenzyme-dependent reactions are known, and the role of the nucleotide portion of the coenzymes in certain reactions is less essential in them.

Vitamin B₁₂ is the only vitamin synthesized exclusively by microorganisms. The primary role belongs to bacteria, actinomycetes, and blue-green Algae. The latter serve as the main source leading to a significant accumulation of vitamin B₁₂ in the bodies of Mollusks, fish, and various aquatic animals. Humans obtain vitamin B₁₂ through food, where it exists in a protein-bound state. Under the action of digestive enzymes, the vitamin is released from this complex and absorbed in the intestine.

The richest natural sources of vitamin B₁₂ are beef liver and kidneys. The daily requirement for vitamin B₁₂ is 2—2.5 mcg.

Vitamin H (biotin). The biotin molecule consists of imidazole and thiophene rings. The heterocycle can be viewed as a thiophene ring fused with a ureido group. The molecule contains three asymmetric C atoms, which accounts for the existence of eight stereoisomers. Biotin is synthesized from oleic acid, which in the first step yields pimeloyl-CoA via standard ß-Oxidation reactions. Alanine is then attached, followed by ring closure. The source of the S atom in the ring remains unknown.

Yeast (Saccharomyces cerevisiae) requires biotin in large quantities when grown on a medium containing urea as a nitrogen source. This is because, prior to cleavage, urea is carboxylated with the help of a biotin-containing enzyme, urea carboxylase.

Biotin deficiency in animals is characterized by growth arrest, weight loss, skin redness and scaling, hair or feather loss, the formation of a red edematous ring around the eyes resembling "spectacles," an ataxic gait, paw edema, and a characteristic posture with a hunched back.

Biotin is widely distributed in nature and has been found in microorganisms, plants, and animals. All green plants, as well as certain bacteria and fungi, synthesize biotin through the progressive elaboration of the pimelic acid molecule. Its content has been determined across various taxonomic groups of animals, with the highest levels found in insect larvae and the lowest in reptiles. Humans fully meet their biotin requirements through synthesis by the intestinal microflora. Particularly rich dietary sources include pork and beef liver, kidneys, beef heart, and egg yolks, while plant-based sources include beans, rice bran, wheat flour, and cauliflower. The minimum daily requirement for humans is approximately 150–200 mcg.

Biotin deficiency impairs several liver functions in animals, including: the synthesis of citrulline from Ornithine, NH₃, and СO₂; the incorporation of СO₂ into purines; the carboxylation of propionic acid leading to succinic acid formation; and the incorporation of СO₂ into acetoacetic acid.

In enzymes, biotin is invariably bound tightly to the protein via an amide linkage with the ε-NН₃ group of a Lysine residue.

All currently known biotin-dependent enzymes catalyze two MAIN TYPES OF reactions: (1) β-carboxylation or СO₂ fixation reactions coupled with ATP cleavage (such as the carboxylation of pyruvate and acetyl-CoA, where carboxybiotin is formed at the expense of ATP energy); and (2) transcarboxylation reactions proceeding without ATP breakdown, in which one substrate is carboxylated while another compound is simultaneously decarboxylated.

Vitamin C (antiscorbutic factor, ascorbic acid). Structurally, ascorbic acid can be classified as a carbohydrate derivative. It is a hexonic acid lactone containing a dienol group. Because of its two asymmetric carbon atoms at positions 4 and 5, ascorbic acid forms four optical isomers and two racemates. Ascorbic acid is a relatively strong acid, a property attributable to the presence of two reversibly dissociating enolic hydroxyl groups:

The synthesis of ascorbic acid can be performed by all animal species except humans, non-human primates, and guinea pigs. During this biosynthetic pathway, D-glucuronic acid is converted into L-gulonic acid, then into L-gulono-γ-lactone, and subsequently transformed via 3-keto-L-gulonolactone into L-ascorbic acid.

The primary symptoms of Vitamin C Deficiency include increased fragility of blood capillaries, general weakness, apathy, fatigue, decreased appetite, growth retardation, heightened susceptibility to infections, as well as sore, swollen, spongy, and bleeding Gums during toothbrushing. In advanced stages of scurvy, symptoms of gingivitis (ulceration of the gums and tooth loosening) become progressively severe.

Ascorbic acid is one of the most widely distributed vitamins in nature. It is synthesized by plants and the vast majority of animals. Seeds of higher plants lack vitamin C, but it appears within them from the very first days of germination. Leaves and fruits are rich in vitamin C, whereas ROOT vegetables contain somewhat lower amounts. The daily requirement for adults ranges from 70 to 120 mg.

One of the Fundamental properties of ascorbic acid is its capacity for reversible oxidation-reduction reactions. The oxidation of the vitamin is catalyzed by ascorbate oxidase, ceruloplasmin, and certain other oxidases. The reduction of dehydroascorbic acid back to ascorbic acid is catalyzed by dehydroascorbate reductase, which is found in both animal and plant tissues. This enzymatic activity requires the presence of Glutathione and NADPH₃.

Thus, plant and animal tissues maintain a relatively stable ratio of ascorbic acid forms through enzymatic regulation, with the highest concentrations found in tissues exhibiting high metabolic activity. This suggests that the oxidation-reduction interconversions of vitamin C play a crucial role in biological reactions involving electron transport. Ascorbic acid is well-known as a cofactor for Proline hydroxylation during Collagen synthesis, the hydroxylation of p-hydroxyphenylpyruvate into homogentisic acid, as well as the metabolism of corticosteroids and transferrin.

It is hypothesized that in plants, the enzyme ascorbate oxidase, which oxidizes ascorbic acid, functions as one of the terminal respiratory oxidases.

Vitamin P (polyphenols, bioflavonoids). Chemically, bioflavonoids do not comprise a single uniform class of compounds, but they all share a diphenylpropane carbon Skeleton. This group includes catechins, leucoanthocyanins, flavanones, flavanols (including rutin), anthocyanins, and flavones.

Bioflavonoids belong to Phenolic Compounds, with shikemic acid serving as the primary precursor for their synthesis. The main physiological targets of bioflavonoid action are capillary stability and permeability. Vitamin P deficiency manifests as fragility of blood vessel walls, increased capillary permeability, and petechial hemorrhages. The daily requirement for bioflavonoids has not been definitively established.

Polyphenols with vitamin P activity are widespread in plants, being particularly abundant in black chokeberries, black currants, sorrel, gooseberries, dark cherries, peaches, pears, grapes, apples, and grapefruit. The Influence of bioflavonoids on the vascular wall is mediated through the Endocrine glands. Polyphenols protect adrenaline from oxidation; adrenaline in turn stimulates the Pituitary Gland, which subsequently promotes the secretion of corticosteroids. Furthermore, bioflavonoids regulate vascular permeability by acting on the hyaluronic acid–hyaluronidase system via hyaluronidase inhibition. Vitamin P compounds also protect ascorbic acid from oxidation. The antioxidant mechanism of bioflavonoids involves blocking the catalytic action of heavy metals by binding them into stable complexes.

Inositol. Inositol is a cyclic hexahydric alcohol of cyclohexane.

Inositol deficiency is virtually never observed in humans; in mice, it manifests as growth retardation, hair loss, decreased gastric tone, anemia, and partial fatty liver infiltration. Inositol is widely distributed in plant and animal tissues. In plants, it is synthesized via the cyclization of glucose molecules and occurs predominantly as an ester with phosphoric acid, known as phytic acid.

In animal tissues, inositol is present mainly as a component of phosphatidylinositol molecules, which are found in numerous tissues and are particularly abundant in cells of The Nervous System. Dietary sources of inositol include meat products, Brain, liver, heart, egg yolks, bread, corn, potatoes, green peas, apples, melons, and mushrooms. The daily human requirement for inositol is 1–1.5 g.