Fundamentals of Biochemistry - A. A. Anisimov 1986

Vitamins
Fat-soluble vitamins

Vitamin A (antixerophthalmic vitamin, retinol, axerophthol). Three Vitamins of this group are known: A₁, A₂ (in which all double bonds are in the trans-configuration), and neovitamin A (the cis-form of vitamin A₁). Vitamin A₂ differs from A₁ by the presence of an additional double bond in the cyclic portion of the molecule.

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An early symptom of Vitamin A deficiency is impaired dark adaptation, progressing to complete loss of Vision in twilight—night blindness (nyctalopia). One of the primary manifestations of vitamin A deficiency is systemic damage to the Epithelial Tissue. Consequently, this leads to lesions of the Cytology/practical/76.html">Cornea of the eye. The Structure of its lining protective epithelium is disrupted; it undergoes keratinization, dries out, and loses transparency, leading to xerophthalmia (from the Greek xeros meaning dry, and ophthalmos meaning eye), which is followed by keratomalacia (softening of the cornea) with subsequent necrosis and ulceration. Healing of these injuries leaves a scar—a corneal leucoma (white opacity)—that blocks light access to the retina. The Skin epithelium also undergoes enhanced keratinization, promoting The Development of skin disorders. Changes in the epithelium lining the mucous membranes of the respiratory tract (Bronchitis) and intestines (colitis) are particularly hazardous.

In vitamin A deficiency, immune mechanisms are weakened. Excessive intake of vitamin A can cause hypervitaminosis and intoxication, which is especially severe in children. The main dietary sources of vitamin A are eggs, heavy cream, sour cream, cow's milk, butter, Kidneys, beef Liver, and cod liver. The recommended daily intake of vitamin A for an adult is 1 mg. Vitamin A is not synthesized in Higher Plants and microorganisms, but its precursors—carotenoids—are formed in them. They are particularly abundant in carrots, tomatoes, spinach, and peppers. The Biosynthesis of carotenes, like that of all Terpenes, proceeds from acetyl-CoA via mevalonic acid (see Section 8.8.3).

Structural isomers of carotene (alpha-, beta-, and gamma-carotenes) can be converted into vitamin A in the body of humans and animals. During The conversion of carotene into vitamin A (retinol), the oxidative Cleavage of the carbon chain of the provitamin occurs via two pathways: at the peripheral double bonds and at the central double bond. In the body, retinol is oxidized to retinal and retinoic acid with the participation of corresponding dehydrogenases and NAD. Retinal occupies a key position in vitamin A METABOLISM and readily undergoes enzymatic reversible reduction to retinol and irreversible oxidation to retinoic acid.

The most specific function of vitamin A is its participation in photoreception processes. Rhodopsin—the photosensitive pigment located in the outer segment of the retinal rods (responsible for twilight vision) in humans, terrestrial vertebrates, and marine fish—is a chromoprotein consisting of a chromophore group (vitamin A aldehyde, or retinal) and the protein opsin. The bond between them is formed via the aldehyde group of retinal and the free NH₂ group of the protein, yielding a Schiff base. Upon exposure to light, 11-cis-retinal dissociates from rhodopsin and simultaneously converts into the trans-form. Bleached As a result of retinal dissociation, the rhodopsin molecule triggers a complex cascade of enzymatic reactions within the visual Cell—an enzymatic Amplification cascade for weak light signals. The bleaching of rhodopsin is also associated with an increase in the permeability of the photoreceptor membrane. All of these processes culminate in the excitation of the Optic nerve.

Evidence suggests that cAMP and adenylate cyclase play an important role in visual reception. Light-induced activation of adenylate cyclase has been established in certain animals. Dopamine, one of the primary Neurotransmitters in the retina, activates adenylate cyclase and increases cAMP levels in intact tissue. According to some authors, cAMP-dependent phosphorylation of rhodopsin may account for membrane hyperpolarization and the Generation of the primary Nerve Impulse. Subsequently, trans-retinal is re-isomerized via trans-retinol into cis-retinal and recombines with opsin.

Cis- or trans-isomers that have absorbed a quantum of light transition from the ground (unexcited) state to a singlet (electronically excited) state. In this state, a single (non-double) bond exists between carbon atoms, which greatly facilitates isomerization—cis-trans transitions. A portion of the retinal is degraded during these transformations, and new vitamin A molecules are required for its regeneration. Due to a deficiency of the latter, The ability to see in the evening and at night is lost.

Over the course of biological evolution, 11-cis-retinal has been conserved as the chromophore group of visual pigments in all vertebrates and invertebrates, such as Mollusks, crustaceans, and insects. Even in evolutionarily ancient halobacteria, which apparently represent an evolutionary dead end, a retinal-containing membrane Protein Functions as the photosensitive receptor molecule.

An important manifestation of the MECHANISM OF ACTION of vitamin A is its involvement in regulating membrane permeability, as well as in The transport of Monosaccharides required for glycoprotein biosynthesis. Vitamin A exerts a clear influence on the assimilation of dietary protein and its Metabolism in the Body, as well as on certain aspects of Lipid Metabolism, including ubiquinone, squalene, Cholesterol, and, partially, Phospholipids.

Vitamin A is hypothesized to participate in oxidation-reduction reactions: given that the vitamin A molecule contains double bonds, it is capable of forming peroxides that increase the oxidation rate of Other Compounds.

Vitamin D (antirachitic vitamin, calciferols). The term calciferols encompasses a group of related compounds possessing antirachitic activity. The most important among them are cholecalciferol (vitamin D₃), ergocalciferol (vitamin D₂), and dihydroergocalciferol (vitamin D₄).

The main structural difference between calciferols and other Steroid compounds lies in the opening of one of the phenanthrene rings, the appearance of three conjugated double bonds in the molecule, and a methylene group in place of a methyl group.

Vitamin D deficiency leads to the development of Rickets. In this condition, the closure of cranial sutures is delayed, and these bones undergo excessive growth, accompanied by enlargement of the frontal eminences. Other bones also become deformed. Due to insufficient Ossification of the rib cartilages, the rib cage assumes an irregular shape. The BONES OF THE legs bend under the weight of the body. Muscles become flaccid, their tone decreases, and the abdomen protrudes. Rickets retards the overall development of a child. Teething is delayed, and the Teeth themselves are easily destroyed; gastrointestinal disorders are frequent, anemia develops, and the child becomes highly susceptible to other diseases.

Large doses of the vitamin can cause vitamin D hypervitaminosis, which manifests as drastic weight loss, growth arrest, elevated Blood pressure, fever, severe joint pain, convulsions, and respiratory distress. Dietary sources of vitamin D include fish oil, cod liver, fish roe, egg yolks, and butter. The daily intake of vitamin D for children under 6 years of age should range from 500 to 1000 IU, while for older children and adults, it should be 100 IU. However, endogenous formation from 7-dehydrocholesterol under the Influence of the ultraviolet spectrum of light plays a crucial role in maintaining the required overall vitamin D content in the body.

The provitamin of cholecalciferol is 7-dehydrocholesterol, which is formed from cholesterol; the provitamin of ergocalciferol is ergosterol, present in plants and microorganisms (particularly abundant in Yeast). Dihydrotachysterol—a catalytically reduced tachysterol formed during ultraviolet irradiation of ergosterol—also exhibits antirachitic activity.

Vitamin D is not synthesized in green plants, but they serve as suppliers of 7-dehydrocholesterol, which is necessary for vitamin D production. Vitamin D performs its specific metabolic functions not as cholecalciferol or ergocalciferol, but in the form of active metabolites derived from them, the most important of which is 1,25-dihydroxycholecalciferol. In the liver, cholecalciferol is converted by mitochondrial Enzymes in the presence of NADH and O₂ into 25-hydroxycholecalciferol. The latter is hydroxylated in the kidneys to yield 1,25-dihydroxycholecalciferol. The principal functions of vitamin D in the body are associated with mediating the transport of Ca and P across Introduction/36.html">Biological Membranes. The involvement of vitamin D in the following processes can be considered well-established: 1. The transport of Ca and P ions across the epithelial Cells of the small intestinal mucosa during their absorption. Vitamin D forms a complex with a Ca-binding protein in the intestine. According to one hypothesis, under The Influence of 1,25-dihydroxycholecalciferol, one of the intestinal mucosal Proteins acquires the ability to actively bind Ca. Another hypothesis suggests that 1,25-dihydroxycholecalciferol affects the biosynthesis of mRNA for the Translation of the Ca-binding protein. 2. The mobilization of calcium from the Skeleton via the resorption of preformed Bone tissue. 3. The reabsorption of phosphate and calcium in the renal tubules. Ultimately, vitamin D ensures the optimal Blood Plasma levels of Ca and P required for bone tissue mineralization.

Vitamin E (antisterility vitamin, tocopherols). The Vitamin E Group comprises methyl derivatives of tocol and tocotrienol. Individual tocopherols, designated by the Greek letters alpha, beta, gamma, and delta, differ from one another in the number and position of additional methyl substituents in the aromatic ring of 6-hydroxychroman. Alpha-, beta-, gamma-, and delta-tocotrienols are analogs of the corresponding tocopherols and differ from them in the STRUCTURE OF THE side polyisoprenoid chain. In all Fat-soluble vitamins, the latter is formed from acetyl-CoA via mevalonate and isopentenyl pyrophosphate.

Vitamin E deficiency is characterized by the following features: 1. Fetal resorption during Pregnancy. 2. Testicular degeneration in males: reduced sperm motility and progressive degeneration of the germinal epithelium accompanied by atrophy and a decrease in testicular mass. 3. Muscular dystrophy with coagulative or hyaline necrosis of Muscle cells, ataxia, and paralysis. This is one of the primary manifestations of vitamin E deficiency in rabbits, guinea pigs, and many domestic animal species. 4. Macrocytic (large-cell) anemia in monkeys and humans, characterized by a reduced erythrocyte lifespan and impaired erythropoiesis in the Bone Marrow. 5. Increased susceptibility of erythrocytes to peroxide hemolysis in vitro—one of the most universal manifestations of vitamin E deficiency, seemingly characteristic of all animal species.

The severity and nature of manifestations of vitamin E deficiency depend significantly on other dietary components. Protein deficiency, selenium deficiency, excessive fat content (especially unsaturated fats), and supplementation with salts of iron, silver, and certain other metals can significantly accelerate and deepen the development of vitamin E deficiency. Deficiency signs such as liver necrosis in rats and myopathy in chicks occur only when vitamin E deficiency is combined with insufficient selenium in the diet. Tocopherols are widely distributed in nature, particularly in plants and plant-derived products. Plant oils (wheat germ, corn, cottonseed, and sunflower oils) are the richest sources. The recommended daily intake of vitamin E for healthy adults is 15 IU.

The exact Molecular Mechanism of action of vitamin E has not been fully elucidated. One of the most thoroughly developed hypotheses that provides a unified explanation for the numerous and diverse manifestations of vitamin E deficiency is the antioxidant hypothesis. According to this hypothesis, tocopherols function in living Tissues as biological antioxidants that scavenge free radicals, thereby preventing unregulated, non-enzymatic, free-radical chain processes of Lipid Peroxidation of unsaturated tissue Lipids by molecular oxygen. Because unsaturated lipids are Components of the Lipoproteins in cell membranes and subcellular Organelles, enhanced lipid peroxidation resulting from lowered tissue tocopherol concentrations leads to structural damage, impaired permeability, and compromised functional activity of cellular and subcellular membranes. This defect underlies the diverse biochemical, morphological, and clinical manifestations of vitamin E deficiency.

Vitamin K (antihemorrhagic vitamin, phylloquinones, menaquinones). Vitamins of the K group are widely distributed in nature and are represented by two series of Quinones: phylloquinones (the vitamin K₁ series) and menaquinones (the vitamin K₂ series). The structural basis for both is 1,4-naphthoquinone.

Phylloquinones differ from menaquinones in the structure of their side chain; in menaquinones, this chain is polyisoprenoid, and the number of isoprene residues is indicated in the name (e.g., menaquinone-4). Phylloquinones and their demethylated derivatives are found in plants, whereas menaquinones are synthesized by various Bacteria or represent transformation products of naphthoquinones within the body. In animal tissues, naphthoquinones are represented by dietary phylloquinones and menaquinones (obtained from food), as well as by menaquinones formed endogenously from phylloquinone. In addition, menaquinone-4 can be produced in the body upon the administration of synthetic naphthoquinones, such as vikasol, synkavit, menadione, etc.

Vitamin K deficiency leads to subcutaneous and intramuscular hemorrhages and a decreased blood clotting rate. Primary vitamin K deficiency in adults is rarely observed. This is because the requirement for it is normally met by dietary intake, as it is widely distributed in foods, and through synthesis by intestinal bacteria. Vitamin K deficiency is frequently observed in newborns due to its low concentration in milk and the absence of synthesizing microflora in the gut.

Secondary vitamin K deficiency arises as a result of liver diseases, particularly obstructive jaundice, chronic intestinal disorders, Treatment with sulfonamides and Antibiotics that suppress intestinal microflora, as well as therapy with vitamin K antagonist drugs. Rich sources of vitamin K include green plants, where it is found in Chloroplasts as phylloquinone. The synthesis of vitamin K in plants is associated with their photosynthetic function. Spinach, cabbage, and pumpkin are particularly rich sources. Various Forms of vitamin K₂ are present in microorganisms and animal tissues. Unlike microorganisms and plants, which have the ability to synthesize vitamin K, it is an exogenous factor for humans and higher animals. Birds have an acute requirement for it.

In humans, the daily requirement for newborns ranges from 2 to 12 mcg/day. The absorption of vitamin K takes place in the Small Intestine. Natural vitamins of the K₁ and K₂ series, possessing lipophilic properties, require the presence of Bile acids and pancreatic lipase, whereas Water-soluble forms of vitamin K do not. The biologically active form of vitamin K in the Human and Animal body is menaquinone-4, since all Other forms of vitamin K are transformed into it. The precise molecular mechanism of action of naphthoquinones has not been fully elucidated. The following hypotheses are considered most probable.

1. Participation of vitamin K in Oxidative Phosphorylation. Phylloquinone reductase and menadione reductase, in which vitamin K performs a coenzyme function, have been isolated from the Mitochondria of Microbial and Plant cells, as well as from chloroplasts. Naphthoquinones, along with benzoquinones, are components of the photosynthetic system and participate in The transfer of light energy to chlorophyll. The involvement of vitamin K in oxidative phosphorylation in certain bacteria is also recognized. However, data proving a specific role of vitamin K in oxidative phosphorylation processes within the animal Organism are currently lacking.

2. Action of vitamin K at the genetic level. Based on experiments using actinomycin D, which blocks Protein Biosynthesis at the mRNA formation stage, it was concluded that vitamin K is involved in the biosynthesis of blood clotting factors by stimulating DNA-dependent Synthesis of the corresponding mRNA, and that the antagonism between vitamin K and dicoumarol occurs at the level of the regulatory Gene.

3. Participation of vitamin K in the synthesis of procoagulants (blood clotting factors II, VII, IX, and X). Vitamin K participates in the post-translational carboxylation of glutamic acid residues within the aforementioned proteins (clotting factors), which is essential for their active function. The carboxylation of glutamic acid residues is carried out by microsomal carboxylase. Solubilized carboxylase requires NADH, vitamin K, HCO₃, and O₂. Vitamin K exhibits a coenzyme function, which is realized in the form of 2,3-epoxide. Oxidation to 2,3-epoxide occurs via a specific oxidoreductase, while reduction is mediated by NADPH-diaphorase. None of the hypotheses presented can currently be considered comprehensive and exclusively correct.