The molecular structure of vitamin D3 is closely allied to that of classical steroids such as cholesterol (see Figure1). Technically, vitamin D is a secosteroid. Secosteroids are those in which one of the rings of the cyclopentanoperhydrophenanthrene ring structure of the classic steroids has undergone fission by breakage of a carbon–carbon bond. In the instance of the vitamins D (both vitamin D3 and vita min D2) this is the 9, 10-carbon bond of ring B.

Fig1. Structural relationship of vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) with their respective provitamins, 7-dehydro-cholesterol and ergosterol. The two structural representations presented at the bottom for both vitamin D3 and vitamin D2 are equivalent (see text); these are simply different ways of drawing the same molecule and reflect the rotation around the C6–C7 single bond. The only structural difference between vitamin D3 and vitamin D2 is the side chain. Vitamin D3 has the side chain of cholesterol while vitamin D2 has the side chain of ergosterol. Vitamin D2 has a C22=C23 double bond and an additional methyl group on C24. It is to be emphasized that vitamin D3 is the naturally occurring form of the vitamin; it is produced from 7-dehydrocholesterol, which is present in the skin, by the action of sunlight (see Figure 2). Vitamin D2 is produced commercially by the irradiation of the plant sterol ergosterol with ultraviolet light. According to Dr. R. P. Heaney vitamin D2 has only ~30% of the biological activity of vitamin D3 in humans and only 10% in birds.

There are several families of vitamin D steroids based upon differences in the structure of the side chain attached to carbon 17. The vitamin D3 family is derived from cholesterol which has an 8 carbon saturated sidechain; see the green sidechain in Figure 1. The vitamin D2 family is derived from ergosterol, which has a 9 carbon sidechain attached to carbon 17, with a 22–23 double bond and an additional methyl group on C-24; see the red sidechain in Figure 1. Collectively, vitamin D3 (or cholecalciferol) and vitamin D2 (or ergocalciferol) can be termed the calciferols or simply vitamin D without a subscript 2 or 3.

Vitamin D3 is normally produced by exposure to sunlight of the precursor, 7-dehydrocholesterol, present in the skin. In contrast, vitamin D2 is only produced synthetically via ultraviolet irradiation of the sterol ergosterol. Ergosterol, while present in yeast, is not present in mammals and thus vitamin D2 cannot be produced via exposure of skin to sunlight.

A formal definition of a vitamin is that it is a trace dietary constituent required to affect the normal function of a physiological process. The emphasis here is on trace and the fact that the vitamin must be sup plied regularly in the diet; this implies that the body is unable to synthesize the vitamin in question. Thus, vitamin D3 becomes a vitamin only when the animal or human does not have regular access to sunlight or ultraviolet light. Under normal physiological circum stances, all mammals, including humans, can generate via ultraviolet photolysis adequate quantities of vita min D to meet their nutritionally defined requirements. It is largely through a historical accident that vitamin D3 has been classified as a vitamin rather than as a steroid hormone. Chemists had certainly appreciated the strong structural similarity between the vitamins D and other steroids, but this correlation was never widely acknowledged in the biological, clinical, or nutritional sciences until 1965–1970.

The chief structural prerequisite of a sterol to be classified as a provitamin D is its ability to be con verted, upon ultraviolet irradiation, to a vitamin D; thus, it is mandatory that it have in its B ring a Δ5,7 -conjugated double-bond system. A summary of the photochemical pathway involved in the production of vitamin D in man and animals is presented in Figure 2. In the skin, the principal ultraviolet irradiation product is previtamin D3. The conversion of previtamin D3 to vitamin D3 involves an intramolecular hydrogen transfer from C-19 to C-9 (see the legend for Figure 2 for details); these chemical transformations can occur in the absence of further ultraviolet expo sure. The resulting vitamin D3 is then transported in the general circulatory system by the 50 kDa vitamin D-binding protein (DBP).

Fig2. Photochemical pathway of production of vitamin D3 (cholecalciferol) from 7-dehydrocholesterol. The starting point is the irradiation of a provitamin D, which contains the mandatory Δ5,7-conjugated double bonds; in the skin this is 7-dehydrocholesterol. After absorption of a quantum of light from sunlight (UV-B), the activated molecule can return to the ground state and generate at least six distinct products. The four steroids that do not have a broken 9, 10-carbon bond (provitamin D, lumisterol, pyrocalciferol, and isopyrocalciferol) represent the four diastereomers with either an α- or a β-orientation of the methyl group on carbon-10 and the hydrogen on carbon-9. The three secosteroid products, vitamin D3, previtamin D3 and tachysterol3, each have differing positions of the three conjugated double bonds. In the skin the principal product is previtamin D3, which then undergoes a 1,7-sigmatropic hydrogen transfer from C-19 to C-9, yielding the final vitamin D3. Vitamin D3 can be drawn as either a 6-s-trans representation (this figure) or a 6-s-cis representation (see Figure 3), depending upon the state of rotation about the 6,7-single bond. The resulting vitamin D3, which is formed in the skin, is removed by binding to the plasma transport protein, the vitamin D-binding protein (DBP), present in the capillary bed of the dermis. The DBP-D3 then enters the general circulatory system. The same overall mechanism applies to the commercial irradiation of ergosterol to yield vitamin D2.

Interest has focused on the effects of latitude (diminished UV-B intensity), skin pigmentation (concentration of melanin), and photochemical regulation upon the efficiency of conversion of 7-dehydrocholesterol present in the skin to epidermal previtamin D3. In order of importance, the significant determinants limiting the rate of cutaneous production of previtamin D3 are (i) photochemical regulation, (ii) pigmentation, and (iii) latitude.

Although the chemical structure of vitamin D was determined in the 1930s, it was not until the era 1965–1995 that the truly unique structural aspects of the molecule became appreciated. In contrast to other steroid hormones  the vitamin D molecule has three structural features that contribute to the extreme conformational flexibility of this secosteroid molecule; these include the presence of (i) an 8-carbon side chain; (ii) a broken B ring, which “unlocks” the A ring; and (iii) the ability to undergo chair–chair inter change many times per second.

A totally new era in the field of vitamin D3 opened in 1967 with the discovery of the metabolism of vita min D3 into a steroid hormone. The biologically active form of vitamin D3 is the steroid lα25-dihydroxyvitamin D3 [1α,25(OH)2D3]. It is now recognized that there is an endocrine system for processing the prohormone, vitamin D3, into its hormonally active daughter metabolite(s) (see Figure 3). The endocrine gland producing the biologically active form of vitamin D3 is the kidney. After metabolic conversion of vitamin D3 into 25-hydroxy vitamin D3 by a liver microsomal enzyme, his circulating form of the secosteroid serves as a substrate for either the renal 25(OH)D-1α-hydroxylase or the 25(OH)D-24-hydroxylase. Both enzymes are located in the mitochondrial fraction of the kidney proximal tubule. The 1α-hydroxylase is localized in the kidneys of members of every vertebrate class from teleosts, through amphibians, reptiles, and aves, to mammals, including primates. It has been shown that the 25(OH)D3-1α-hydroxylase enzyme system is a classical mixed-function steroid hydroxylase similar to the steroid hormone hydroxylases found in the adrenal cortex mitochondria. The 1α- hydroxylase is a cytochrome P450-containing enzyme that involves an adrenodoxin component incorporating molecular oxygen into the 1α-hydroxyl functionality of 25(OH)D3. 1α,25(OH)2D3 acting as a steroid hormone is also known to genomically induce the renal 24-hydroxylase to permit the coproduction of 24,25(OH)2D3. Emerging evidence suggests a role for 24,25(OH)2D3 in mediating normal bone development. Thus, 1α,25(OH)2D3 and 24,25(OH)2D3 are the two principal forms of the parent vitamin D3 that mediate the biological responses characteristic of this vitamin.

Fig3. A summary of the key aspects of vitamin D metabolism. The secosteroid vitamin D3 itself is biologically inert and does not stimulate or mediate any biological responses. Vitamin D3 produced photochemically in the skin (see Figure 9-7) or obtained dietarily is 25-hydroxylated in the liver to generate 25(OH)D3 and then further metabolized in the kidney. Thus vitamin D3 is a precursor to three key daughter metabolites. Accordingly, there are three key enzymes involved in conversion of vitamin D3 into 25(OH)D3, 1α,25(OH)2D3, or 24R,25(OH)2D3. They include the following: (a) the vitamin D3-25-hydroxylase (a liver mitochondrial CYP27A1); (b) a 25(OH)D3-1α-hydroxylase (the proximal kidney tubule mitochondrial CYP27B1); and (c) a 25(OH)D3-24R-hydroxylase (the proximal kidney tubule mitochondrial CYP24). The liver 25-hydoyxlase is not subject to physiological regulation. Thus, the amount of 25(OH)D3 produced is dependent upon the substrate concentration of vitamin D3 present. In contrast, both the kidney 1α-hydroxylase and the 24R-hydroxylase are highly regulated. As shown in the figure, the activity of the 1α-hydroxylase is increased by PTH, and low serum Ca2+ and decreased by FGF-23 and the circulating n t concentration of 1α,25(OH)2D3. Both the kidney-produced 1α,25(OH)2D3 and 24R,25(OH)2D3 as well as the liver-produced 25(OH)D3 move to the circulatory system where they bind to the vitamin D binding protein (DBP) for transport throughout the circulatory system. Target tissues for 1α,25(OH)2D3 are defined by the presence of the VDR.

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Parathyroid Hormone

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Sanger Was the First to Determine the Sequence of a Polypeptide

The α-R Groups Determine the Properties of Amino Acids

Properties of the Functional Groups of Amino Acids

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Phospholipase A2