Clinical Biochemistry of Vitamin A (SIMS-305
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Vitamin A plays an important role in vision, epithelial tissue maintenance, and immune function. It is obtained through foods like cod liver oil, meat, eggs, dairy, and certain fruits and vegetables. The biologically active forms, retinoids, aid in vision through roles in rhodopsin and the visual cycle. Vitamin A supports epithelial tissues and helps prevent keratinization of skin, eyes, and mucous membranes. It also promotes immune response and may have anticancer effects by increasing immune cell receptors. Deficiency can lead to night blindness and xerophthalmia.
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Clinical Biochemistry of Vitamin A (SIMS-305
- 1. Clinical Biochemistry (SIMS-305) Dr. Ali Raza Senior Lecturer Centre for Human Genetics and Molecular Medicine (CHGMM), Sindh Institute of Medical Sciences (SIMS), SIUT. 1
- 2. Vitamin A 2
- 3. Dietry Sources of vitamin A • Cod liver oil • Meat • Egg • Milk • Dairy products • Carrot • Spinach • Papaya • Apricots 3
- 4. Vitamin A • Major vitamin-A precursors (provitamins) → plants carotenoids. • Animals : Esters (retinyl palmitate) – retinol and long fatty acid 4
- 5. Vitamin A • Derivative of certain carotenoids which are hydrocarbon (polyene) pigments (yellow, red). • Carotenes are C40H56 hydrocarbons. • These are called as “Provitamins A” , Carotenes. 5
- 6. vitamin A contain common structural unit Trimethyl cyclohexenyl ring (β-ionone) A trans configurated polyene chain, with four double bonds. 6
- 7. Biologically active forms of Vitamin A - Retinoids • Retinol • Retinal • Retinoid acid 7
- 8. Vitamin A Absorption, Storage and Transport 8
- 9. 9
- 10. Retinol esters hydrolyzed by pancreatic enzymes to Retinol Transport of retinol to target organs tightly bound to retinol-binding protein, RBP. b-caroten is cleaved by b- carotene dioxygenase to Retinal Intestinal cells → esterification of retinol → transported in chylomicrons. ` Remnants of chylomicrons → liver→ esters are stored 10
- 11. 11
- 12. 12 Functions of Vitamin A
- 13. Wald’s visual cycle (Rhodopsin cycle) 13
- 14. George Wald (Nobel Prize) discovered the overall mechanism through which vitamin A functions in visual system Wald’s visual cycle (Rhodopsin cycle) 14
- 15. 15 Wald’s visual cycle (Rhodopsin cycle)
- 16. Vitamin A and Vision Conformation changes of opsin Photorhodopsin Absorption of light 16
- 17. Vitamin A and vision • Vit. A is necessary to form rhodopsin (in rodes, night vision) iodopsins (photopsins, in cones – color vision) - visual pigment. • Retinaldehyde is a prosthetic group of light-sensitive opsin protein. 17
- 18. Vitamin-A and vision Isomerized Oxidized reacts with opsin (Lys) to form the holoprotein rhodopsin. 18
- 19. Signal Transduction in the Retina. rhodopsin 19
- 20. Vitamin A and vision • The following is a series of isomerisation→ initiation of nerve impulse. • The final step is hydrolysis to release all-trans-retinaldehyde and opsin. 20
- 21. Vitamin A and other functions Night blindness (Nyctalopia): • Inability to see well at night or in poor light. • It is not a disease in itself, but rather a symptom of an underlying problem, usually a retina problem. • One of the earliest signals of vitamin A deficiency 21
- 22. Vitamin A--- Role in Epithelialisation The epithelial structures of skin and mucous membrane show gross structural changes in deficiency. • Skin: Skin becomes dry, scaly and rough. These changes are called as keratinisation. • Lacrimal glands: Similar changes occur in lacrimal glands Leading to dryness of conjunctivae and cornea, Xerophthalmia. Lacrimal glands 22
- 23. Role in Epithelialisation • Cornea: White opaque spots called Bitot’s spots appear in the conjunctiva on either side in each eye. Corneal epithelium becomes Keratinised, opaque and may become softened and ulcerated keratomalacia. 23
- 24. Vitamin A and other functions Role in Epithelialisation • Respiratory tract: Keratinisation occurring in the mucous membrane of respiratory tract leads to increased susceptibility to infection and lowered resistance to disease. • Urinary tract: Keratinisation of UT leads to calculi ‘formation’. 24
- 25. β-carotene as an Anticancer β-carotene increases the number of receptors on white blood cells for major histocompatibility complex I (MCH I). Cancerous cells have different proteins on their surfaces from normal cells. Immune system cells (killer T-cells or CD 8 cells) use surface proteins to identify foreign invaders or cancer cells. 25
Editor's Notes
- Light waves striking these receptors produce chemical changes which in turn give rise to nerve impulses. Vitamin A plays significant role in the photochemical phase of this process. Visual activity of rod cells is dependent on their content of photosensitive pigment called rhodopsin or visual purple which is a conjugated protein with a molecular weight of 40,000. It contains Opsin as its apoprotein and retinene as its prosthetic group. Retinene or retinal or retinaldehyde present in rhodopsin is 11-cis-retinal. The aldehyde group of 11-cis-retinal is bound to ε –NH2 group of lysine of opsin. Rhodopsin has a light absorbing property due to polyene group of 11-cis-retinal. Even dim light can break rhodopsin. When the light falls on rhodopsin it is split into opsin and all-trans-retinal in a series of events. It first forms photorhodopsin, bathorhodopsin, then lumirhodopsin, then metarhodopsin I, II and III. Finally metarhodopsin gets split into opsin and all-trans-retinal. At this stage the eye becomes less sensitive to light. All-trans-retinal is inactive in synthesis of rhodopsin, it has to be converted to 11-cis-retinal. It can take place in the following ways: • All-trans-retinal may be isomerised to its 11-cis-isomer in presence of blue light—but in the eye this isomerisation is not significant. • The all-trans-retinal can be converted to all-transretinol by retinene reductase by making use of NADH and all-trans-retinol then can be isomerised to its cis isomer. • All-trans-retinol from blood can be first isomerised to 11-cis-retinol. All 11-cis-retinol then can be converted to 11-‘cis’-retinal by retinol dehydrogenase, in presence of NAD+. • Now 11-cis-retinene (retinal) which is active, can combine with opsin to form back rhodopsin in dark. Thus the visual process involves continual removal of the active cis-retinol from blood into retina. • Role of cyclic GMP in retinal light-dark adaptation . The closing of Na+ channels occur by a light-regulated enzymatic reactions in which the original signal-absorption of a single photon by rhodopsin is amplified manifold. The regulatory protein transducin is involved in this process. Transducin is a guanine-nucleotide binding protein (G protein), the structure and function of which is similar to those of G-proteins that take part in hormonal signals across biological membranes. Transducin binds to GDP when it is “inactive”, and in “active state” it binds to GTP. Transducin is “trimeric” and composed of three subunits, α, β and γ. GDP/GTP binding site is associated with α-subunit.
- Light waves striking these receptors produce chemical changes which in turn give rise to nerve impulses. Vitamin A plays significant role in the photochemical phase of this process. Visual activity of rod cells is dependent on their content of photosensitive pigment called rhodopsin or visual purple which is a conjugated protein with a molecular weight of 40,000. It contains Opsin as its apoprotein and retinene as its prosthetic group. Retinene or retinal or retinaldehyde present in rhodopsin is 11-cis-retinal. The aldehyde group of 11-cis-retinal is bound to ε –NH2 group of lysine of opsin. Rhodopsin has a light absorbing property due to polyene group of 11-cis-retinal. Even dim light can break rhodopsin. When the light falls on rhodopsin it is split into opsin and all-trans-retinal in a series of events. It first forms photorhodopsin, bathorhodopsin, then lumirhodopsin, then metarhodopsin I, II and III. Finally metarhodopsin gets split into opsin and all-trans-retinal. At this stage the eye becomes less sensitive to light. All-trans-retinal is inactive in synthesis of rhodopsin, it has to be converted to 11-cis-retinal. It can take place in the following ways: • All-trans-retinal may be isomerised to its 11-cis-isomer in presence of blue light—but in the eye this isomerisation is not significant. • The all-trans-retinal can be converted to all-transretinol by retinene reductase by making use of NADH and all-trans-retinol then can be isomerised to its cis isomer. • All-trans-retinol from blood can be first isomerised to 11-cis-retinol. All 11-cis-retinol then can be converted to 11-‘cis’-retinal by retinol dehydrogenase, in presence of NAD+. • Now 11-cis-retinene (retinal) which is active, can combine with opsin to form back rhodopsin in dark. Thus the visual process involves continual removal of the active cis-retinol from blood into retina. • Role of cyclic GMP in retinal light-dark adaptation . The closing of Na+ channels occur by a light-regulated enzymatic reactions in which the original signal-absorption of a single photon by rhodopsin is amplified manifold. The regulatory protein transducin is involved in this process. Transducin is a guanine-nucleotide binding protein (G protein), the structure and function of which is similar to those of G-proteins that take part in hormonal signals across biological membranes. Transducin binds to GDP when it is “inactive”, and in “active state” it binds to GTP. Transducin is “trimeric” and composed of three subunits, α, β and γ. GDP/GTP binding site is associated with α-subunit.
- Rhodopsin (also known as visual purple) is a light-sensitive receptor protein involved in visual phototransduction. It is named after ancient Greek ῥόδον (rhódon) for “rose”, due to its pinkish color, and ὄψις (ópsis) for “sight”.[3] Rhodopsin is a biological pigment found in the rods of the retina and is a G-protein-coupled receptor (GPCR). Rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions.[4] When rhodopsin is exposed to light, it immediately photobleaches. Rhodopsin consists of a protein moiety also called scotopsin, which binds covalently a cofactor called retinal. Scotopsin is an opsin. Opsins are G protein coupled receptors and have seven transmembrane domains. The seven transmembrane domains form a pocket, where the retinal (as photoreactive chromophore) binds to a lysine residue in the seventh transmembrane domain. The retinal lies horizontally to the cell membrane. And the cell membrane lipid bilayer embeds half of the rhodopsin. Thousands of rhodopsin molecules are found in each outer segment disc of the host rod cell. Retinal is produced in the retina from Vitamin A, from dietary beta-carotene. Isomerization of 11-cis-retinal into all-trans-retinal by light induces a conformational change (bleaching) in opsin, continuing with metarhodopsin II, which activates the associated G protein transducin and triggers a Cyclic Guanosine Monophosphate, second messenger, cascade.[5][8][9] Rhodopsin of the rods most strongly absorbs green-blue light and, therefore, appears reddish-purple, which is why it is also called "visual purple".[10]It is responsible for monochromatic vision in the dark.[5] Photopsins (also known as Cone opsins) are the photoreceptor proteins found in the cone cells of the retina that are the basis of color vision. Prosthetic :an artificial body part; a prosthesis.
- Rhodopsin (also known as visual purple) is a light-sensitive receptor protein involved in visual phototransduction. It is named after ancient Greek ῥόδον (rhódon) for “rose”, due to its pinkish color, and ὄψις (ópsis) for “sight”.[3] Rhodopsin is a biological pigment found in the rods of the retina and is a G-protein-coupled receptor (GPCR). Rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions.[4] When rhodopsin is exposed to light, it immediately photobleaches. Rhodopsin consists of a protein moiety also called scotopsin, which binds covalently a cofactor called retinal. Scotopsin is an opsin. Opsins are G protein coupled receptors and have seven transmembrane domains. The seven transmembrane domains form a pocket, where the retinal (as photoreactive chromophore) binds to a lysine residue in the seventh transmembrane domain. The retinal lies horizontally to the cell membrane. And the cell membrane lipid bilayer embeds half of the rhodopsin. Thousands of rhodopsin molecules are found in each outer segment disc of the host rod cell. Retinal is produced in the retina from Vitamin A, from dietary beta-carotene. Isomerization of 11-cis-retinal into all-trans-retinal by light induces a conformational change (bleaching) in opsin, continuing with metarhodopsin II, which activates the associated G protein transducin and triggers a Cyclic Guanosine Monophosphate, second messenger, cascade.[5][8][9] Rhodopsin of the rods most strongly absorbs green-blue light and, therefore, appears reddish-purple, which is why it is also called "visual purple".[10]It is responsible for monochromatic vision in the dark.[5] Photopsins (also known as Cone opsins) are the photoreceptor proteins found in the cone cells of the retina that are the basis of color vision. Prosthetic :an artificial body part; a prosthesis.
- In the retina, all-trans-retinol is isomerized to 11-cis-retinol 11-cis-retinol → oxidized to 11-cis-retinaldehyde 11-cis-retinaldehyde reacts with opsin (Lys) to form the holoprotein rhodopsin. Absorption of light → conformation changes of
- Activation of rhodopsin by light results in the hydrolysis of cyclic guanosine monophosphate (cGMP), causing cation channels to close. When a photon activates a rhodopsin protein, this triggers GTP-for-GDP exchange on transducin, and the activated α subunit of transducin then activates PDE6, which cleaves cGMP. The ligand-gated channels close, and the transmembrane potential becomes more negative (adapted from A. Stockman et al., Journal of Vision 8: 1, 2008.)
- Night blindness (nyctalopia) is the inability to see well at night or in poor light. It is not a disease in itself, but rather a symptom of an underlying problem, usually a retina problem. The early sign → a loss of sensitivity to green light, prolonged deficiency → impairment to adapt to dim light more prolonged deficiency leads to night blindness Night Blindness Caused Due to Cataract, retina pigmentosa. since Cataract is something that comes with age taking foods rich in antioxidants, vitamins and minerals can delay this condition for as long as possible.
- organic process by which keratin is deposited in cells and the cells become horny (as in nails and hair) the lacrimal glands are paired, almond-shaped exocrine glands, one for each eye, that secrete the aqueous layer of the tear film. They are situated in the upper lateral region of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone.
- Transformation of respiratory epithelium – loss of protective airway function (antibacterial properties) → bronchitis. Decrease Immunosuppression Conversion of the urinary tract epithelium → higher frequency of urinary stone formation