Vitamin A Flashcards
1
Q
Vitamin A Roles
A
- maintenance of vision
- development of the embryo
2
Q
Active Forms of Vitamin A
A
- retinol
- retinal (retinaldehyde)
- retinoic acid
3
Q
Vitamin A is used to treat […] and […] subtype M3.
A
Vitamin A is used to treat measles and acute myeloid leukemia (AML) subtype M3.
4
Q
Dietary Vitamin A: Plants
A
- In vegetables, vitamin A exists as a provitamin in the form of the yellow pigment beta-carotene, which consists of 2 molecules of retinal joined at the aldehyde end of their carbon chains.
- Because beta-carotene is not efficiently metabolized to vitamin A, it is only about one sixth as effective a source of vitamin A as retinol, weight for weight.
- Ingested beta-carotenes are oxidized and then irreversibly cleaved in intestinal cells.
- This cleavage reaction utilizes molecular oxygen, and generates two molecules of retinaldehyde (retinal).
- Next in the intestinal mucosa cell, retinal is reduced to retinol utilizing NADPH.
5
Q
Dietary Vitamin A: Liver and Dairy
A
- An alternative, but direct dietary source of retinol is retinol esters that are hydrolyzed in the intestinal lumen, followed by absorption from micelles into the intestinal enterocyte.
- The ingested retinol (including that derived from beta-carotene) is esterified with saturated fatty acids and incorporated into lymph chylomicrons. The chylomicrons enter the thoracic duct and, eventually, the bloodstream, where they are converted to chylomicron remnants and then taken up by the liver together with their content of retinol esters.
- In the liver, vitamin A is stored as an ester.
6
Q
When the body needs the stored esters from the liver…
A
- For transport to peripheral tissues, retinol palmitate is hydrolyzed by an esterase and the free retinol binds to retinol binding protein (RBP).
- The resulting holo-RBP is processed in the Golgi apparatus and then secreted into the blood.
- From the blood retinol is taken up into tissues via cell surface receptors and the RBP, to which retinol is bound, remains in the circulation.
- Once inside extrahepatic cells, retinol is bound by a cellular retinol binding protein (CRBP).
- Retinol in the eye is oxidized to retinal.
- Retinal is the form utilized in the retina for vision
- In all epithelial cells (including the cornea and conjunctiva of the eye), retinal metabolism continues to the formation of retinoic acid isomers.
7
Q
Vitamin A Deficiency
A
- defective night vision
- xerophthalmia
- Vitamin A deficiency still occurs with frequency in the poor countries of the world and is especially damaging in the neonate. It also occurs in the U.S.A., perhaps mildly in many individuals (where the incidence of respiratory and GI infection increases), but mainly in patients with fat malabsorption syndromes.
Disorders such as abetalipoproteinemia, steatorrhea and disorders of the biliary system affect the digestion and absorption of the lipid-soluble vitamins leading to potentially severe deficiencies
8
Q
Retinol
A
- Retinol, the alcohol form of vitamin A, is stored in the liver esterified to palmitic acid.
- In the circulation, retinol is transported by retinol binding protein (RBP), and on entering the target cells in the gonads it binds to cellular retinol binding protein (CRBP).
- Retinol appears to act as a nuclear hormone in the gonads.
-Retinol may bind to an as yet unidentified receptor in the nucleus, where the complex controls the expression of certain genes.
•The requirement of vitamin A for normal reproduction may be ascribed to this retinol function in the gonads, facilitating spermatogenesis in males and preventing resorption of the fetus by the female.
9
Q
Retinal
A
- This form is required for the visual cycle and enables rhodopsin to mediate vision.
- Retinal is produced in the retina by the oxidation of retinol.
- The isoform of retinal initially produced is the all-trans configuration, which must be isomerized to 11-cis retinal to generate the photoreceptor.
- The photoreceptor cells of the eye are the rods and the cones.
- The rods on the periphery of the retina are for low intensity light, and the central cones mediate high intensity and color vision.
- There are flattened disks in both the rods and the cones that contain a photoreceptor pigment.
•Rhodopsin is the pigment that occurs in the rod cells of the retina.
10
Q
Retinoic Acid
A
- The sequential oxidation of retinol and then retinal in target cells produces retinoic acid, which is required for embryonic development of tissues originating in the neural crest, and for the growth and differentiation of rapidly turning over epithelial cells (e.g., GI tract, lungs, skin, cornea, etc.).
- Though retinoic acid can be carried in blood bound to albumin, it is usually generated locally in the cell cytoplasm via oxidation.
- Once produced, it associates with the cellular retinoic acid binding protein (CRABP).
- Recall that retinoic acid exists in two forms, alltrans and the 9-cis-isomer.
- As with retinol, each form binds to a nuclear receptor to control gene expression.
- All-trans retinoic acid binds to RAR (retinoic acid receptor), whereas the 9-cisisomer of retinoic acid binds to the nuclear retinoid X receptor (RXR).
- Retinoid-occupied RAR and RXR form a receptor heterodimer that controls the expression of genes coding for proteins involved in embryonic development, cell growth and differentiation.
11
Q
Visual Cycle
A
- Nutritional vitamin A (retinol esters) can be oxidized to all-trans-retinal in the eye.
- In the retina, 11-cis-retinal, an isomer of all-trans-retinal, forms in the retinal isomerase reaction.
- 11-cisretinal covalently attaches to a lysine on opsin, the visual protein.
- The rhodopsin molecule becomes a G-protein coupled receptor and accordingly contains 7-transmembrane alpha- helices.
- The “ligand” for rhodopsin, the photoreceptor molecule, is a photon of light. Exposure of rhodopsin to light causes the attached retinal to convert to its all trans configuration forming bathorhodopsin.
- Bathorhodopsin spontaneously undergoes a conformational change via several intermediates triggering its activation to metarhodopsin II, the active species.
-The signal from metarhodopsin II is transduced by binding to transducin, a protein found in the retinal rods and cones. Transducin, a G-protein (Gt), plays a major role in visual signal transduction, paralleling that of other G-proteins associated with hormone action via receptors that are coupled to G-proteins.
- cyclic GMP phosphodiesterase (PDE) is activated. The activation of PDE by t is mediated by the release of two regulatory subunits (PDEgamma) allowing activation of catalytic subunits (PDEalpha and PDEbeta). This is reminiscent of the mechanism by which cAMP activates protein kinase A by causing release of two regulatory subunits.
- Cyclic GMP phosphodiesterase catalyzes the destruction of cGMP (cGMP → GMP) near the membrane of the rod cell.
- Normally cGMP keeps inward Na+ /Ca2+ channels open to maintain membrane depolarization releasing glutamate as a neurotransmitter signal.
-When cGMP concentrations fall, inward Na+ /Ca2+ channels close thereby lowering both intracellular Na+ and Ca2+.
•The fall in Na+ elicits hyperpolarization causing the rod cell to release less glutamate neurotransmitter.
-The reduced amount of neurotransmitter then triggers perception of light.
- The visual process is a true biochemical “cycle”.
- Because of its dynamic nature and the need to rapidly perceive ever-changing intensities of light, there exist built in “cessation” and “recovery” facets of the cycle.
- Active metarhodopsin stimulates many transducin molecules to propagate the signal, before the signal is terminated.
- The “recovery” phase, during which the cycle returns to a state that is preparatory for the next flash of light, involves replenishment of the cGMP.
- Production of cGMP is triggered by the low intracellular Ca2+ that was induced by the decline in the concentrations of cGMP caused by the flash of light.
- Replacement of cGMP is accomplished through direct inhibition of phosphodiesterase preventing further breakdown of cGMP, and cGMP production from GTP via guanylyl cyclase, which is stimulated by low intracellular calcium via a “recoverin” mediator protein.
- At the same time the receptor components are recycled by dissociation of metarhodopsin into opsin and trans-retinal that can be converted again in the dark to cis-retinal by retinal isomerase.
12
Q
Transducin in the visual cycle and dark recovery…
A
- The signal from metarhodopsin II is transduced by binding to transducin, a protein found in the retinal rods and cones (Figure 3). Transducin, a G-protein (Gt), plays a major role in visual signal transduction, paralleling that of other G-proteins associated with hormone action via receptors that are coupled to G-proteins.
- Gt, like other G-proteins, contains alpha, beta, and gamma subunits.
- Prior to a signal from metarhodopsin II, the alphat-subunit is in its inactive (GDP-bound) state.
- The signal from metarhodopsin II activates the alphat-subunit; by GTP binding that displaces GDP. The alphat-subunit then dissociates, from the intact Gt-protein, and activates cyclic GMP phosphodiesterase (PDE).
- The activation of PDE by alphat is mediated by the release of two regulatory subunits (PDEgamma) allowing activation of catalytic subunits (PDEalpha and PDEgamma). This is reminiscent of the mechanism by which cAMP activates protein kinase A by causing release of two regulatory subunits.
13
Q
Symptoms of Vitamin A Deficiency
A
- embryos: wide range of abnormalities, including defects in the CNS, craniofacial and cardiac malformations
- first indicator: defective night vision
- keratinization of epithelial tissues: retinol/retinoic acid prevent keratin synthesis
14
Q
Retinitis Pigmentosa
A
- impaired visual adaptation, defective night vision, loss of midperipheral visual field in adolescence
- advanced stages: degeneration of rod and cone photoreceptor cells
- common forms of disease treated with vitamin A
- mutations identified in genes encoding for: -rhodopsin (10% of cases)-unstable or poorly bind 11-cis-retinal
- alpha and beta subunits of rod cGMP phosphodiesterase
- rod cGMP-gated ion channel loss of outer segment disc structure (also in vitamin A deficiency)
15
Q
Xerophthalmia
A
•deterioration in the tissues of the eye, leads to blindness
- conjunctival drying
- Bitot’s Spots
- corneal drying
16
Q
Bitot’s Spots
A
- Bitot’s spots are triangular areas of abnormal squamous cell proliferation and keratinization of the conjunctiva.
- If untreated, proteolytic destruction and rupture of the cornea ensues with permanent blindness, although vitamin A treatment of patients with corneal ulcers can also result in blindness due to permanent corneal scarring. If the cornea becomes perforated (“keratomalacia”), it is vulnerable to invasion by microorganisms and this can be fatal.
17
Q
Keratomalacia
A
•corneal perforation
