Eye Metabolism and Vision PDF

The Eye: Metabolism and Vision  Light enters the eye; passes progressively through the cornea, the anterior chamber that contains aqueous humor, the lens, the vitreous body that contains vitreous humor; and finally focuses on the retina that contains the visual sensing apparatus.  Tears bath...

The Eye: Metabolism and Vision  Light enters the eye; passes progressively through the cornea, the anterior chamber that contains aqueous humor, the lens, the vitreous body that contains vitreous humor; and finally focuses on the retina that contains the visual sensing apparatus.  Tears bathe the exterior of the cornea while the interior is bathed by the aqueous humor, an isoosmotic fluid that contains sales, albumin, globulin, glucose, and other constituents.  The aqueous humor brings nutrients to the cornea and to the lens, and it removes end products of metabolism from them.  The vitreous humor is a gelatinous mass that helps maintain the shape of the eye while allowing it to remain somewhat pliable.  Cornea Derives ATP from Aerobic Metabolism  The eye is an extension of the nervous system and, like other tissues of the central nervous system, its major metabolic fuel is glucose.  The cornea is a clear tissue that, like the lens, diffracts light. Its clearness is due in part to the arrangement of collagen molecules of the stroma.  The cornea is permeable to water and oxygen.  The water content of the corneal stroma must be controlled for it to maintain clarity, and this is done by an ATP-driven water pump.  Another reason for its clarity is the lack of blood vesicles in the epithelial layer. There is a large amount of the protein VEGFR-3 (vascular endothelial growth factor receptor-3) on the anterior epithelial layer of the cornea. VEGFR -3 prevents growth of blood vessels by binding to or neutralizing growth factors that are produced to stimulate growth of blood vessels.  The cornea obtains its ATP from aerobic glucose metabolism; glycolysis, and the TCA cycle.  Lactate does not accumulate to any significant extent because of efficient use of pyruvate by oxidative metabolism.  About 30% of the glucose it metabolizes is by glycolysis, and about 65% by the hexose monophosphate pathway.  On a relative weight basis, the cornea has the highest activity of the hexose monophosphate pathway of any mammalian tissue.  It also has a high activity of glutathione reductase that requires NADPH, a produce of the hexose monophosphate pathway. Corneal epithelium is permeable to atmospheric oxygen. Reactions of oxygen can lead to formation of various active oxygen species that are harmful to tissues, in some cases by oxidizing protein sulfhydryl groups to disulfides and by lipid peroxidation, mostly of cellular medium-chain lipids of six carbons or more. Reduced glutathione (GSH) is used to reduce those disulfide bonds and lipid peroxides back to their original native states while GSH itself is convened to oxidized glutathione (GSSG). GSSG may also be formed directly by active oxygen species. Glutathione reductase uses NADPH to reduce GSSG to 2GSH. Pentose Phosphate Pathway The Nonoxidative Phase of the Pentose Phosphate Pathway  The nonoxidative reactions of this pathway are reversible reactions that allow intermediates of glycolysis (specifically, glyceraldehyde 3-P and fructose 6-P) to be  converted to five-carbon sugars (such as ribose 5-P), and vice versa.  The needs of the cell determine which direction this pathway proceeds.  If the cell has produced ribose 5-P but does not need to synthesize nucleotides, then the ribose 5-P is converted to glycolytic intermediates.  If the cell still requires NADPH, the ribose 5-P is converted back into glucose 6-P using nonoxidative reactions (see the following sections).  And finally, if the cell already has a high level of NADPH but needs to produce nucleotides, the oxidative reactions of the pentose phosphate pathway are inhibited, and the glycolytic intermediates fructose 6-P and glyceraldehyde 3-P are used to produce the five-carbon sugars using exclusively the nonoxidative phase of the pentose phosphate pathway. Oxidative portion of the pentose phosphate pathway.  Carbon 1 of glucose 6-P is oxidized to an acid and then released as CO2 in an oxidation followed by a decarboxylation reaction.  Each of the oxidation steps generates a NADPH.  The epimerase and isomerase convert ribulose 5-P to two other five-carbon sugars (Fig.).  The isomerase converts ribulose 5-P to ribose 5-P.  The epimerase changes the stereochemical position of one hydroxyl group (at carbon 3), converting ribulose 5- P to xylulose 5-P.  Transketolase transfers two-carbon fragments of keto sugars (sugars with a keto group at carbon 2) to other sugars.  Transketolase picks up a two-carbon fragment from xylulose 5-P by cleaving the carbon–carbon bond between the keto group and the adjacent carbon, thereby releasing glyceraldehyde 3-P (Fig.).  The twocarbon fragment is covalently bound to thiamine pyrophosphate, which transfers it to the aldehyde carbon of another sugar, forming a new ketose.  The role of thiamine  pyrophosphate here is, thus, very similar to its role in the oxidative decarboxylation of pyruvate and α-ketoglutarate.  Two reactions in the pentose phosphate pathway use transketolase.  In the first, the two-carbon keto fragment from xylulose 5-P is transferred to ribose 5-P to form sedoheptulose 7-phosphate (sedoheptulose 7-P); and in the other, a two-carbon keto fragment (usually derived from xylulose 5-P) is transferred to erythrose 4-phosphate (erythrose 4-P) to form fructose 6-P.  Glutathione  Glutathione is a tripeptide composed of glutamate, cystein, glycine. Glutathione is often found (in the cell) in the millimolar range (1 to 10 mM, depending on cell type).  Reduced glutathione (GSH) maintains the normal reduced state of the cell. Reduced glutathione (GSH) Glutathione has a gamma linkage between the first two amino acids (instead of the typical alpha linkage), which resists degradation by intracellular peptidases.  The enzyme glutathione reductase uses NADPH as a cofactor to reduce GSSG back to two moles of GSH.  Thus, the pentose pathway is linked to the supply of adequate amounts of GSH. So, what happens if glucose 6-phosphate DH is defective? Insufficient production of NADPH. Which translates into insufficient glutathione. Is this a medical problem? YES  The pentose phosphate pathway and glutathione reductase help protect the cornea by effectively neutralizing active oxygen species.  Some lipids that are subjected to peroxidation may spontaneously form active aldehydes that react with other tissue components and lead to various pathological conditions.  The cornea also contains an isoform of aldehyde dehydrogenase (ALDH3Al), a member of a superfamily of enzymes that uses either NAD+ or NADP+ to inactivate these active aldehydes by oxidizing them to their corresponding acids. Lens Consists Mostly of Water and Protein  The lens is bathed on one side by aqueous humor and supported on the other side by vitreous humor.  It has no blood supply, but is metabolically active.  It obtains nutrients from and eliminates waste into the aqueous humor.  The lens is mostly water and proteins. The majority of vertebrate lens proteins are α- , β-, and γ-crystallins.  There are also albuminoids, enzymes, and membrane proteins that are synthesized in an epithelial layer around the edge of the lens.  Other animals have different crystallins, some of which are enzymes that probably function as such in other tissues. The most important physical requirement of these proteins is that they maintain a clear crystalline state.  They are sensitive to changes in osmolarity, excessively increased oxidation- reduction, concentrations of metabolites, and UV irradiation. Structural integrity of the lens is maintained:  for osmotic balance by the Na+/K+ exchanging ATPase;  for redox-state balance by glutathione reductase and  for growth and maintenance by protein synthesis and other metabolic processes that take place mostly in cells on the periphery of the lens.  The primary role of most lens proteins is to function as crystallins, but many are expressed in other tissues and serve other roles such as enzymes and/or have other functional roles.  α- and β-Crystallin are small heat shock proteins (sHSP) or chaperones that function to help maintain lens proteins in their native, unaggregated states. Their highest expression is in eye lens, but they also occur in other tissues such as skeletal and cardiac muscle where they are involved in filament assembly. Mutations in crystallins, therefore, not only predispose an individual to cataract formation, but also to possible muscle weakness and heart failure.  Energy for these processes comes from the metabolism of glucose.  About 85% of glucose used by lens tissue is metabolized by glycolysis and about 3% by the TCA cycle, presumably by cells located at the periphery.  Most of the remaining portion of glucose metabolized by lens goes through the pentose phosphate pathway.  The central area of the lens, the nucleus or core, consists of lens cells that were present at birth. The lens grows from the periphery and in humans increases in weight and thickness with age and becomes less elastic. This leads to a loss of near vision, a normal condition referred to as presbyopia. On average, the lens may increase threefold in size and approximately 12- fold in thickness from birth to about age 80. Cataract Cataract, the only known disease of the lens, is an opacity of lenses brought about by many different conditions. The two most common types of cataracts are (1) senile cataracts (2) diabetic cataracts In senile cataracts changes in the architectural arrangement of the lens crystallins and other lens proteins are age related and due to such changes as breakdown of the protein molecules starting at the C-terminal ends, deamidation, and racemization of aspartyl residues. Diabetic cataracts result from loss of control of osmolarity of the lens due to increased activity of aldose reductase and polyol (aldose) dehydrogenase of the polyol metabolic pathway.  When glucose concentration in the lens is high, aldose reductase converts some of it to sorbitol that may be converted to fructose by polyol dehydrogenase.  In human lens, the ratio of activities of these two enzymes favors sorbitol accumulation , especially; since sorbitol is not used by other pathways and it diffuses out of the lens rather slowly.  Accumulation of sorbitol increases osmolarity of the lens, affects the structural organization of the crystallins, and enhances the rate of protein aggregation and denaturation. Areas where this occurs have increased lightscattering properties, which is the definition of cataracts.  Normally, sorbitol formation is not a problem because the Km of aldose reductase for glucose is about 200 mM and very little sorbitol would be formed.  In diabetics, where circulating concentration of glucose is high, activity of this enzyme can be significant. Cataracts affect millions of people per year throughout the world , and there are no known cures or preventative measures, especially for the senile type. The most common remedy is lens replacement; a routine operation in many countries. A side effect of cataract and surgical treatment for it can be glaucoma; but this is rare. A third cause of cataracts, especially among young people, is due to inherited mutations in crystallins that function in lens as chaperones. When there are mutations in chaperones that interfere with their function, misfolded proteins can occur and result in cataract formation. Retina Derives ATP from Anaerobic Glycolysis  The retina, like the lens, depends heavily on anaerobic glycolysis for ATP production.  Unlike the lens, the retina is a vascular tissue.  In its center is the macula, and in the center of the macula is the fovea centralis, an a vascular concave area that contains only cones. This is the area of greatest visual activity.  Mitochondria are present in retinal rods and cones but not in the outer segments where visual pigments are located. Glucose conversion to fructose via sorbitol  Most sugars are rapidly phosphorylated following their entry into cells.  Therefore, they are trapped within the cells, because organic phosphates cannot freely cross membranes without specific transporters.  An alternate mechanism for metabolizing a monosaccharide is to convert it to a polyol (sugar alcohol) by the reduction of an aldehyde group, thereby producing an additional hydroxyl group.  Sorbitol synthesis: Aldose reductase reduces glucose, producing sorbitol, but the Km is high.  This enzyme is found in many tissues, including the retina, lens, kidneys, peripheral nerves, ovaries, and seminal vesicles.  A second enzyme, sorbitol dehydrogenase, can oxidize sorbitol to fructose in cells of the liver, ovaries, and seminal vesicles. The two-reaction pathway from glucose to fructose in the seminal vesicles benefits sperm cells, which use fructose as a major carbohydrate energy source.  The pathway from sorbitol to fructose in the liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis.