Ординатура / Офтальмология / Английские материалы / Biochemistry of the Eye 2nd edition_Whikehart_2003

280 • Biochemistry of the Eye

mechanism. The operation of apoptosis in several ocular cell types are

known in detail. Liquefaction of the vitreous is a process in which the

vitreous gel decreases while liquid volumes increase. This is a normal

process in the aging eye. However, the mechanism tends to destabilize

the retina and may lead to retinal detachment. The vitreal gel’s stability

is thought to depend upon the interaction of collagens II and IX in par-

ticular with the GAG component of type IX collagen serving as a molec-

ular spring between collagen fibers. Opticin, a recently discovered

protein, attaches to collagen and prevents the fibers from aggregating.

Hyaluron, also a GAG, is not necessary for gel formation. The changes

that occur in these molecular relationships during aging are currently not

understood. Alkali burns in the cornea produce three immediate effects:

cellular destruction; distortion and lysis of collagen fibers; and removal

of GAGs from their proteoglycan protein cores. This is accompanied by

varying degrees of cloudiness and opacification of the cornea. A later

event is the invasion of PMNs into the cornea due to a chemotactic

attraction of collagen peptide remnants. This inflammatory invasion is

accompanied by the release of matrix metalloproteinases that bring

about further destruction of collagen and may cause an ultimate perfo-

ration of the cornea upon the development of ulceration.

P R O B L E M S ● 1. Distinguish between the cell death mechanisms of necrosis and apoptosis. Include both anatomical and biochemical differences.

2.What is wrong with this statement: “Bax protein supports and amplifies the apoptosis mechanism of all corneal cells in patients with Fuch’s dystrophy?” Explain your answer.

3.What three proteins are essential for the formation of the vitreous gel and what GAG is not essential for gel formation? How can you explain this?

4.Given the information at hand, how might you conduct an investigation to determine how aging affects vitreal liquefaction? Consider that studies on opticin have, as yet, failed to reveal any clues.

5.Given the destructive mechanism for alkali burns of the cornea, explain how a mineral acid, such as sulfuric acid, might cause initial corneal damage.

Ocular Biochemical Degradation • 281

References

Barber AJ, Makamura M, Wolpert EB, Reiter CEN, Seigel GM, Antonetti DA, Gardner TW: Insulins rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3, J Biol Chem 276:32814–32821, 2001.

Bishop PN: Structural macromolecules and supramolecular organization of the vitreous gel, Progress Ret Eye Res 19:323–344, 2000.

Bishop PN, McLeod D, Reardon A: the role of glycosaminoglycans in the structural organization of mammalian vitreous, Invest Ophthalmol Vis Sci 40:2173–2178, 1999.

Cameron R, Feuer G: Incidence of apoptosis and its pathological and biochemical manifestations. In Cameron R, Feuer G, editors:

Apoptosis and its modulation by drugs. Springer, 2000, Berlin. Crowston JG, Chang LH, Constable PH, Daniels JT, Akbar AN, Khaw

PT: Apoptosis gene expression and death receptor signaling in mito- mysin-C-treated human tenon capsule fibroblasts, Invest Ophthalmo Vis Science 43:692–699, 2002.

Debbasch C, Pisella P-J, De Saint Jean M, Rat P, Warnet J-M, Baudouin C: Mitochondria activity and glutathione injury in apoptosis induced by unpreserved and preserved β-blockers on Chang conjunctival cells,

Invest Ophthalmol Vis Sci 42:2525–2533, 2001.

Friedman JS, Faucher M, Hiscott P, Biron VL, Malenfant M, Turcotte P, Raymond V, Walter MA: Protein localization in the human eye and genetic screen of opticin, Human Mol Genet 11:1333–1342, 2002.

Haddix JL, Pfister RR, Muccio DD, Villain M, Sommers CI, Chaddha M, Anantharamaiab GM, Brouillette WJ, DeLucas LJ: Bioactivity of peptide analogs of the neutrophil chemoattractant, N-acetyl-proline- glycine-proline, Invest Ophthalmol Vis Sci 40:2427–2429, 1999.

Li QJ, Ashraf MF, DeFen S, Green WR, Stark WJ, Chan C-C, O’Brien TP: The role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy of the cornea, Arch Ophthalmol 119:1597–1604, 2001.

Mayne R, Brewton RG, Ren Z-X: Vitreous body and zonular apparatus. In Harding JJ, editor: Biochemistry of the eye. London, 1997, Chapman & Hall.

Neuberger A, Gottschalk A, Marshall RD, Spiro RG: Carbohydratepeptide linkages in glycoproteins and methods for their elucidation. In Gottschalk A., editor: Glycoproteins, Amsterdam, 1972, Elsevier.

Nishi O, Nishi K, Wada K, Ohmoto Y, Akura J: Inhibition of lens epithelial cells by Fas-specific antibody activating Fas-Fas ligand system, Cur Eye Res 23:192–198, 2001.

Parish CA, Hashimoto M, Nakanishi M, Dillon J, Sparrow JR: Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium, Proc Natl Acad Sci USA. 95:14609–14613, 1998.

Parrish CM, Chandler JW: Corneal trauma. In Kaufman HE, Barron BA, McDonald MB, editors: The cornea, Boston, 1998, ButterworthHeinemann.

Paterson CA, Williams RN, Parker AV: Characteristics of polymorphonuclear leukocyte infiltration into the alkali burned eye and the influence of sodium citrate, Exp Eye Res 37:701–708, 1984.

Pfister RR, Haddox JL, Sommers CI, Lam K-W: Identification and synthesis of chemotactic tripeptides from alkali-degraded whole cornea,

Invest Ophthalmol Vis Sci 36:1306–1316, 1995. Sebag, J: The Vitreous. New York, 1989, Springer-Verlag.

282 • Biochemistry of the Eye

Sparrow JR and Cai B: Blue light-induced apoptosis of A2E-containing REP: involvement of caspase-3 and protection by Bcl-2, Invest Ophthalmol Vis Sci 42:1356–1362, 2001.

Takanosu M, Boyd TC, Le Goff M, Henry SP, Zhang Y, Bishop PN, Mayne R: Structure, chromosomal location, and tissue-specific expression of the mouse optician gene, Invest Ophthalmol Vis Sci 42:2202–2210, 2001.

Tsen G, Halfter W, Kroger S, Cole GJ: Agrin is a heparan sulfate proteoglycan. J Biol Chem 270:3392–3399, 1995.

Wenzel A, Grimm C, Seeliger MW, Jaissle G, Hafezi F, Kretschmer R, Zrenner E, Reme CE: Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor, Invest Ophthalmol Vis Sci 42:1653–1659, 2001.

Whikehart DR, Edwards WC, Pfister RR: Sorption of sodium hydroxide by type I collagen and bovine corneas, Cornea 10:54–58, 1991.

Wilson SE, Kim W-J: Keratocyte apoptosis: implications on corneal wound healing, tissue organization, and disease, Invest Ophthalmol Vis Sci 39:220–226, 1998.

Wilson SE: Stimulus-specific and cell type-specific cascades: emerging principles relating to control of apoptosis in the eye, Exp Eye Res 69:255–266, 1999.

Zimmerman KC, Bonzon C, Green DR: The machinery of programmed cell death, Pharm Therap 92:57–70, 2001.

284 • Biochemistry of the Eye

Agrin — A protein known to attach to heparan sulfate in the chick vitreous. Its role in human vitreous has not been studied.

α-Helix — A secondary protein structure in which the amino acid structure forms a helical form having 3.6 amino acids per turn. The helical structure is reinforced by hydrogen bonding.

Akt — A serine/threonine kinase that inhibits members of the apoptotic pathway by phosphorylating them.

Alkylating agents — Chemicals that form covalent alkyl bridges with nucleic acid bases.

Allosteric enzyme — An enzyme whose activity is influenced by substances that bind at alternate sites (see text).

Amadori rearrangement — Early stage binding of glucose to an amino group on a protein. The relatively stable product formed is a ketimine. These are the initial reactions of glycation.

Amino acid — An acid containing at least one amino group linked to the carbon adjacent to its carboxylic acid (α-carbon).

Amphipathic — Literally means having two characteristics. For lipids this means being both hydrophobic (i.e., not compatible with water) and hydrophilic (i.e., compatible with water).

Amylose/amylopectin — Polysaccharide components of starch. Amylose is unbranched while amylopectin is branched, but to a lesser degree than glycogen.

Anabolic process — One or more chemical reactions in which energy is used to carry out cellular functions. For example, the synthesis of proteins.

Anaerobic metabolism — Any metabolic process that does not require molecular oxygen.

Anaphylactic shock — Also known as anaphylaxis, is a strong immune reaction that results in a marked blood vessel dilation and smooth muscle constriction that may result in death.

Anaphylatoxins — Biochemical substances capable of causing severe immunological reactions.

Antagonist — Any chemical substance that can bind to the same postsynaptic receptor of a given neurotransmitter without causing any postsynaptic effect.

Antibody — A protein that bind to an antigen. Also known as an immunoglobulin (abbreviated: Ig), which usually reacts with a foreign molecule (i.e., antigen) within body tissues and fluids. (See Chapter 8.)

Antibody diversity hypothesis — A hypothesis that states that there are genes to produce antibodies for every known antigen. The hypothesis fails to account for the appearance of new antigens or antigenic determinants.

Anticodon — A three-base code on t-RNA that corresponds (= binds) to the codon on mRNA for a specific amino acid.

Antigen — Any substance that will cause an antibody to be produced against it and to which it will bind.

Antigenic determinant — The exact chemical site at which an antibody binds to an antigen (also known as an epitope).

Glossary • 285

Antiport — Transport of substances in opposite directions.

Apoprotein — The protein portion of a complete protein (holoprotein) which consists of a prosthetic group (non-protein portion) + an apoprotein (protein protion).

Apoptosis — A term from the Greek meaning a falling down. Apoptosis (pronounced: apo-tosis) is a form of biochemically programmed cell death. Fragmentation of cellular DNA and cell shrinkage are characteristics of the process.

ATP synthase — The enzyme in the mitochondrion that converts ADP to ATP and releases it when a proton passes through its structure.

Autocatalytic properties — Properties of an enzyme that can initiate its own activation.

Autocrine — Affecting the same cells. Autocrine hormones affect the same cells that produce the hormones.

Autonomic nervous system — Nerves under involuntary control

(coming from either the brain or the spinal chord) that operate a variety of physiological functions. In the eye this includes control of pupil size, accommodation, intraocular pressure, and blood flow. The sympathetic and parasympathetic divisions tend to control opposing functions (such as increasing and decreasing pupil size), but there are exceptions.

B cell — A white blood cell (lymphocyte) that can produce any of a large number of antibodies. The label “B” originates from the chicken bursa where these cells were orginially found.

β-Elimination — Chemical reaction in which functional groups (on adjacent carbons) are removed from the compound. Such reactions may be carried out in alkali.

Basement membrane — A tissue scaffolding or sheet that supports or separates cells from other noncellular parts of a tissue.

Bax protein — Stands for Bcl-2-associated protein X. This protein promotes apoptosis by causing (indirectly) the release of cytochrome C from mitochondria.

Bcl protein — Also known as Bcl-2 protein. This protein binds to Bax protein and cancels its effects. That is, it is anti-apoptotic.

Beer’s law — Relationship of light to the concentration of a substance expressed as A = abc. “A” is the absorbance of light by a sample. “a” is the absorptivity of the sample that is an empirically determined quantity containing the physical-chemical characteristics of the molecule. “b” is the path length of light through the molecular sample and is usually 1 cm. “c” is the concentration of the sample molecule.

Best’s disease — A congenital degeneration of the macula.

Bleaching of rhodopsin — Conversion of rhodopsin to opsin plus alltrans retinal.

Buffer — A combination of a salt and acid or salt and base that is able to resist changes of pH in solution.

Calmodulin — Calcium binding protein involved with the second messenger effects of calcium.

286 • Biochemistry of the Eye

Cancer — Derived from the Latin word for crab. It is a cellular tumor composed of cells whose cell division is uncontrolled. The term carcinoma (Greek: crab) has a similar meaning.

Capacitance — The ability of a potential difference to be stored between two charged surfaces. If the density of charge per unit area is increased, the capacitance is increased. If the distance between the charged surfaces is increased, the capacitance is decreased.

Carbohydrate — A polyhydroxy compound with the general formula: Cn(H2O)n that may have other functional groups such as a carbonyl group. Sugar and saccharide are alternate names.

Cardiolipin — A trigycerolic lipid complex variant of a phospholipid that is found significantly in mitochondria. Its function is unknown.

Cascade — A term borrowed from electronics that refers to any enzyme amplifying mechanism that increases the original biological signal made to a cell.

Caspase — A protease requiring Asp as part of its substrate and which itself contains Cys as part of its amino acid sequence.

Cassette — Any segment of DNA that is introduced into a host’s

DNA may be referred to as a DNA cassette.

Catabolic process — One or more chemical reactions in which energy is extracted from a chemical compound. For example, the formation of adenosine triphosphate from glucose.

Catalyst — Any chemical substance that can speed up a chemical reaction without itself being altered by the reaction. It achieves its goal by lowering the activation energy for the reaction.

Cataract — Any opacity in the lens that causes an alteration to perceived vision.

Centimorgan — A distance on a chromosome equal to approximately 1 million base pairs. It is computed on the basis of a distance at which a genetic recombination will occur by a given percentage.

Centromere — Central location of a chromosome that is an attachment point for proteins involved in chromosome segregation during cell division.

Ceramide — The compound formed when a fatty acid is esterfied to sphingosine (see Figure 4–12).

Cerebroside — A ceremide to which a single sugar molecule is bonded via an oxygen bridge.

Cervonic acid — Fatty acid, also known as docosahexaenoic acid. This highly unsaturated fatty acid (22:6) is a common constituent of photoreceptor discs and membranes where it imparts a high degree of fluidity to the membrane.

Chalazia — A granual-like inflammation of the eyelid margin.

Channel forming proteins — Proteins that are capable of initiating a passageway for transport of some substance(s) through a membrane (usually a plasma membrane).

Channel protein — A protein that conducts any substance across a cell membrane. Such substances are often ions. Gate protein has the same meaning.

Glossary • 287

Chaperone — A protein that tends to renature denatured proteins; that is, return them to their normal conformation.

Chemoattractant — Any substance that can cause a directional movement of a cell (usually a white blood cell) based on the concentration gradient of that substance.

Chemotaxis — A process in which white blood cells are drawn to the site of a complement reaction by complement fragments C3a, C4a, and C5a.

Chromatid — Two joined chromosomes.

Chromatin — The genetic material in a cell that is readily stainable in the nucleus.

Chromosome — A single double-stranded molecule of DNA and its associated proteins that are found in eukaryotic cells, viruses, bacteria, or even an organelle. However, at metaphase a “chromosome” actually consists of two chromosomes (chromatids) bound together.

Cicatricial pemphigoid — A presumed autoimmune conjunctivitis affecting the mucosal tissue on the ocular surface. An immune attack is made on the conjunctival epithelial cells.

Codon/anticodon — A codon is the portion of mRNA that contains the code for a specific amino acid (or start or stop signal). The anticodon is the portion of tRNA that binds to an mRNA codon.

Co-enzyme — Another name for a second substrate.

Collagen — An extracellular protein that gives structural support to tissues. Nineteen different types exist. (See description in Chapters 2 and 10.)

Collagen fiber — A structural edifice of collagen that is made up of several “fibrils” (10 to 300 nm diameter). Fibrils are composed of five rows of topocollagen units.

Committed B cell — A B cell in the process of development toward making a specific Ig.

Comparative metabolism — The process in which different forms of metabolism are contrasted and measured to note their advantage to each cell type.

Complement — A collection of proteins that initiate lysis of an antigenic organism.

Complement activation — The process in which complement proteins are induced to react in sequence to initiate a complement reaction. This is also known as complement fixation.

Condensation reaction — The formation of a larger compound from two smaller compounds (also known as ligation).

Cone transducing proteins — Proteins similar to rhodopsin that are found in cone photoreceptors.

Conformational structure — A three-dimensional structural representation of carbohydrates and other carbon chemical structures based on carbon as the center of a tetrahedron (see Figure 4–2). Term may also apply to any macromolecule.

Constant domain — A domain of an Ig that has a fixed sequence of amino acids. Constant regions, however, may vary between Ig classes.

288 • Biochemistry of the Eye

Corneal dystrophies — A collection of inherited, bilateral, primary alterations of the cornea that are not associated with a prior disease or pathological condition. They may exist in the epithelium, stroma, and/or endothelium.

Cotransport — The simultaneous transport of more than one substance by the same transport mechanism.

Crystallins — Proteins unique to the crystalline lens. There are three major classes in the human adult eye.

Crystallography — The science of determining the three-dimensional structure of compounds using x-rays to produce a diffraction pattern from a crystal of a pure compound.

Cyclic nucleotides — Second messenger hormones that are either cyclized adenosine monophosphate and cyclized guanosine monophosphate.

Dalton (D) — A unit of mass nearly equal to that of hydrogen (1.000).

One thousand Daltons = one kilodalton (kD).

Dark current — The flow of cations through photoreceptors that is maximal in the dark.

Deamidation — The removal of an amide group from a compound. In lens biochemistry, the conversion of asparagine/glutamine to aspartic acid/glutamic acid.

Death receptor — A protein receptor on a cell which when bound to a death signal initiates apoptosis. On ocular cells the protein is often Fas.

Death signal — Any substance that binds to a receptor on a cell and initiates apoptosis.

Decorin — A proteoglycan found in the cornea.

Defensins — Cysteine-rich, cationic polypeptides that form pores in bacterial membranes prior to their destruction by lysosomal enzymes in phagocytes.

Degradation — The breaking of peptide bonds in proteins.

Denaturation — In reference to proteins, the process in which proteins lose their function by an alteration in their structure.

Deoxyribonucleic acid (DNA) — A genetic molecule that preserves the genome of a cell. It consists of four kinds of bases, as well as deoxyribose and phosphate. The phosphate imparts acidity to the molecule.

Depolarization — The decrease in charge difference between the outside and inside of a cell. Usually, this means that the inside of the membrane becomes more positive while the outside of a membrane becomes more negative.

Detached retina — Separation of the retina from the pigment epithelial layer.

Deturgescence — A physiological and biochemical process that maintains the cornea in a clear state.

Diabetes — A disease that results in the unequal distribution of glucose inside and outside of cells as a result of the inability of certain cells to transport glucose sufficiently.