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STUDENT DIGITAL NEWSLETTER ALAGAPPA INSTITUTIONS |
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Mr. Paul A. Banaszkiewicz FRCS (Glas) FRCS (Ed)
Gangliosides are formed from ceramides by attachment of oligosaccharides that contain a sialic acid residue impotence forum generic caverta 50 mg with mastercard, also at the primary alcohol group impotence quoad hoc meaning purchase caverta 50mg with amex. Fatty acids are linked to a backbone molecule erectile dysfunction diabetes uk buy cheap caverta 100mg on-line, such as glycerol for triacylglycerols or phosphoacylglycerols erectile dysfunction pills over the counter buy caverta 50mg free shipping, or sphingosine for sphingolipids erectile dysfunction doctors tucson az safe 50mg caverta. The condensation of three acetyl groups produces mevalonate best erectile dysfunction pills at gnc buy 100mg caverta with visa, which contains six carbons. Decarboxylation of mevalonate produces the five-carbon isoprene unit frequently encountered in the structure of lipids. The involvement of isoprene units is a key point in the biosynthesis of steroids and of many other compounds that have the generic name terpenes. Vitamins A, E, and K come from reactions involving terpenes that humans cannot carry out. That is why we must consume these vitamins in our diets; vitamin D, the remaining lipidsoluble vitamin, is derived from cholesterol (Section 8. Isoprene units are often added to proteins to act as anchors when the protein is attached to a membrane. Finally, squalene is converted to cholesterol, which contains 27 carbon atoms (Figure 21. Acetate 3 Mevalonate 3 [Isoprene] 3 Squalene 3 Cholesterol C2 C6 C5 C30 C27 It is well established that 12 of the carbon atoms of cholesterol arise from the carboxyl carbon of the acetyl group; these are the carbon atoms labeled "c" in Figure 21. When ceramides are formed, they can react (a) with choline to yield sphingomyelins, (b) with sugars to yield cerebrosides, or (c) with sugars and sialic acid to yield gangliosides. The conversion of three acetyl groups of acetyl-CoA to mevalonate takes place in several steps (Figure 21. We already saw the first of these steps, the production of acetoacetyl-CoA from two molecules of acetyl-CoA, when we discussed the formation of ketone bodies and the anabolism of fatty acids. Each letter "m" indicates a methyl carbon and each letter "c" indicates a carbonyl carbon, all of which come from acetyl-CoA. This step is inhibited by high levels of cholesterol and is the major control point of cholesterol synthesis. Drugs such as lovastatin are inhibitors of hydroxymethyl-CoA reductase and are widely prescribed to lower blood cholesterol levels. Isopentenyl pyrophosphate and dimethylallyl pyrophosphate, another isoprenoid derivative, can be interconverted in a rearrangement reaction catalyzed by the enzyme isopentenyl pyrophosphate isomerase. Condensation of isoprenoid units then leads to the production of squalene and, ultimately, cholesterol. Two molecules of farnesyl pyrophosphate condense to form squalene, a 30-carbon compound. Squalene epoxide then undergoes a complex cyclization reaction to form lanosterol. The mechanism of the reaction is a concerted reaction-that is, one in which each part is essential for any other part to take place. No portion of a concerted reaction can be left out or changed because it all takes place simultaneously rather than in a sequence of steps. It is known that 20 steps are required to remove three methyl groups and to move a double bond, but we shall not discuss the details of the process. After cholesterol is formed, it can be converted to other steroids of widely varying physiological function. Most of the cholesterol formed in the liver, which is the principal site of cholesterol synthesis in mammals, is converted to bile acids, such as cholate and glycocholate (Figure 21. These compounds aid in the digestion of lipid droplets by emulsifying them and rendering them more accessible to enzymatic attack. The primary route from lanosterol involves 20 steps, the last of which converts 7-dehydrocholesterol to cholesterol. Steroids are best known as sex hormones (they are components of birth-control pills), but they play other roles as well. Pregnenolone is formed from cholesterol, and progesterone is formed from pregnenolone. Progesterone is a sex hormone and is a precursor for other sex hormones, such as testosterone and estradiol (an estrogen). Cortisone is an example of glucocorticoids, a group of hormones that play a role in carbohydrate metabolism, as the name implies, as well as in the metabolism of proteins and fatty acids. Mineralocorticoids constitute another class of hormones that are involved in the metabolism of electrolytes, including metal ions ("minerals") and water. Atherosclerosis is a condition in which arteries are blocked to a greater or lesser extent by the deposition of cholesterol plaques, which can lead to heart attacks. Both 638 Chapter 21 Lipid Metabolism Unesterified cholesterol Phospholipid Apoprotein B-100 Cholesteryl ester diet and genetics are instrumental in the development of atherosclerosis. A diet high in cholesterol and fats, particularly saturated fats, will lead to a high level of cholesterol in the bloodstream. The body also makes its own cholesterol because this steroid is a necessary component of cell membranes. It is possible for more cholesterol to come from endogenous sources (synthesized within the body) than from the diet. Cholesterol must be packaged for transport in the bloodstream; several classes of lipoproteins (summarized in Table 21. The major lipids are generally cholesterol and its esters, in which the hydroxyl group is esterified to a fatty acid; triacylglycerols are also found in these aggregates. Chylomicrons are involved in the transport of dietary lipids, whereas the other lipoproteins primarily deal with endogenous lipids. The interior consists of many molecules of cholesteryl esters (the hydroxyl group of the cholesterol is esterified to an unsaturated fatty acid, such as linoleate). On the surface, protein (apoprotein B-100), phospholipids, and unesterified cholesterol are in contact with the aqueous medium of the plasma. Free cholesterol can then be used directly as a component of membranes; the fatty acids can have any of the catabolic or anabolic fates discussed earlier in this chapter (Figure 21. Cholesterol not needed for membrane synthesis can be stored as oleate or palmitoleate esters in which the fatty acid is esterified to the hydroxyl group of cholesterol. In addition, cholesterol inhibits both the synthesis and the activity of the enzyme Table 21. This enzyme catalyzes the production of mevalonate, the reaction that is the committed step in cholesterol biosynthesis. Dietary cholesterol suppresses the synthesis of cholesterol by the body, especially in tissues other than the liver. An individual who has one gene that codes for the active receptor and one defective gene is 640 Chapter 21 Lipid Metabolism Biochemical Connections Atherosclerosis Atherosclerosis causes more deaths every year than cancer. The figure shows a more realistic and complicated picture of the formation of atherosclerosis. The endothelial cells of the artery wall also secrete chemokines that attract the monocytes into the intima of the artery. In step 2, the monocytes mature into active macrophages and produce many inflammatory molecules. These cells form a fatty streak that is the first outward signal of atherosclerosis. In step 4, inflammation promotes growth of the plaque and formation of a fibrous cap over the lipids. The cap protrudes out into the bloodstream but also protects the blood from the deposits. The ruptured plaque leads to the formation of a thrombus, or blood clot in the artery. If the clot is big enough, it can cause a heart attack-the death of cardiac cells. However, when scientists try to come up with medical countermeasures, this full understanding of all the chemical factors involved in atherosclerosis is critical to the development of cures. Stimulated endothelial cells display adhesion molecules and secrete chemokines that lure monocytes andcells into the intima. The macrophages along withcells produce inflammatory mediators such as cytokines, which promote cell division. These fat-filled macrophages (called foam cells), along withcells are the earliest form of atherosclerotic plaque. If the weakened cap ruptures, tissue factors, which display on the foam cell, interact with clot-promoting elements in the blood causing a clot (thrombus). The formation of atherosclerosis, depicting the growth of an atherosclerotic plaque in a coronary artery. Heterozygotes have blood cholesterol levels that are above average; therefore, they are at higher risk for heart disease than the general population. Homozygotes have very high blood cholesterol levels from birth, and there are recorded cases of heart attacks in two-year-olds with this condition. Patients who are homozygous for familial hypercholesterolemia usually die before age 20. We have already seen how carbohydrates are processed catabolically and anabolically. The catabolic oxidation of lipids releases large quantities of energy, whereas the anabolic formation of lipids represents an efficient way of storing chemical energy. After an initial activation step in the cytosol, with formation of an acyl-CoA corresponding to each fatty acid, each acyl group is transesterified to carnitine for transport across the intermembrane space of the mitochondrion. The oxidation of fatty acids, which takes place in the mitochondrial matrix, is the chief source of energy in the catabolism of lipids. In this process, two-carbon units are successively removed from the carboxyl end of the fatty acid to produce acetyl-CoA, which subsequently enters the citric acid cycle. How does the oxidation of unsaturated fatty acids differ from that of saturated fatty acids The pathway of catabolism of fatty acids includes reactions in which unsaturated, as well as saturated, fatty acids can be metabolized. Odd-numbered fatty acids can 642 Chapter 21 Lipid Metabolism also be metabolized by converting their unique breakdown product, propionyl-CoA, to succinyl-CoA, an intermediate of the citric acid cycle. Ketone bodies are substances related to acetone that are produced when an excess of acetyl-CoA results from -oxidation. This situation can arise from a large intake of lipids and a low intake of carbohydrates or can occur in diabetes, in which the inability to metabolize carbohydrates causes an imbalance in the breakdown products of carbohydrates and lipids. Fatty-acid biosynthesis occurs in the cytosol, catalyzed by an ordered multienzyme complex called fatty-acid synthase. Most compound lipids, such as triacylglycerols, phosphoacylglycerols, and sphingolipids, have fatty acids as precursors. In the case of phosphoacylglycerols, two fatty acids and phosphoric acid are added to a glycerol backbone. The addition of remaining groups requires nucleoside triphosphates and differs between mammals and bacteria. Other moieties, including sugars, are added, producing gangliosides and other compounds. Isoprene units are formed from acetyl-CoA in the early stages of a lengthy process that leads ultimately to cholesterol. Cholesterol is converted to other steroids, including bile acids, sex hormones, glucocorticoids, and mineralocorticoids. Cholesterol must be packaged for transport in the bloodstream; several classes of lipoproteins are involved. Both dietary cholesterol and genetic factors influence the role of cholesterol in heart disease. Reflect and Apply (a) the major energy storage compound of animals is fats (except in muscles). Recall Outline the role of carnitine in the transport of acylCoA molecules into the mitochondrion. Recall What is the difference between the type of oxidation catalyzed by acyl-CoA dehydrogenase and that catalyzed by -hydroxyCoA dehydrogenase Recall Draw a six-carbon saturated fatty acid and show where the double bond is created during the first step of -oxidation. Reflect and Apply Why does the degradation of palmitic acid (see Question 12) to eight molecules of acetyl-CoA require seven, rather than eight, rounds of the -oxidation process Reflect and Apply Given the nature of the hormonal activation of lipases, what carbohydrate pathways would be activated or inhibited under the same conditions Recall Compare the energy yields from the oxidative metabolism of glucose and of stearic acid. Reflect and Apply It is frequently said that camels store water in their humps for long desert journeys. Recall Describe briefly how -oxidation of an odd-chain fatty acid is different from that for an even-chain fatty acid. Recall You hear a fellow student say that the oxidation of unsaturated fatty acids requires exactly the same group of enzymes as the oxidation of saturated fatty acids. Recall What are the unique enzymes needed to -oxidize a monounsaturated fatty acid Recall What are the unique enzymes needed to -oxidize a polyunsaturated fatty acid Consider the -oxidation steps, processing of acetyl-CoA through the citric acid cycle, and electron transport. Reflect and Apply How many cycles of -oxidation are required to process a fatty acid with 17 carbons Reflect and Apply It has been stated many times that fatty acids cannot yield a net gain in carbohydrates. Recall How are the two redox reactions of -oxidation different from their counterparts in fatty-acid synthesis What step in production of polyunsaturated fatty acids are mammals unable to perform
Syndromes
Phenylalanine is a precursor of tyrosine and together they lead to the formation of thyroxine or thyroid hormone and of adrenaline and noradrenaline which is converted into a neurotransmitter erectile dysfunction doctors in charleston sc purchase 50 mg caverta free shipping, a brain chemical which transmits nerve impulses erectile dysfunction treatment brisbane generic caverta 100 mg overnight delivery. Phlorotannins are a class of polyphenolic compounds (tannins) derived from pholorglucinol (1 erectile dysfunction ed treatment caverta 100 mg low price,3 erectile dysfunction pump review 100 mg caverta with amex,5-trihydroxybenzene) erectile dysfunction what is it cheap caverta 100 mg with amex. As a biological molecule erectile dysfunction pump price buy discount caverta 50mg on-line, it is composed of phosphorus and oxygen and plays a major role in biological processes of many organisms. Phosphatidic acid is a major constituent of cell membranes and acts as a biosynthetic precursor for the formation of all acylglycerol lipids in the cell. A phospholipid comprising choline linked to phosphatidic acid; it is a major component of cell membranes and is localized preferentially in the outer surface of the plasma membrane. A phospholipid containing serine that is an important constituent of cell membranes and is localized preferentially in the inner surface of the plasma membrane. Synonym(s): arginine phosphate the biological role played by a material entity when bound by a receptor of the adaptive immune system. Also: Choline phosphate, N-Trimethyl-2aminoethylphosphonate, O-Phosphocholine, Phosphocholine, Phosphorylcholine. A compound of creatine and phosphoric acid occurring in muscle, being the most important storage form of high-energy phosphate, the energy source in muscle contraction. Phosphorylation also regulates the activity of proteins, such as enzymes, which are often activated by the addition of a phosphate group and deactivated by its removal (called dephosphorylation). Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a serine moiety. Also Serine Phosphoglyceride Quenching of chlorophyll fluorescence by oxidised Q, the electron acceptor of photosystem 2; includes qQ-quenching. Phycoerythrin is the metal-free red phycobilin pigment in a conjugated chromoprotein of red algae. They are found in plants, fungi, nematodes and all groups of algae including cyanobacteria. Phytochelatins act as chelators, and are important for heavy metal detoxification. Two molecules of the 20 carbon geranylgeranyl pyrophosphate are condensed in a tail-to-tail configuration to give the forty carbon phytoene, the first committed step in carotenoid biosynthesis. A member of the class of pterocarpans that is the 3-O-methyl ether of (+)-6a-hydroxymaackiain (the 6aR,12aR stereoisomer). A phytoalexin found in pods of garden peas (Pisum sativum) and other plants of the pea family, including Tephrosia candida. Platelets are disk-shaped, contain no hemoglobin, and are essential for the coagulation of blood and in maintenance of hemostasis. This class of compounds includes many substances that play important roles in both eukaryotic and prokaryotic cells, such as putrescine, cadaverine, spermidine, and spermine. A carbohydrate polymer that is formed from three or more molecules of simple carbohydrates. Examples of polysaccharides are dextrin, starch, glycogen, cellulose, gums, and inulin. Any of various heterocyclic compounds, derived from pyrrole, that occur universally in protoplasm, contain a central metal atom, and provide the foundation structure for hemoglobin, chlorophyll, and certain enzymes. Physiologically inactive substances that can be converted to active enzymes, specific precursor form is referred to as a procarboxypeptidase A. In the case of pancreatic carboxypeptidase A, the inactive zymogen form, pro-carboxypeptidase A, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. This mechanism ensures that the cells wherein procarboxypeptidase A is produced are not themselves digested. In the case of pancreatic carboxypeptidase B, the inactive zymogen form, pro-carboxypeptidase B, is converted to its active form - carboxypeptidase A - by the enzyme enteropeptidase. A protein that may play a role in the regulation of both apoptosis and cell proliferation. A cyclic, nonessential amino acid occurring in proteins; it is a major constituent of collagen. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. Also: Malonic acid, Dicarboxymethane, Carboxyacetic acid, Methanedicarboxylic acid. The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Markers of oxidative stress measured as 2,4dinitrophenylhydrazine incorporated into protein Protein: any of a group of complex organic compounds containing carbon, hydrogen, oxygen, nitrogen, and sulfur. Proteins, the principal constituents of the protoplasm of all cells, are of high molecular weight and consist of -amino acids joined by peptide linkages. Twenty different amino acids are commonly found in proteins, each protein having a unique, genetically defined amino acid sequence that determines its specific shape and function. Their roles include enzymatic catalysis, transport and storage, coordinated motion, nerve impulse generation and transmission, control of growth and differentiation, immunity, and mechanical suppport. Any of a group of complex organic compounds which contain carbon, hydrogen, oxygen, nitrogen and usually sulphur, the characteristic element being nitrogen and which are widely distributed in plants and animals. In this case: Insoluble proteins Total amount of protein in a sample A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. A crystalline acid C7H6O4 produced from various resins and found in combination in many plant products A phenolic acid derivative. An immediate precursor of chlorophyll a, which lacks the phytol side-chain of chlorophyll. A kind of porphyrin that combines with iron and protein to form various important organic molecules, including catalase, hemoglobin, and myoglobin. An important precursor to biologically essential prosthetic groups such as heme, cytochrome c, and chlorophylls. Either of two oily liquid esters: C21H28O3 and C22H28O5 having insecticidal properties and occurring especially in the flowers of pyrethrum. Pyruvate is the end product of glycolysis and may be metabolized to lactate or to acetyl CoA. The ratio of reduced Glutathione to Glutathione disulfide the ratio of reduced glutathione to total glutathione (reduced plus oxidized) found in a sample. A potent antioxidant shown to directly destroy superoxide, hydroperoxy and hydroxyl radicals; also has neuroprotective and anti-tumour effects. A sugar that serves as a reducing agent due to its free aldehyde or ketone functional groups in its molecular structure. Examples are glucose, fructose, glyceraldehydes, lactose, arabinose and maltose, except for sucrose. Refractive index generally increases with the atomic number of the constituent atoms. The two isomers 11-cis retinal and all-trans retinal are interconverted in the visual cycle. Retinoid analogs have been used in the prevention and treatment of various skin cancers and treatment of the digestive and respiratory tracts. The all trans form of retinol where all of the double bonds are in the trans configuration. Also known as Tretinoin and is used as chemotherapy for acute promyelocytic leukemia, a subtype of acute myelogenous leukemia. Deficiency causes skin disorders, increased susceptibility to infection, nyctalopia, xerophthalmia and other eye disorders, anorexia, and sterility. As vitamin A it is mostly found in liver, egg yolks, and the fat component of dairy products; its other major dietary source is the provitamin A carotenoids of plants. It is toxic when taken in excess A cell-surface adhesion molecule expressed by photoreceptor and bipolar cells of the retina. Vertebrate opsins are proteins of 38 kD Riboflavin: a B vitamin that prevents skin lesions and weight loss. Otherwise known as vitamin B2, this vitamin is essential for the metabolic processes of all animals. Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. The level of Rubidium in a sample the compound formed by the demethylation of sadenosyl-l-methionine. Also: 2-Hydroxybenzoic acid, o-hydroxybenzoic acid, o-Carboxyphenol, 2Carboxyphenol, Salonil, and Rutranex. Saturated Fatty Acids are fatty acids that have no double bonds between the carbon atoms of the fatty acid chain and are thus fully saturated with hydrogen atoms. A fatty acid with all potential hydrogen binding sites filled (totally hydrogenated fat). A crystalline lactone C10H8O that is found in various solanaceous plants (as members of the genus Scopolia or belladonna). Generally, the term refers to silkworm silk gum protein secreted in the middle section of silk gland cells of silkworms, Bombyx mori. It is synthesized from glycine or threonin and a precursor of the amino acids purine, cysteine, and others. Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Any of a group of structurally related proteins that typically are serine protease inhibitors (as antithrombin and antitrypsin) whose inhibiting activity is conferred by an active site in a highly variable and mobile peptide loop and that include some (as ovalbumin and angiotensinogen) which have apparently lost the inhibitory action due to mutation in the course of evolutionary change. A cyclohexenecarboxylic acid that is cyclohex-1ene-1-carboxylic acid substituted by hydroxy groups at positions 3, 4 and 5 (the 3R,4S,5R stereoisomer). A protein involved in catalysis of the calcium concentration-regulatable energy-independent passage of cations across a lipid bilayer down a concentration gradient. An older laboratory measurement that represents the portion of crude protein that goes into solution when mixed in a buffered solution. If 30% of the protein goes into solution, by definition, 30% of the crude protein is soluble. The soluble solids content is the total of all the solids dissolved in the water, including sugar, salts, protein, acids, etc. They are involved in the responses to a number of stresses, and they act as nutrient and metabolite signalling molecules that activate specific or hormone-crosstalk transduction pathways, thus resulting in important modifications of gene expression and proteomic patterns. Various metabolic reactions and regulations directly link soluble sugars with the production rates of reactive oxygen species, such as mitochondrial respiration or photosynthesis regulation, and, conversely, with anti-oxidative processes, such as the oxidative pentosephosphate pathway and carotenoid biosynthesis. A dimensionless unit defined as the ratio of the density of a substance to the density of water at a specified temperature. A polyamine compound, C7H19N3, found in ribosomes and living tissues and having various metabolic functions. Any of a group of crystalline phosphatides that are obtained especially from nerve tissue and that on hydrolysis yield a fatty acid (as lignoceric acid), sphingosine, choline, and phosphoric acid. Plants use starch as a way to store excess glucose, and thus also use starch as food during mitochondrial oxidative phosphorylation. A saturated 18-carbon fatty acid occurring in most fats and oils, particularly of tropical plants and land animals; used pharmaceutically as a tablet and capsule lubricant and as an emulsifying and solubilizing agent. Also C18:0 Stearidonic acid is and omega-3 faty acid sometimes called moroctic acid. Sterol esters are present in plant tissues, but as relatively minor components other than in waxes. Usually the sterol components of sterol esters are similar to the free sterols, although there may be relatively less of stigmasterol. Any steroid-based alcohol having a hydrocarbon (aliphatic) side-chain of 8-10 carbons at the 17beta position and a hydroxyl group at the 3-beta position (therefore an alcohol). Proteins with a role in structure and support in tissue and within the cell; the collagens. A disaccharide of glucose and fructose from sugar cane, sugar beet, or other sources; used as a food and sweetening agent and pharmaceutical aid. Sugar phosphates (sugars that have added or substituted phosphate groups) are often used in biological systems to store or transfer energy. Cerebroside sulfuric esters containing one or more sulfate groups in the sugar portion of the molecule. A green pigment formed by the reaction of hemoglobin with a sulfide in the presence of oxygen or hydrogen peroxide. Is among the first costameric proteins to assemble during myogenesis and it contributes to myogenic membrane structure and differentiation. An isoform of synapsin 2, a neuronal phosphoprotein that coats synaptic vesicles, binds to the cytoskeleton, and is believed to function in the regulation of neurotransmitter release. Synaptophysin is a 38-kd calcium-binding glycoprotein that is present in the presynaptic vesicles of neurons and in the neurosecretory granules of neuroendocrine cells. A protein that may play an important role in the synaptic function of specific neuronal systems. Also: 4-Hydroxy-3,5dimethoxybenzoic acid, 3,5-Dimethoxy-4hydroxybenzoic acid, Cedar acid, Gallic acid 3,5dimethyl ether. Any of various soluble astringent complex phenolic substances of plant origin used especially in tanning leather and dyeing fabric, manufacturing ink, clarifying wine and beer, and in medicine. Tenuazonic acid is a metabolite found in a strain of the fungus Alternaria tenuis Auct. The diphosphoric ester of thiamin, a coenzyme of several (de)carboxylases, transketolases, and oxoacid dehydrogenases. Synonym(s): aneurine pyrophosphate, cocarboxylase, diphosphothiamin A barbituric acid derivative C6H4N2O2S that is used to form a series of thio analogs of the barbiturates. It is both a breakdown product of cyanide and is known to be important in the biosynthesis of hypothiocyanite by a lactoperoxidase.
Others such as blood clot formation pomegranate juice impotence order caverta 50mg otc, clot dissolution erectile dysfunction virgin buy caverta 50 mg without a prescription, and tissue repair are brought "on line" only in response to pressing physiologic or pathophysiologic need erectile dysfunction at age 17 buy 50mg caverta amex. The processes of blood clot formation and dissolution clearly must be temporally coordinated to achieve homeostasis impotence back pain order 100mg caverta mastercard. Enzymes needed intermittently but rapidly often are secreted in an initially inactive form since the secretion process or new synthesis of the required proteins might be insufficiently rapid to respond to a pressing pathophysiologic demand such as the loss of blood (see Chapter 51) impotence jelqing order caverta 100mg with amex. Because organisms lack the ability to reunite the two portions of a protein produced by hydrolysis of a peptide bond erectile dysfunction vacuum therapy caverta 100mg lowest price, proteolysis constitutes an irreversible modification. The phosphorylation of proteins on seryl, threonyl, or tyrosyl residues, catalyzed by protein kinases, is thermodynamically favored. Equally favored is the hydrolytic removal of these phosphoryl groups by enzymes called protein phosphatases. The activities of protein kinases and protein phosphatases are themselves regulated, for if they were not, their concerted action would be both thermodynamically and biologically unproductive. Activation of Prochymotrypsin Requires Selective Proteolysis Selective proteolysis involves one or more highly specific proteolytic clips that may or may not be accompanied by separation of the resulting peptides. Most importantly, selective proteolysis often results in conformational changes that "create" the catalytic site of an enzyme. Note also that contact and catalytic residues can be located on different peptide chains but still be within bondforming distance of bound substrate. Modifications such as prenylation, glycosylation, hydroxylation, and fatty acid acylation introduce unique structural features into newly synthesized proteins that tend to persist for the lifetime of the protein. Among the covalent modifications that regulate protein function (eg, methylation, acetylation), the most common by far is phosphorylation-dephosphorylation. Some protein kinases target the side chains of histidyl, lysyl, arginyl, and aspartyl residues. The unmodified form of the protein can be regenerated by hydrolytic removal of phosphoryl groups, catalyzed by protein phosphatases. A typical mammalian cell possesses thousands of phosphorylated proteins and several hundred protein kinases and protein phosphatases that catalyze their interconversion. Phosphorylationdephosphorylation permits the functional properties of the affected enzyme to be altered only for as long as it serves a specific need. Once the need has passed, the enzyme can be converted back to its original form, poised to respond to the next stimulatory event. A second factor underlying the widespread use of protein phosphorylation-dephosphorylation lies in the chemical properties of the phosphoryl group itself. Consequently, the amino acids targeted by phosphorylation can be and typically are relatively distant from the catalytic site itself. Covalent Modification Regulates Metabolite Flow In many respects, sites of protein phosphorylation and other covalent modifications can be considered another form of allosteric site. Both phosphorylation-dephosphorylation and feedback inhibition provide short-term, readily reversible regulation of metabolite flow in response to specific physiologic signals. Both act on early enzymes of a protracted and often biosynthetic metabolic sequence, and both act at allosteric rather than catalytic sites. Others are subject to regulation both by phosphorylationdephosphorylation and by the binding of allosteric ligands, or by phosphorylation-dephosphorylation and another covalent modification. Phosphorylation-dephosphorylation at any one site can be catalyzed by multiple protein kinases or protein phosphatases. Many protein kinases and most protein phosphatases act on more than one protein and are themselves interconverted between active and inactive forms by the binding of second messengers or by covalent modification by phosphorylation-dephosphorylation. The interplay between protein kinases and protein phosphatases, between the functional consequences of phosphorylation at different sites, between phosphorylation sites and allosteric sites, or between phosphorylation sites and other sites of covalent modification provides the basis for regulatory networks that integrate multiple environmental input signals to evoke an appropriate coordinated cellular response. For example, modification of histones by a combination of acetylation and phosphorylation constitutes the basis for the "histone code," which modulates chromatin structure to enhance or silence the expression of genes (Chapter 38). In these sophisticated regulatory networks, individual enzymes respond to different environmental signals. For example, if an enzyme can be phosphorylated at a single site by more than one protein kinase, it can be converted from a catalytically efficient to an inefficient (inactive) form, or vice versa, in response to any one of several signals. If the protein kinase is activated in response to a signal different from the signal that activates the protein phosphatase, the phosphoprotein becomes a decision node. The functional output, generally catalytic activity, reflects the phosphorylation state. This state or degree of phosphorylation is determined by the relative activities of the protein kinase and protein phosphatase, a reflection of the presence and relative strength of the environmental signals that act through each. The ability of many protein kinases and protein phosphatases to target more than one protein provides a means for an environmental signal to coordinately regulate multiple metabolic processes. Hence, interconvertible enzymes and the enzymes responsible for their interconvesion do not act as isolated "on" and "off " switches. In order to meet the demands of maintaining homeostasis, these building blocks are linked to form integrated regulatory networks. One well-studied example of such a network is the eukaryotic cell cycle that controls cell division. Elaborate monitoring systems, called checkpoints, assess key indicators of progress to ensure that no phase of the cycle is initiated until the prior phase is complete. The genome is replicated during S phase, while the two copies of the genome are segregated and cell division occurs during M phase. Each of these phases is separated by a G, or growth, phase characterized by an increase in cell size and the accumulation of the precursors required for the assembly of the large macromolecular complexes formed during S and M phases. Each step in the cascade provides a conduit for monitoring additional indicators of cell status prior to entering S phase. Binding of metabolites and second messengers to sites distinct from the catalytic site of enzymes triggers conformational changes that alter Vmax or Km. Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues-and subsequent dephosphorylation by protein phosphatases-regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades that respond to hormonal or second messenger signals constitute regulatory networks that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. This is achieved via appropriate changes in the rates of biochemical reactions in response to physiologic need. The substrates for most enzymes are usually present at a concentration close to their Km. This facilitates passive control of the rates of product formation in response to changes in levels of metabolic intermediates. Active control of metabolite flux involves changes in the concentration, catalytic activity, or both of an enzyme that catalyzes a committed, rate-limiting reaction. Selective proteolysis of catalytically inactive proenzymes initiates conformational changes that form the active site. Slowly but surely scientists are unveiling the complex chemical underpinnings of memory. Tu B et al: Logic of the yeast metabolic cycle: Temporal compartmentalization of cellular processes. Malaria was caused by the amoeba Plasmodium falciparum, tuberculosis by the bacterium Mycobacterium tuberculosis, sickle cell disease by a mutation in a gene encoding one of the subunits of hemoglobin, poliomyelitis by poliovirus, and scurvy by a deficiency in ascorbic acid. The strategy for treating or preventing disease thus could be reduced to a straightforward process of tracing the causal agent and then devising some means of eliminating it, neutralizing its effects, or blocking its route of transmission. This approach has been successfully employed to understand and treat a wide range of infectious and genetic diseases. The challenge posed by multifactorial diseases demands a quantum increase in the breadth and depth of our knowledge of living organisms capable of matching their sophistication and complexity. We must identify the many as yet unknown proteins encoded within the genomes of humans and of the organisms with which they interact, the functional relationships between these proteins, and the impact of dietary, genetic, and environmental factors thereupon. The sheer mass of information that must be processed to understand, as completely and comprehensively as possible, the molecular mechanisms that underlie the behavior of living organisms, as well as the manner in which perturbations can lead to disease or dysfunction, lies well beyond the ability of the human mind to review and analyze. Biomedical scientists therefore have turned to sophisticated computational tools to collect and evaluate biologic information on a mass scale. The chronology below lists several of the milestone events that led to the determination of the entire sequence of the human genome. Computer algorithms were then used to identify matching sequence information from overlapping fragments to piece together the complete sequence. The correct positions of these scaffolds were then determined by using sequence-tagged sites. While genome-based "designer medicine" promises to be efficient and effective, significant technical and scientific challenges remain to be addressed before the promise of genomics can be completely fulfilled in both biology and medicine. Genomes and Medicine Ready access to genome sequences from organisms spanning all three phylogenetic domains, the Archaea, Bacteria, and Eukarya, coupled with access to powerful algorithms for manipulating and transforming data derived from these sequences, has already effected major transformations in biology and biochemistry. The early decades of the 21st century will witness the expansion of the "Genomics Revolution" into the practice of medicine as physicians and scientists exploit new knowledge of the human genome and of the genomes of the organisms that colonize, feed, and infect Homo sapiens. Today, comparisons between the genomes of pathogenic and nonpathogenic strains of a microorganism can highlight likely determinants of virulence. Similarly, comparative genomics is being applied to pathogens and their hosts to identify lists of gene products unique to the former from which to select potential drug targets. In future, physicians will diagnose the opportunities offered by the advancing genomic revolution will present society with profound challenges in the areas of ethics, law, and public policy. The first harbingers of these challenges can be glimpsed in the ongoing controversies regarding genetically modified foods, the cloning of whole animals, and the utilization of human embryonic stem cells in research. Forthcoming insights into the molecular and genetic contributions to human traits and behavior, as well as to physical health or to disease, will require the development of a new generation of national and international policies in the areas of law, medicine, agriculture, etc. The central objective of a typical bioinformatics project is to assemble all of the available information relevant to a particular topic in a single location, often referred to as a library or database, in a uniform format that renders the data amenable to manipulation and analysis by computer algorithms. The size and capabilities of bioinformatic databases can vary widely depending upon the scope and nature of their objectives. The construction of a comprehensive and user-friendly database presents many challenges. For example, the coding information in a genome, although voluminous, is composed of simple linear sequences of four nucleotide bases. Second, anticipating the manner in which users may wish to search or analyze the information within a database, and devising algorithms for coping with these variables, can prove extremely challenging. For example, even the simple task of searching a gene database commonly employs, alone or in various combinations, criteria as diverse as the name of the gene, the name of the protein that it encodes, the biologic function of the gene product, a nucleotide sequence within the gene, a sequence of amino acids within the protein it encodes, the organism in which it is present, or the name of an investigator who works on that gene. Researchers wishing to determine whether the impact of a genetic polymorphism on longevity is influenced by the nature of the climate where a person resides may need to compare data from multiple databases. Similarly, a diverse range of criteria may apply when describing the subjects of a biomedical study: height; weight; age; gender; body mass index; diet; ethnicity; medical history; profession; use of drugs, alcohol, or tobacco products; exercise; blood pressure; habitat; marital status; blood type; serum cholesterol level; etc. Each complements the other by focusing on a different aspect of macromolecular structure. The aim of the atlas was to facilitate studies of protein evolution using the amino acid sequences being generated consequent to the development of the Edman method for protein sequencing (Chapter 4). Detailed study of each region should reveal variants in genes that contribute to a specific disease or response. In 2002, scientists from the United States, Canada, China, Japan, Nigeria, and the United Kingdom launched the International HapMap Project. The resulting haplotype map (HapMap) should lead to earlier and more accurate diagnosis, and hopefully also to improved prevention and patient management. These genetic markers will also provide labels with which to identify and track specific genes as scientists seek to learn more about the critical processes of genetic inheritance and selection. Entrez Gene also lists, where known, the function of the encoded protein and the impact of known single-nucleotide polymorphisms in the coding region. Access to sensitive data requires that the user apply for authorization to a data access committee. Other databases dealing with human genetics and health include Online Mendelian Inheritance in Man. Consortium investigators with diverse backgrounds and expertise collaborate in the development and evaluation of new high-throughput techniques, technologies, and strategies to address current deficiencies in our ability to identify functional elements. In addition to the sheer size of the human genome and the cryptic nature of much of its sequence, scientists must cope with the variations in genome function that characterize different cell types and developmental stages. Given the complexity of the issues, it is clear that no single experimental approach or cell type will suffice to provide a complete overview of the interrelationships between genome sequence, architecture, and function. Unlike bioinformatics, whose major focus is the collection and evaluation of existing data, computational biology is experimental and exploratory in nature. By performing virtual experiments and analyses "in silico," computational biology offers the promise of greatly accelerating the pace and efficiency of scientific discovery. Computational biologists are attempting to develop predictive models that will (1) permit the three-dimensional structure of a protein to be determined directly from its primary sequence, (2) determine the function of unknown proteins from their sequence and structure, (3) screen for potential inhibitors of a protein in silico, and (4) construct virtual cells that reproduce the behavior and predict the responses of their living counterparts to pathogens, toxins, diet, and drugs. The creation of computer algorithms that accurately mimic the behavior of proteins, enzymes, cells, etc will enhance the speed, efficiency, and the safety of biomedical research. Computational biology will also enable scientists to perform experiments in silico whose scope, hazard, or nature renders them inaccessible to or inappropriate for conventional laboratory or clinical approaches. Identities with the English word are shown in dark red; linguistic similarities in light red. The major evolutionary question addressed was whether the similarities reflected (1) descent from a common ancestral protein (divergent evolution) or (2) the independent selection of a common mechanism for meeting some specific cellular need (convergent evolution), as would be anticipated if one particular solution was overwhelmingly superior to the alternatives.
Aspartate Y acts as an acid to facilitate breakdown of the tetrahedral intermediate and release of the split products by donating a proton to the newly formed amino group erectile dysfunction medication list cheap caverta 50 mg fast delivery. Subsequent shuttling of the proton on Asp X to Asp Y restores the protease to its initial state erectile dysfunction drugs herbal generic caverta 100 mg mastercard. A highly reactive seryl residue online doctor erectile dysfunction buy 50 mg caverta, serine 195 erectile dysfunction estrogen generic caverta 100mg overnight delivery, participates in a charge-relay network with histidine 57 and aspartate 102 ginkgo biloba erectile dysfunction treatment generic 100mg caverta with visa. Far apart in primary structure impotence ring buy 100 mg caverta otc, in the active site these residues are within bond-forming distance of one another. Aligned in the order Asp 102-His 57-Ser 195, they constitute a "charge-relay network" that functions as a "proton shuttle. The enhanced nucleophilicity of the seryl oxygen facilitates its attack on the carbonyl carbon of the peptide bond of the substrate, forming a covalent acyl-enzyme intermediate. The charge-relay system removes a proton from Ser 195, making it a stronger nucleophile. Activated Ser 195 attacks the peptide bond, forming a transient tetrahedral intermediate. Release of the amino terminal peptide is facilitated by donation of a proton to the newly formed amino group by His 57 of the charge-relay system, yielding an acylSer 195 intermediate. His 57 and Asp 102 collaborate to activate a water molecule, which attacks the acyl-Ser 195, forming a second tetrahedral intermediate. The charge-relay system donates a proton to Ser 195, facilitating breakdown of tetrahedral intermediate to release the carboxyl terminal peptide. The portion of the original peptide with a free amino group then leaves the active site and is replaced by a water molecule. The charge-relay network now activates the water molecule by withdrawing a proton through His 57 to Asp 102. While modified during the process of catalysis, chymotrypsin emerges unchanged on completion of the reaction. Trypsin and elastase employ a similar catalytic mechanism, but the numbers of the residues in their Ser-His-Asp proton shuttles differ. Catalysis involves a "catalytic triad" of one Glu and two His residues and a covalent phosphohistidyl intermediate. Most enzyme families arose through gene duplication events that create a second copy of the gene that encodes a particular enzyme. The proteins encoded by the two genes can then evolve independently to recognize different substrates-resulting, for example, in chymotrypsin, which cleaves peptide bonds on the carboxyl terminal side of large hydrophobic amino acids, and trypsin, which cleaves peptide bonds on the carboxyl terminal side of basic amino acids. Proteins that diverged from a common ancestor are said to be homologous to one another. The common ancestry of enzymes can be inferred from the presence of specific amino acids in the same position in each family member. Among the most highly conserved residues are those that participate directly in catalysis. However, the amplification conferred by their ability to rapidly transform thousands of molecules of a specific substrate into products imbues each enzyme with the ability to reveal its presence. Assays of the catalytic activity of enzymes are frequently used in research and clinical laboratories. Under appropriate conditions (see Chapter 8), the rate of the catalytic reaction being monitored is proportionate to the amount of enzyme present, which allows its concentration to be inferred. Like the members of other protein families, these protein catalysts or isozymes arise through gene duplication. Isozymes may exhibit subtle differences in properties such as sensitivity to particular regulatory factors (Chapter 9) or substrate affinity (eg, hexokinase and glucokinase) that adapt them to specific tissues or circumstances. Some isozymes may also enhance survival by providing a "backup" copy of an essential enzyme. Single-Molecule Enzymology the limited sensitivity of traditional enzyme assays necessitates the use of a large group, or ensemble, of enzyme molecules in order to produce measurable quantities of product. Recent advances in nanotechnology have made it possible to observe, usually by fluorescence microscopy, catalysis by individual enzyme and substrate molecules. Drug Discovery Requires Enzyme Assays Suitable for "High-Throughput" Screening Enzymes constitute one of the primary classes of biomolecules targeted for the development of drugs and other therapeutic agents. Many antibiotics, for example, inhibit enzymes that are unique to microbial pathogens. The discovery of new drugs is greatly facilitated when a large number of potential pharmacophores can be assayed in a rapid, automated fashion- a process referred to as high-throughput screening. Highthroughput screening takes advantage of recent advances in robotics, optics, data processing, and microfluidics to conduct and analyze many thousands of simultaneous assays of the activity of a given enzyme. High-throughput screening is ideal for surveying the numerous products of combinatorial chemistry, the simultaneous synthesis of large libraries of chemical compounds that contain all possible combinations of a set of chemical precursors. Enzyme assays that produce a chromagenic or fluorescent product are ideal, since optical detectors are readily engineered to permit the rapid analysis of multiple samples. At present, the sophisticated equipment required for truly large numbers of assays is available only in pharmaceutical houses, government-sponsored laboratories, and research universities. Serum or other biologic samples to be tested are placed in a plastic microtiter plate, where the proteins adhere to the plastic surface and are immobilized. Any remaining absorbing areas of the well are then "blocked" by adding a nonantigenic protein such as bovine serum albumin. The presence and quantity of bound antibody is then determined by adding the substrate for the reporter enzyme. Enzyme-Linked Immunoassays the sensitivity of enzyme assays can be exploited to detect proteins that lack catalytic activity. Examples include pseudocholinesterase, lipoprotein lipase, and components of the cascade of events in blood clotting and clot dissolution. While these latter enzymes perform no physiologic function in plasma, their appearance or levels can assist in the diagnosis and prognosis of diseases and injuries affecting specific tissues. Following injury, the plasma concentration of a released enzyme may rise early or late, and may decline rapidly or slowly. Proteins from the cytoplasm tend to appear more rapidly than those from subcellular organelles. The speed with which enzymes and other proteins are removed from plasma varies with their susceptibility to proteolysis and permeability through renal glomeruli. Quantitative analysis of the activity of released enzymes or other proteins, typically in plasma or serum but also in urine or various cells, provides information concerning diagnosis, prognosis, and response to treatment. Assays of enzyme activity typically employ standard kinetic assays of initial reaction rates. For example, elevated blood levels of prostatic acid phosphatase are associated typically with prostate cancer, but also with certain other cancers and noncancerous conditions. Consequently, enzyme assay data must be considered together with other factors elicited through a comprehensive clinical examination. Factors to be considered in interpreting enzyme data include patient age, sex, prior history, possible drug use, and the sensitivity and the diagnostic specificity of the enzyme test. Spectrophotometric assays exploit the ability of a substrate or product to absorb light. In each case, the rate of change in optical density at 340 nm will be proportionate to the quantity of enzyme present. Many Enzymes Are Assayed by Coupling to a Dehydrogenase the assay of enzymes whose reactions are not accompanied by a change in absorbance or fluorescence is generally more difficult. In some instances, the product or remaining substrate can be transformed into a more readily detected compound. In other instances, the reaction product may have to be separated from unreacted substrate prior to measurement. An alternative strategy is to devise a synthetic substrate whose product absorbs light or fluoresces. For example, p-nitrophenyl phosphate is an artificial substrate for certain phosphatases and for chymotrypsin that does not absorb visible light. However, following hydrolysis, the resulting p-nitrophenylate anion absorbs light at 419 nm. Typically, a dehydrogenase whose substrate is the product of the enzyme of interest is added in catalytic excess. Enzymes Assist Diagnosis of Myocardial Infarction An enzyme useful for diagnostic enzymology should be relatively specific for the tissue or organ under study, should appear in the plasma or other fluid at a time useful for diagnosis (the "diagnostic window"), and should be amenable to automated assay. Enzymes that only appear in the plasma 12 h or more following injury are thus of limited utility. Tissue-specific expression of the H and M genes determines the relative proportions of each subunit in different tissues. Pattern A is serum from a patient with a myocardial infarct; B is normal serum; and C is serum from a patient with liver disease. Immunological measurement of plasma levels of cardiac troponins I andprovide sensitive and specific indicators of damage to heart muscle. The search for additional markers for heart disease, such as ischemia modified albumin, and the simultaneous assessment of a spectrum of diagnostic markers via proteomics, continues to be an active area of clinical research. Enzymes also can be employed in the clinical laboratory as tools for determining the concentration of critical metabolites. For example, glucose oxidase is frequently utilized to measure plasma glucose concentration. Enzymes are employed with increasing frequency as tools for the treatment of injury and disease. The isolation of an individual enzyme, particularly one present in low concentration, from among the thousands of proteins present in a cell can be extremely difficult. If the gene for the enzyme of interest has been cloned, it generally is possible to produce large quantities of its encoded protein in Escherichia coli or yeast. However, not all animal proteins can be expressed in active form in microbial cells, nor do microbes perform certain posttranslational processing tasks. For these reasons, a gene may be expressed in cultured animal cell systems employing the baculovirus expression vector to transform cultured insect cells. The gene of interest is linked to an oligonucleotide sequence that encodes a carboxyl or amino terminal extension to the encoded protein. The resulting modified protein, termed a fusion protein, contains a domain tailored to interact with a specific affinity support. One popular approach is to attach an oligonucleotide that encodes six consecutive histidine residues. The expressed "His tag" protein binds to chromatographic supports that contain an immobilized divalent metal ion such as Ni2+. Fusion proteins also often encode a cleavage site for a highly specific protease such as thrombin in the region that links the two portions of the protein. Specific proteases can then remove affinity "tags" and generate the native enzyme. Site-Directed Mutagenesis Provides Mechanistic Insights Once the ability to express a protein from its cloned gene has been established, it is possible to employ site-directed mutagenesis to change specific aminoacyl residues by altering their codons. Used in combination with kinetic analyses and x-ray crystallography, this approach facilitates identification of the specific roles of given aminoacyl residues in substrate binding and catalysis. For example, the inference that a particular aminoacyl residue functions as a general acid can be tested by replacing it with an aminoacyl residue incapable of donating a proton. Fersht A: Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding. Sundaresan V, Abrol R: Towards a general model for proteinsubstrate stereoselectivity. Urichet al: X-ray structure of a self-compartmentalizing sulfur cycle metalloenzyme. Organic and inorganic prosthetic groups, cofactors, and coenzymes play important roles in catalysis. Aminoacyl residues that participate in catalysis are highly conserved among all classes of a given enzyme. Substrates and enzymes induce mutual conformational changes in one another that facilitate substrate recognition and catalysis. The catalytic activity of enzymes reveals their presence, facilitates their detection, and provides the basis for enzymelinked immunoassays. Combinatorial chemistry generates extensive libraries of potential enzyme activators and inhibitors that can be tested by high-throughput screening. Assay of plasma enzymes aids diagnosis and prognosis, for example, of myocardial infarction. Restriction endonucleases facilitate diagnosis of genetic diseases by revealing restriction fragment length polymorphisms. A complete, balanced set of enzyme activities is of fundamental importance for maintaining homeostasis. An understanding of enzyme kinetics, thus, is important to understanding how physiologic stresses such as anoxia, metabolic acidosis or alkalosis, toxins, and pharmacologic agents affect that balance. Kinetic analysis can reveal the number and order of the individual steps by which enzymes transform substrates into products. Together with site-directed mutagenesis and other techniques that probe protein structure, kinetic analyses can reveal details of the catalytic mechanism of a given enzyme. The involvement of enzymes in virtually all physiologic processes makes them the targets of choice for drugs that cure or ameliorate human disease. Applied enzyme kinetics represents the principal tool by which scientists identify and characterize therapeutic agents that selectively inhibit the rates of specific enzyme-catalyzed processes.
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