By D. Gembak. University of Texas Health Science Center at Houston. 2018.

Because of these progressive ing the basal ganglia results in the move- ment disorder buy pariet 20 mg cheap. The doctor suspected that her patient probably had primary or idiopathic parkin- In ventricular fibrillation order pariet 20mg otc, rapid pre- sonism (Parkinson’s disease) and referred Mr quality 20 mg pariet. In Parkin- mature beats from an irritative son’s disease buy discount pariet 20mg on line, neurons of the substantia nigra pars compacta buy generic pariet 20mg online, containing the pigment focus in ventricular muscle occur in melanin and the neurotransmitter dopamine, degenerate. Persistent fibrilla- tion compromises cardiac output, leading to death. This arrythmia can result from severe Cora Nari had done well since the successful lysis of blood clots in her ischemia (lack of blood flow) in the ventricu- coronary arteries with the use of intravenous recombinant tissue plasmino- lar muscle of the heart caused by clots form- gen activator (TPA)(see Chapters 19 and 21). This therapy had quickly ing at the site of a ruptured atherosclerotic relieved the crushing chest pain (angina) she experienced when she won the lottery. However, Cora Nari’s rapid beats At her first office visit after discharge from the hospital, Cora’s cardiologist told her began during the infusion of TPA as the clot she had developed multiple premature contractions of the ventricular muscle of her was lysed. Thus, they probably resulted from heart as the clots were being lysed. This process could have led to a life-threatening reperfusing a previously ischemic area of her arrhythmia known as ventricular fibrillation. However, Cora’s arrhythmia heart with oxygenated blood. This phenome- responded quickly to pharmacologic suppression and did not recur during the non is known as ischemia–reperfusion injury, remainder of her hospitalization. O AND THE GENERATION OF ROS 2 sion injury also may occur when tissue oxy- genation is interrupted during surgery or The generation of reactive oxygen species from O2 in our cells is a natural everyday transplantation. They are formed as accidental products of nonenzymatic and enzymatic CHAPTER 24 / OXYGEN TOXICITY AND FREE RADICAL INJURY 441 reactions. Occasionally, they are deliberately synthesized in enzyme-catalyzed The two unpaired electrons in oxy- reactions. Ultraviolet radiation and pollutants in the air can increase formation of gen have the same (parallel) spin toxic oxygen-containing compounds. In contrast, carbon–carbon and carbon–hydrogen bonds each contain two A. The Radical Nature of O2 electrons, which have antiparallel spins and A radical, by definition, is a molecule that has a single unpaired electron in an form a thermodynamically stable pair. A free radical is a radical capable of independent existence. Without the electron from a neighboring molecule to complete their own orbitals. Although the spin restriction, organic life forms could not transition metals (e. Instead, O2 is con- The oxygen atom is a biradical, which means it has two single electrons in dif- fined to slower one-electron reactions cat- ferent orbitals. These electrons cannot both travel in the same orbital because they alyzed by metals (or metalloenzymes). Although oxygen is very reactive from a thermodynamic standpoint, its single electrons cannot react rapidly with the O2 paired electrons found in the covalent bonds of organic molecules. As a conse- quence, O reacts slowly through the acceptance of single electrons in reactions Oxygen 2 that require a catalyst (such as a metal-containing enzyme). Superoxide is still – O2 a radical because it has one unpaired electron remaining. This reaction is not ther- Superoxide modynamically favorable and requires a moderately strong reducing agent that can e–, 2H+ donate single electrons (e. When super- oxide accepts an electron, it is reduced to hydrogen peroxide, which is not a radi- cal. The hydroxyl radical is formed in the next one-electron reduction step in the H O 2 2 reduction sequence. Finally, acceptance of the last electron reduces the hydroxyl Hydrogen peroxide radical to H2O. Characteristics of Reactive Oxygen Species H2O + OH• Reactive oxygen species (ROS) are oxygen-containing compounds that are highly Hydroxyl reactive free radicals, or compounds readily converted to these oxygen free radi- radical cals in the cell. The major oxygen metabolites produced by one-electron reduction e–, H+ of oxygen (superoxide, hydrogen peroxide, and the hydroxyl radical) are classified as ROS (Table 24. Reactive free radicals extract electrons (usually as hydrogen atoms) from other H2O compounds to complete their own orbitals, thereby initiating free radical chain reactions.

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What is the ratio of [glu- determined by G0 for the reaction cheap pariet 20mg otc. It is often said that a reaction with a negative G proceeds spontaneously in the forward direction quality pariet 20mg, meaning that products accumulate at the expense of reactants order pariet 20mg overnight delivery. However order 20 mg pariet free shipping, G is not an indicator of the velocity of the reaction generic pariet 20 mg, or the rate at which equilibrium can be reached. In the cell, the velocity of the reaction depends on the efficiency and amount of enzyme available to catalyze the reaction (see Chapter 9), and, therefore, “spontaneously” in this context can be misleading. ENERGY TRANSFORMATIONS TO DO MECHANICAL AND TRANSPORT WORK To do work in the cell, a mechanism must be available for converting the chemical bond energy of ATP into another form, such as an Na gradient across a membrane. These energy transformations usually involve intermediate steps in which ATP is bound to a protein, and cleavage of the bound ATP results in a conformational change of the protein. Muscle fiber is made of thick filaments composed of bundles of the protein myosin, and thin filaments composed of the protein actin (which is activated by Ca2 binding). At many positions along the actin filament, a terminal domain of a myosin molecule, referred to as the “head,” binds to a specific site on the actin. The myosin head has an ATP binding site and is an ATPase; it can hydrolyze ATP to ADP and Pi. This change of conformation at multiple association points between actin and myosin slides the actin filament forward (5). For this reaction, Keq In mechanical work, the high-energy phosphate bond of ATP is converted into [glucose-1-phosphate]/[glucose-6- 3 movement by changing the conformation of a protein (Fig. Substituting in equa- changes the conformation of myosin so that it is in a “cocked” position ready to tion 1 then gives 1. Thus, exercising muscle fibers have almost P]/[glucose-6-P]. Thus, ln[glucose 1-P]/[glu- a hundred-fold higher rate of ATP utilization and caloric requirements than resting cose 6-P] 2. Motor proteins, such as kinesins that transport chemicals along [glucose-6-phosphate] e 2. So fibers, provide another example of mechanical work in a cell. Transport Work In transport work, called active transport, the high-energy phosphate bond of ATP is Otto Shape has not followed his used to transport compounds against a concentration gradient (see Chapter10, proposed diet and exercise regi- men and has been gaining weight. The equations for calculating G are based on the first law of thermodynamics He has a positive caloric balance, because (see Table 19. The change in chemical bond energy that occurs during a reac- his daily energy expenditure is less than his tion is H, the change in enthalpy of the reaction. At constant temperature and daily energy intake (see Chapter 2). G, the maximum amount of useful work available from a reaction, is equal cal exercise is only approximately 30% of the to H minus T S. T S is a correction for the amount of energy that has gone into an BMR (basal metabolic rate) in a sedentary increase in the entropy (disorder in arrangement of molecules) of the system. The large increase is the change in entropy, or increased disorder of the system. S is often negligible in in ATP utilization for muscle contraction dur- reactions such as ATP hydrolysis in which the number of substrates (H2O, ATP) and prod- ing exercise accounts for its contribution to ucts (ADP, Pi) are equal and no gas is formed. Under these conditions, the values for G the daily energy expenditure. In P-ATPases (plasma membrane ATPases) and V-ATPases (vesicular X. Teefore has increased blood ATPases), the chemical bond energy of ATP is used to reversibly phosphorylate the levels of thyroid hormones, which transport protein and change its conformation. For example, as Na ,K -ATPase binds accelerate basal metabolic processes that use ATP in our organs (e. An increased BMR was used for a pre- cellular concentration of Na.

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Liver alcohol dehydrogenase cat- an increase of reaction rate is usually observed as the pH goes from a very acidic alyzes the oxidation of ethanol (shown in blue) to acetaldehyde 20 mg pariet otc. The active site of liver alcohol level to the physiologic range purchase 20mg pariet with visa; a decrease of reaction rate occurs as the pH goes dehydrogenase contains a bound zinc atom purchase pariet 20 mg with amex, from the physiologic range to a very basic range (Fig purchase pariet 20 mg otc. The shape of this and a serine side chain –OH and a histidine curve in the acid region usually reflects the ionization of specific functional groups nitrogen that participate in the reaction purchase pariet 20 mg on-line. The in the active site (or in the substrate) by the increase of pH, and the more general histidine pulls an H off the active site serine, formation of hydrogen bonds important for the overall conformation of the which pulls the H off of the substrate –OH enzyme. The loss of activity on the basic side usually reflects the inappropriate group, leaving the oxygen with a negative ionization of amino acid residues in the enzyme. The parietal cells of the stomach secrete HCl into the lumen of the stomach, resulting in a pH between 1 and 2. This strongly acidic environment is capable of irreversibly denaturing most proteins by protonating amino acids, thereby preventing the hydrogen bond formation necessary for tertiary structure. Many of the peptide bonds in proteins would not be accessible to digestive proteases unless the protein was denatured. Pepsin, a digestive protease present in the stomach, is an exceptional enzyme because its pH optimum is approximately 1. As denatured dietary proteins pass into the intestinal lumen, the pH of the gastric juice is raised above 6 by secretion of bicarbonate from the exocrine pancreas. At this higher pH, chymotrypsin and other proteases from the pancreas can act on the denatured proteins. The rate of the reaction increases as the pH increases from 6 to 7. The exact shape of the curve depends on the protonation state of active site amino acid residues or on the hydrogen bonding required for maintenance of three-dimen- sional structure in the enzyme. For the enzyme shown in the figure, the increase of reaction rate corresponds to deprotonation of the active site histidine. Other enzymes might have a lower pH maximum, a broader peak, or retain their activity in the basic side of the curve. Most human enzymes function optimally at a temperature of approximately 37 C. An increase of temperature from 0 C to 37 C increases the rate of the reac- tion by increasing the vibrational energy of the substrates. The maximum activity for most human enzymes occurs near 37 C because denaturation (loss of secondary and tertiary structure) occurs at higher temperatures. MECHANISM-BASED INHIBITORS Inhibitors are compounds that decrease the rate of an enzymatic reaction. Mecha- nism-based inhibitors mimic or participate in an intermediate step of the catalytic reaction. The term includes transition state analogs and compounds that can react irreversibly with functional groups in the active site. Covalent Inhibitors Dennis Veere resulted from inhibi- Covalent inhibitors form covalent or extremely tight bonds with functional groups tion of acetylcholinesterase. These functional groups are activated by their interac- cholinesterase cleaves the neurotransmitter tions with other amino acid residues, and are therefore far more likely to be targeted acetylcholine to acetate and choline in the by drugs and toxins than amino acid residues outside the active site. The lethal compound diisopropyl phosphofluoridate (DFP, or diisopropylfluo- 8. Malathion is metabolized in the liver to rophosphate) is an organophosphorus compound that served as a prototype for the a toxic derivative (malaoxon) that binds to development of the nerve gas Sarin and other organophosphorus toxins, such as the the active site serine in acetylcholinesterase insecticides malathion and parathion (Fig. DFP exerts its toxic effect by and other enzymes, an action similar to that of forming a covalent intermediate in the active site of acetylcholinesterase, thereby diisopropylfluorophosphate. As a result, preventing the enzyme from degrading the neurotransmitter acetylcholine. Once the acetylcholine accumulates and overstimulates covalent bond is formed, the inhibition by DFP is essentially irreversible, and activ- the autonomic nervous system (the involun- ity can only be recovered as new enzyme is synthesized. DFP also inhibits many tary nervous system, including heart, blood other enzymes that use serine for hydrolytic cleavage, but the inhibition is not as vessels, glands), thereby accounting for Den- lethal. Acetylcholine is also a neuro- transmitter for the somatic motor nervous that exerts its effect through the covalent acetylation of an active site serine in system, where its accumulation resulted in the enzyme prostaglandin endoperoxide synthase (cycloxygenase). Aspirin Dennis’s involuntary muscle twitching (mus- resembles a portion of the prostaglandin precursor that is a physiologic substrate cle fasciculations). Normal reaction of acetylcholinesterase Acetylcholine Choline Acetate O + + O H3 C O 2 CH2 N(CH3)3 HO CH2 CH2 N(CH3)3 + H3 O– O OH O 3 H2O OH Enz Ser Enz Ser Enz Ser B. Reaction with organophosphorus inhibitors CH O CH 3 3 H C O P –, H+ OH CH3 F CH3 O CH3 CH3 Enz Ser + H C O P CH3 O CH3 Enz Ser Fig.

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CHAPTER 1 / METABOLIC FUELS AND DIETARY COMPONENTS 11 and we lose weight order pariet 20 mg visa. Conversely cheap pariet 20mg visa, if we eat more food than we require for our Are Ivan Applebod and Ann energy needs pariet 20 mg discount, the excess fuel is stored (mainly in our adipose tissue) order pariet 20mg fast delivery, and we O’Rexia gaining or losing weight? When we draw on our adipose tissue to meet our energy needs pariet 20mg line, we lose approximately 1 lb whenever we expend approximately 3,500 calories more than we consume. In other words, if we eat 1,000 calories less than we expend per day, we will lose about 2 lb/week. Because the average individual’s food intake is only about 2,000 to 3,000 calories/day, eating one-third to one-half the normal amount will cause a person to lose weight rather slowly. Fad diets that promise a loss of weight much more rapid than this have no scientific merit. In fact, the rapid initial weight loss the fad dieter typically experiences is attributable largely to loss of body water. This loss of water occurs in part because muscle tissue pro- tein and liver glycogen are degraded rapidly to supply energy during the early phase of the diet. When muscle tissue (which is approximately 80% water) and glycogen (approximately 70% water) are broken down, this water is excreted from the body. DIETARY REQUIREMENTS Consumption > Expenditure In addition to supplying us with fuel and with general-purpose building blocks for biosynthesis, our diet also provides us with specific nutrients that we need to remain healthy. We must have a regular supply of vitamins and minerals and of the essential fatty acids and essential amino acids. Nutrients that the body requires in the diet only under certain conditions are called “conditionally essential. The RDA for a nutrient is the average daily dietary intake level necessary to meet the requirement of nearly all (97–98%) healthy individuals in a particular gender and life stage group. Life Caloric balance Consumption = Expenditure stage group is a certain age range or physiologic status (i. The RDA is intended to serve as a goal for intake by individuals. The AI is a recommended intake value that is used when not enough data are available to estab- lish an RDA. Carbohydrates No specific carbohydrates have been identified as dietary requirements. Carbohydrates can be synthesized from amino acids, and we can convert one type Malnutrition, the absence of an adequate intake of nutrients, occurs in the United States principally among children of families with incomes below the poverty level, the elderly, individuals whose diet is influenced by alcohol and drug usage, and those who make poor food choices. More than 13 million children in the Negative caloric balance United States live in families with incomes below the poverty level. Of these, approxi- Consumption < Expenditure mately 10% have clinical malnutrition, most often anemia resulting from inadequate iron Fig. A larger percentage have mild protein and energy malnutrition and exhibit growth retardation, sometimes as a result of parental neglect. Childhood malnutrition may also lead to learning failure and chronic illness later in life. A weight for age measurement is one of the best indicators of childhood malnourishment because it is easy to measure, and weight is one of the first parameters to change during malnutrition. Ivan Applebod’s weight is classi- The term kwashiorkor refers to a disease originally seen in African children suffering fied as obese. It is characterized by marked hypoalbuminemia, anemia, 704/70 in2 37. Ann O’Rexia is edema, pot belly, loss of hair, and other signs of tissue injury. Her BMI is 99 lb 704/67 used for prolonged protein–calorie malnutrition, particularly in young children. Applebod expends about 2,952 of carbohydrate to another. However, health problems are associated with the com- kcal/day and consumes 4,110. By plete elimination of carbohydrate from the diet, partly because a low-carbohydrate this calculation, he consumes 1,158 diet must contain higher amounts of fat to provide us with the energy we need. Therefore, she expends 1,294 more kcal/day than she consumes, so she is losing weight. Essential Fatty Acids Although most lipids required for cell structure, fuel storage, or hormone synthesis can be synthesized from carbohydrates or proteins, we need a minimal level of cer- tain dietary lipids for optimal health.

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