By M. Tragak. Alabama State University. 2018.

These studies show that obesity CHAPTER 33 / SYNTHESIS OF FATTY ACIDS generic cialis sublingual 20mg overnight delivery erectile dysfunction doctor, TRIACYLGLYCEROLS cialis sublingual 20 mg overnight delivery impotence pumps, AND THE MAJOR MEMBRANE LIPIDS 615 is an independent risk factor not only for heart attacks and strokes, but for the devel- opment of insulin resistance, type 2 diabetes mellitus, hypertension, and gallblad- der disease. Percy did not want to become overweight and decided to follow his new diet faithfully. Because Cora Nari’s lipid profile indicated an elevation in both serum triacylglycerols and LDL cholesterol, she was classified as having a com- bined hyperlipidemia. The dissimilarities in the lipid profiles of Cora and her two siblings, both of whom were experiencing anginal chest pain, is charac- teristic of the multigenic syndrome referred to as familial combined hyperlipi- demia (FCH). Approximately 1% of the North American population has FCH. It is the most common cause of coronary artery disease in the United States. In contrast to patients with familial hypercholesterolemia (FH), patients with FCH do not have fatty deposits within the skin or tendons (xanthomas) (see Chapter 34). In FCH, coronary artery disease usually appears by the fifth decade of life. Treatment of FCH includes restriction of dietary fat. Patients who do not respond adequately to dietary therapy are treated with antilipidemic drugs. Selection of the appropriate antilipidemic drugs depends on the specific phenotypic expression of the patient’s multigenic disease as manifest by their particular serum lipid profile. In Cora’s case, a decrease in both serum triacylglycerols and LDL cholesterol must be achieved. If possible, her serum HDL cholesterol level should also be raised to a level above 40 mg/dL. To accomplish these therapeutic goals, her physician initially prescribed fast- release nicotinic acid (niacin), because this agent has the potential to lower serum triacylglycerol levels and cause a reciprocal rise in serum HDL cholesterol levels, as well as to lower serum total and LDL cholesterol levels. The mechanisms sug- gested for niacin’s triacylglycerol-lowering action include enhancement of the action of LPL, inhibition of lipolysis in adipose tissue, and a decrease in esterifi- cation of triacylglycerols in the liver (see Table 34. The mechanism by which niacin lowers the serum total and LDL cholesterol levels is related to the decrease in hepatic production of VLDL. When the level of VLDL in the circulation decreases, the production of its daughter particles, IDL and LDL, also decreases. Cora found niacin’s side effects of flushing and itching to be intolerable, and the drug was discontinued. Pravastatin inhibits cholesterol synthesis by 22 Amniotic fluid inhibiting hydroxymethylglutaryl CoA (HMG-CoA) reductase, the rate-limiting 20 enzyme in the pathway (see Chapter 34). After 3 months of therapy, pravastatin 18 16 decreased Cora’s LDL cholesterol from a pretreatment level of 175 to 122 mg/dL 14 Phosphatidyl (still higher than the recommended treatment goal of 100 mg/dL or less in a patient choline 12 with established coronary artery disease). Her fasting serum triacylglycerol con- 10 centration was decreased from a pretreatment level of 280 to 178 mg/dL (a treat- 8 Sphingomyelin ment goal for serum triacylglycerol when the pretreatment level is less than 500 6 mg/dL has not been established). RDS is preventable if pre- Gestation (weeks) maturity can be avoided by appropriate management of high-risk preg- Fig. Before delivery, the obstetrician must attempt to predict and pos- choline and sphingomyelin in amniotic fluid. For example, estimation of fetal head Phosphatidylcholine is the major lipid in lung circumference by ultrasonography, monitoring for fetal arterial oxygen saturation, surfactant. The concentration of phosphatidyl- and determination of the ratio of the concentrations of phosphatidylcholine choline relative to sphingomyelin rises at 35 (lecithin) and that of sphingomyelin in the amniotic fluid may help to identify pre- weeks of gestation, indicating pulmonary mature infants who are predisposed to RDS (Fig. The administration of one dose of surfactant into the trachea of the premature infant immediately after birth may transiently improve respiratory function but does not improve overall mortality. In Colleen’s case, intensive therapy allowed her to survive this acute respiratory complication of prematurity. BIOCHEMICAL COMMENTS Biochemically, what makes people become obese? Obviously, the amount of fat an individual can store depends on the number of fat cells in the body and the amount of triacylglycerol each cell can accommodate. In obese individuals, both the number of fat cells and the size of the cells (i. To fill these stores, however, an individual must eat more than required to support the basal metabolic rate and physical activity. Fat cells begin to proliferate early in life, starting in the third trimester of gesta- tion. Proliferation essentially ceases before puberty, and thereafter fat cells change mainly in size. However, some increase in the number of fat cells can occur in adult- hood if preadipocytes are induced to proliferate by growth factors and changes in the nutritional state. Weight reduction results in a decrease in the size of fat cells rather than a decrease in number.

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For some enzyme-catalyzed reactions order cialis sublingual 20 mg with mastercard erectile dysfunction only at night, the transition state is a condi- transition state analogs are highly unstable tion in which bonds in the substrate are maximally strained purchase cialis sublingual 20mg with visa zyrtec causes erectile dysfunction. For other enzyme-cat- when not bound to the enzyme, and would have great difficulty making it from the alyzed reactions, the electronic configuration of the substrate becomes very strained digestive tract or injection site to the site of and unstable as it enters the transition state. Some of the approaches in drug the most unstable substrate configuration, and the condition in which the changing design that are being used to deal with the substrate molecule is most tightly bound to participating functional groups in the instability problem include: designing drugs enzyme. The difference in energy between the substrate and the transition state com- that are almost transition state analogs but plex is called the activation energy. Enzymes increase the rate of the reaction by decreasing this acti- tion state analog to design a complementary vation energy. They use various catalytic strategies, such as electronic stabilization of antibody. Once the transition state complex is formed, it can collapse back to substrates or Abzymes (catalytic antibodies) are decompose to form products. The enzyme does not change the initial energy level made as antibodies against analogs of the transition state complex. They of the substrates or the final energy level of the products. CATALYTIC MECHANISM OF CHYMOTRYPSIN to the active site of the enzyme in the transi- tion state. Consequently, they can act as artifi- The enzyme chymotrypsin provides a good example of the strategies and amino acid cial enzymes. For example, abzymes have side chains used by enzymes to lower the amount of activation energy required. Chy- been developed against analogs of the transi- motrypsin is a digestive enzyme released into the intestine that catalyzes the hydrol- tion state complex of cocaine esterase, the ysis of specific peptide bonds in denatured proteins. It is a member of the serine pro- enzyme that degrades cocaine in the body. In the overall hydrolysis reaction, an OH from water monthly injections of the abzyme drug can be used to rapidly destroy cocaine in the blood, is added to the carbonyl carbon of the peptide bond, and an H to the N, thereby cleav- thereby decreasing the dependence of ing the bond (Fig. The bond that is cleaved is called the scissile bond. The Reaction in the Absence of Enzyme In the reaction carried out in the absence of enzyme, the negatively charged Hydrolysis is the use of water to lyse (break) a bond. Proteolysis is hydroxyl group of water attacks the carbonyl carbon, which carries a partial posi- the hydrolysis of a peptide bond in tive charge. An unstable oxyanion tetrahedral transition state complex is formed in a protein, a reaction catalyzed by enzymes which the oxygen atom carries a full negative charge. The rate of the chemical reaction in the absence of chymotrypsin is slow because there are too few OH called proteases. CHAPTER 8 / ENZYMES AS CATALYSTS 121 molecules in H2O with enough energy to form the transition state complex and too Poly- few OH molecules colliding with the substrate at the right orientation. Catalytic Strategies in the Reaction Catalyzed R1 OH– + H+ R2 by Chymotrypsin H2O In the reaction catalyzed by chymotrypsin, the same oxyanion intermediate is chymotrypsin formed by using the hydoxyl group of a serine residue for the attack instead of a O H free hydroxyl anion. The rate of the chymotrypsin-catalyzed reaction is faster CH C OH + N CH because functional groups in the enzyme active site activate the attacking hydroxyl H group, stabilize the oxyanion transition state complexes, form a covalent intermedi- R1 R2 ate, and destabilize the leaving group. Chymotrypsin hydrolyzes certain cleavage of the peptide bond in the denatured substrate protein and formation of a peptide bonds in proteins. The scissile bond is covalent acyl-enzyme intermediate (Fig. The carbonyl carbon, which acyl-enzyme intermediate to release the remaining portion of the substrate protein carries a partial positive charge, is attacked by (Fig. The names of the catalytic strategies employed in the various a hydroxyl group from water. An unstable steps are in italics in the following paragraphs. SPECIFICITY OF BINDING TO CHYMOTRYPSIN electrons return to the carbonyl carbon, it becomes a carboxylic acid, and the remaining Chymotrypsin hydrolyzes the peptide bond on the carbonyl side of a phenylalanine, proton from water adds to the leaving group to tyrosine, or tryptophan in a denatured protein. The substrate recognition site consists form an amine. The substrate protein must be denatured to fit into the pocket and be held rigidly in place by glycines in the enzyme peptide backbone. Scissile bond specificity is also provided by the sub- sequent steps of the reaction, such as moving serine 195 into attacking position (proximity and orientation). FORMATION OF THE ACYL-ENZYME INTERMEDIATE In the stomach, gastric acid IN CHYMOTRYPSIN decreases the pH to 1 to 2 to dena- ture proteins through disruption of In the first stage of the reaction, the peptide bond of the denatured protein substrate hydrogen bonding. The protease in the stom- is cleaved as an active site serine hydroxyl group attacks the carbonyl carbon of the ach, pepsin, is a member of the aspartate pro- scissile bond (nucleophilic catalysis-a nucleophile is a chemical group that is tease superfamily, enzymes that use two attracted to the positively charged nucleus) (Fig. Aspartate and histi- aspartate residues in the active site for acid- dine cooperate in converting this hydroxyl group (with a partial negative charge on base catalysis of the peptide bond.

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Mortality Rates for Parkinson’s disease and Parkinsonism in Italy (1969–1987) buy discount cialis sublingual 20mg on-line tobacco causes erectile dysfunction. SG Diamond cialis sublingual 20mg on line erectile dysfunction pills wiki, CH Markham, MM Hoehn, FH McDowell, MD Muenter. An examination of male-female differences in progression and mortality of Parkinson’s disease. Epidemiologic and genetic character- istics of parkinsonism: a review. An epidemiological overview of amyotrophic lateral sclerosis, Parkinson’s disease, and dementia of the Alzheimer type. AH Rajput, WRG Gibb, XH Zhong, KS Shannak, S Kish, LG Chang, O Hornykiewicz. Dopa-responsive dystonia: pathological and biochemical observations in a case. Parkinsonism-dementia complex, an endemic disease on the island of Guam. Epidemiology of Parkinson’s disease in a Japanese city. Regional disparities in the annual prevalence rates of Parkinson’s disease in Canada. Evidence from a geographic comparison with multiple sclerosis. DE Lilienfeld, D Sekkor, S Simpson, D Perl, J Ehland, G. Parkinsonism death rates by race, sex and geography: a 1980’s update. AH Rajput, RJ Uitti, W Stern, W Laverty, K O’Donnell, D O’Donnell, WK Yuen, A Dua. Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson’s disease. Parkinson’s disease: a case-control study of occupational and environmental risk factors. W Koller, B Vetere-Overfield, C Gray, C Alexander, T Chin, J Dolezal, R Hassanein, C Tanner. CM Tanner, B Chen, W Wang, M Peng, Z Liu, X Liang, L Kao, DW Gilley, BS Schoenberg. Environmental factors in the etiology of Parkinson’s disease. JP Hubble, T Cao, RES Hassanein, JS Neuberger, WC Koller. Is Parkinson’s disease of early onset a separate disease entity? Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case- control study in Germany. Environmental factors and Parkinson’s disease: a case-control study in China. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. A case control study of smoking habits, dementia and other illnesses in idiopathic Parkinson’s disease. M Shiba, JH Bower, DM Maraganore, SK McDonnell, BJ Peterson, JE Ahlskog, DJ Schaid, WA Rocca. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. The premorbid personality of patients with Parkinson’s disease. Dopamine-related personality traits in Parkinson’s disease. Risk factors for Parkinson’s disease: the Leisure World Cohort Study. DM Morens, A Grandinetti, D Reed, LR White, GW Ross. Cigarette smoking and protection from Parkinson’s disease: False association or etiologic clue. MD Benedetti, JH Bower, DM Maraganore, SK McDonnell, BJ Peterson, JE Ahlskog, DJ Schaid, WA Rocca. Smoking, alcohol, and coffee consumption preceding Parkinson’s disease—a case-control study. Parkinson’s disease and its comorbid disorders: an analysis of Michigan mortality date, 1970 to 1990. Smoking in relation to the death of one million men and women. In: Epidemiologic Approaches to the Study of Cancer and Other Chronic Diseases.

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