Examination III PHRM 836 Biochemistry for Pharmaceutical Sciences II December 12, 2012

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1 Examination III PHRM 836 Biochemistry for Pharmaceutical Sciences II December 12, 2012 Name: Instructions PHRM 836 Exam III Check your exam to make certain that it has 9 pages including this cover page. Ask for a new copy of the exam if you are missing any pages. 2. Use a pencil for filling in the answer sheet for computerized grading. 3. Write your name on the line above (this page) AND on the answer sheet for computerized grading. Fill in the circles underneath where you write your name. Do NOT place any identification numbers anywhere on this exam or on the answer sheet. Also, do NOT fill in anything for section number and do NOT write your name on the back of the exam. 4. Your answers to problems 1 through 25 will be graded by computer. All computer-graded questions will be worth three points each. Put your answers for these problems on the answer sheet and fill in the appropriate circle using a pencil. It is your responsibility to be certain that the answers for these problems are correctly marked on the answer sheet at the time you hand in your completed exam. You are strongly encouraged to double check this at the time you submit the answer sheet, as no points will be given for having mistakenly marked your answer sheet. The computer grading answer sheets will not be returned to the students, so you are encouraged to record your answers to the computer-graded questions on this exam as well as on the answer sheet. However, the computerized grading of your answers to these questions will be done solely on the basis of the optically scanned answer sheet, not on what is recorded on your exam. The course policy is that there will be no re-grading of the computer answer sheets. 5. Examination problems 26 through 31 are to be answered with short answers, brief essays, or drawings. Put your answer to each of these directly on this exam, in the space provided below each of these questions. 6. After completing your exam, both the exam and the answer sheet must be submitted for grading and both must be identified only with your name. 7. This is a closed-book, closed-notes exam. Calculators and electronic devices of any kind are not allowed to be used during this exam. Any electronic device that is not in a backpack, bookbag, purse, pocket, etc, will be considered to be in use, so put away all electronic devices including cell phones and calculators. Anyone observed to be using a calculator, any book, handouts, notes, printed or handwritten material of any kind, or the exam or answer sheet of any other student will be considered to have committed an act of academic dishonesty. Students that do so will not be allowed to complete the exam and will be given a zero for this exam. Also remember that the first instance of academic dishonesty also results in a grade of "F" in this course and reporting this episode to the Pharmacy Dean and the Dean of Students office.

2 PHRM 836 Exam III - 2 MULTIPLE CHOICE. For problems 1 to 25, select from the list immediately following each question the single most correct choice to complete the statement, solve the problem, or answer the question. Mark that answer on your answer sheet. [3 points each] 1. One way in which ketone bodies are very similar to fatty acids is that both of them are able to cross the blood-brain barrier deoligomerized by β-oxidation deoligomerized to produce acetyl-coa for generation of ATP via the tricarboxylic acid cycle oxidized in the peroxisomes important sources of energy for hepatic gluconeogenesis during fasting able to be used as carbon sources for gluconeogenesis during fasting important components of triglycerides and phospholipids 2. One way that ketone bodies are very dissimilar from fatty acids is that ketone bodies are much more water soluble than fatty acids are made in the liver, while fatty acids are never made in the liver are consumed by all tissues (except erythrocytes) while fatty acids cannot be used by the liver are oxidized for energy only by the liver and brain, while fatty acids can be oxidized for energy by all tissues, except erythrocytes. can be used for as a carbon source gluconeogenesis while fatty acids cannot be used as a carbon source for gluconeogenesis 3. How does the regulation of fatty acid metabolism ensure that when fatty acid synthesis is occurring, fatty acid oxidation is shut off? Acyl Co-A carboxylase is shut off during fatty acid synthesis and this also shuts off fatty acid oxidation by inhibiting the synthesis of acyl-coa synthetase. Fatty acid synthase produces palmitoylcoa which inhibits acyl-coa synthetase Acyl Co-A carboxylase makes malonyl Co-A during synthesis of fatty acids and malonyl CoA inhibits carnitine palmitoyltransferase I. Acetyl CoA, which is abundant during fatty acid synthesis, inhibits acyl-coa synthetase Citrate, which is abundant during fatty acid synthesis, inhibits carnitine palmitoyltransferase I 4. Triglycerides that are ingested are absorbed as triglycerides from the lumen of the intestine and travel to the liver via the portal vein hydrolyzed in the lumen, then the parts are absorbed and reassembled into triglycerides by the intestinal cells which then secretes them to the blood where they travel to the liver via the portal vein. absorbed as triglycerides from the lumen of the intestine and are then secreted into the lymph hydrolyzed in the lumen, then the parts are absorbed and reassembled into triglycerides by the intestinal cells which then secrete them into the lymph as aggregates consisting almost completely of lipids hydrolyzed in the lumen, then the parts are absorbed by the intestinal cells which then secrete the free fatty acids bound to proteins into the lymph.

3 PHRM 836 Exam III Peroxisomes have an important role in fatty acid metabolism because all fatty acid synthesis and oxidation occurs in peroxisomes all fatty acid oxidation occurs in peroxisomes all fatty acid synthesis occurs in the peroxisomes all fatty acid oxidations except for some beta oxidation occurs in persoxisomes all fatty acid desaturation, such as that needed for making polyunsaturated fatty acids, occurs in the peroxisomes all eicosanoid lipid production occurs via fatty acid peroxidation in the peroxisomes 6. A ganglioside is a class of steroid hormones a type of pigment molecule a member of a class of molecules that consists of neurotransmitters and neuro-hormones a long branched chain fatty acid made in plants and normally attached to the ring structure in chlorophyll a sphingolipid that contains N-acetylneuraminic acid or another sialic acid any glycosylated sphingolipid a class of antibiotics that inhibit ribosome function a peroxidated derivative of a 20 carbon long fatty acid that acts by binding to G-protein coupled receptors 7. The primary reason cells need cholesterol is for synthesis of steroid hormones modulating the synthesis of fatty acids modulating the synthesis of polyunsaturated fatty acids modulating the level of peroxisomes in cells decreasing the fluidity of the cell s plasma membrane transport of triglycerides in the blood modulating the synthesis of lipoproteins in the liver 8. The primary function of bile acids (also known as bile salts) is to decrease the fluidity of the cell s plasma membrane to increase the fluidity of cell s plasma membrane to emulsify lipids and hydrophobic nutrients in the intestinal lumen to emulsify indigestible fibers in the intestinal lumen to facilitate antiviral surveillance by immune cells in the intestine to emulsify bilirubin breakdown products in the intestinal lumen so they can be absorbed and then excreted in the urine to make receptor mediated endocytosis possible to facilitate assembly of VLDL in the endoplasmic reticulum of hepatic cells

4 PHRM 836 Exam III Polyunsaturated fatty acids are important because they are essential in sterol biosynthesis are essential in sphingolipid biosynthesis are required for cells to increase the fluidity of their membranes are required for cells to decrease the fluidity of their membranes are key regulators of ketone body synthesis 10. The initial product of pathway of prostaglandin synthesis is thromboxane A 5-HPETE 5-HETE Leukotriene A prostaglandin E prostaglandin G prostaglandin I 11. In thrombosis, prostacyclin inhibits platelet activation stimulates platelet activation simulates thromboxane synthesis inhibits thromboxane synthesis slows thrombosis by inhibiting prostaglandin synthesis slows thrombosis by inhibiting thromboxane synthesis 12. Anti-inflammatory steroids act on eicosanoid metabolism by inhibiting thromboxane synthase lipid peroxidase cyclooxygenase phospholipase C phospholipase A 2 leukotriene binding to its receptors prostaglandin binding to its receptor catabolism of prostaglandins 13. Copper is essential for what aspect of iron metabolism? reducing iron in the intestinal lumen oxidizing iron in the intestinal lumen oxidizing iron in cells and serum inserting iron into protoporphyrin IX to make heme transporting iron across membranes

5 14. Hydroxylation of aromatic amino acids uses what coenzyme? PHRM 836 Exam III - 5 tetrahydrofolate tetrahydrobiopterin pyridoxal phosphate vitamin B 12 biotin thiamine NAD + lipoamide 15. Which amino acids are conditionally essential in humans? alanine, glutamate, and aspartate arginine, lysine, and histidine phenylalanine and tryptophan phenylalanine, tyrosine, and tryptophan phenylalanine and methionine tyrosine and cysteine arginine, tyrosine, and cysteine arginine, methionine, and cysteine arginine, methionine, and phenylalanine 16. Ornithine is made de novo from citrulline and is essential for the synthesis of urea made de novo from arginine and is essential for the synthesis of urea made de novo from glutamate and is essential for the synthesis of citrulline, arginine, and urea made de novo from succinyl-coa and is essential for the synthesis of porphyrins made de novo from glutamine and is essential for the synthesis of urea made de novo from aspartate and ammonia during the synthesis of urea 17. Jaundiced individuals have abnormally colored skin due to the presence of elevated levels of biliverdin bilirubin protoporphyrin IX uroporphyrinogin III coproporphyrinogen I protoporphyrinogen IX heme hydroxymethylbilane delta-aminolevulinate urobilin

6 18. Porphyria is an PHRM 836 Exam III - 6 inherited deficiency of an enzyme involved in heme catabolism inherited deficiency of an enzyme involved in heme biosynthesis inherited deficiency of an enzyme or transport protein involved in iron metabolism inherited deficiency of an enzyme involved in sphingolipid catabolism inherited deficiency of an enzyme involved in cholesterol catabolism inherited deficiency of an enzyme involved in purine catabolism inherited deficiency of an enzyme involved in purine biosynthesis 19. In normal healthy people, iron in serum is predominantly free (not bound to anything) bound to ferritin bound to serum albumin (as heme) bound in hemoglobin bound to transferrin bound to ceruloplasmin bound to hephaestin 20. The pain suffered by patients with gout is caused by liver cell toxicity peripheral neuropathy that causes hypersensitivity of pain nerves chronic hyperglycemia hyperuremia hyperuricacdiemia sodium urate crystals in the joints inadequate tetrahydrobiopterin levels in the brain severe deficiency of purines deficiency of deoxynucleotides 21. ADA deficiency causes ADA-SCID because of elevated purine biosynthesis increases uric acid levels elevated adenosine inhibits GTP synthesis and causes deficiency of tetrahydrobiopterin elevated deoxyadenosine causes accumulation of datp which inhibits ribonuclotide reductase elevated adenosine inhibits pyrimidine biosynthesis and causes deficiency of dttp elevated AMP causes activation of AMPK elevated metabolites tie up all the folates causing inadequate purine and dtmp synthesis 22. How does metabolic syndrome progress to become type 2 diabetes mellitus? insulin levels become inadequate to control blood sugar levels glucose levels become elevated all the time insulin levels continually increase no progression is needed, since individuals with metabolic syndrome are already diabetic when all the pancreatic beta cells have died the patient becomes diabetic

7 23. A major difference between type 1 and type 2 diabetes is PHRM 836 Exam III - 7 only type 1 is treated with insulin injections only type 1 has a risk of hyperglycemia type 2 can be treated with oral anti-diabetes drugs in combination with exercise, diet, and weight loss while type 1 is not responsive to such treatment only type 2 has a risk of hypoglycemia type 2 never occurs in children type 1 only occurs in children the rate of occurrence of type 2 is declining while the rate of type 1 is increasing type 1 can be treated with oral anti-diabetes drugs in combination with exercise, diet, and weight loss while type 2 is not responsive to such treatment 24. Gestational diabetes is caused by eating too much while pregnant physical damage to the maternal pancreas as a result of fetal development increased demand for blood glucose due to fetal metabolic needs placental hormones interferes with insulin receptor function negative nitrogen balance adversely affects gluconeogenesis by the mother 25. Cachexia associated with cancer is a strongly catabolic state caused by endocrine hormones secreted by most tumors a strongly catabolic state caused by metabolic disruptions due to increased demand for nutrients by the tumor increased appetite caused by metabolic demands of the tumor and resulting weight gain by the patient a form of metabolic syndrome caused by the tumor and its impact on metabolism strongly decreased appetite and physical wasting and weakness caused by stress, metabolic demands of the tumor, and elevated levels of cytokines produced by immune cells in response to host-tumor interactions ESSAY PROBLEMS. Write your answers to problems 26 to 31 in the space immediately below each problem. 26. [2 points] What are the indications that make up metabolic syndrome?

8 PHRM 836 Exam III [6 points] Concerning the thiolazolidine class of anti-diabetic drugs, also known as glitazones: A. [3 points] These drugs bind to and affect the function of what target molecule? Also, how do they affect the function of this target molecule (not the mechanism, but what is the functional change caused by the binding)? B. [3 points] What is the pharmacologic/physiologic outcome of these drugs (in terms of serum lipid levels) that produces the anti-diabetic effect? Why does this change in serum lipid levels have an anti-diabetic effect? 28. [3 points] How does obesity cause insulin resistance? 29. [5 points] Bisguanide drugs such as metformin are used as oral anti-diabetic drugs. What is the molecular mechanism by with these drugs produce their impact on diabetes?

9 PHRM 836 Exam III [4 points] In one-carbon metabolism, there is a methionine-dependent component and a methionineindependent component. For each of these two components of one-carbon metabolism: A. Describe the molecule or class of molecules primarily involved in each component which has as its primary role in metabolism the carrying and donating of a one-carbon unit. Methionine-dependent: Methionine-independent: B. Provide an example of a molecule that has a one-carbon unit donated to it by the one-carbon carrier molecule described in part A. Methionine-dependent: Methionine-independent: 31. [5 points] Concerning Lesch-Nyhan syndrome: A. [2 points] Briefly describe the molecular abnormality that is the cause of this syndrome. B. [1 point] What metabolic pathway is primarily affected by your answer to part A? C. [2 points] Why does this syndrome produce some indications and symptoms that are similar to gout? Your answer must explain the molecular mechanism going all the way back to your answers in parts A and B.