SYLLABUS MBMB/CHEM/BCHM 451b 2013 This class meets from pm every Tuesday and Thursday in Room 1059 (Auditorium) LS III.

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1 1 SYLLABUS MBMB/CHEM/BCHM 451b 2013 This class meets from pm every Tuesday and Thursday in Room 1059 (Auditorium) LS III. FACULTY P. M. D. Hardwicke, Room 210W, Neckers "C" Wing, Tel ; , FAX, Web site, R. Weilbaecher, Room 215, Neckers "C" Wing Tel ; , FAX Web site,

2 2 OVERALL ORGANIZATION This class represents the second semester of a two-semester biochemistry course for senior undergraduates and graduate students. The class will be taught in two parts: Part I (Tuesday 13 th Jan - Tuesday 5 th Mar 2013) will be given by P. M. D. Hardwicke. Part II (Thursday 7 th Mar - Friday 3 rd May 2013) will be given by R. Weilbaecher. (Spring Break is Sat 9 th Mar - Sunday 17 th Mar.) TESTS AND EXAMS 1. The contributions of the two halves of the course will be equally weighted in the final grade. One half of the final grade will derive from testing on material from the first half of the course, and one half from testing of the material presented in the second half of the course. Thus, doing very well in one part of the course, but badly in the other will result in a poor grade: i.e., the student is expected to perform equally well in all aspects of the course. Scores are determined from the overall performance during the entire course (Part 1 plus Part 2). There will be three 1 hour Tests and one cumulative 2 hour Final Exam. The lowest scoring of the three Tests will be dropped from the final grade. The two Tests counted will each contribute 25% to the final grade, and the cumulative Final Exam will contribute 50%. AS A GENERAL POLICY, THERE WILL BE NO MAKE-UP EXAMINATIONS. DO NOT SCHEDULE INTERVIEWS FOR MEDICAL SCHOOL, GRADUATE SCHOOL, ETC, THAT CONFLICT WITH EXAM TIMES. NO EXCEPTIONS WILL BE MADE. AUDITS of the class must be arranged by consultation with the Instructors. WITHDRAWALS from the class must be made by the appropriate date (8 th week of class, plus 1 day). Friday Mar 15 th WITHDRAW in good time so that your GPA is not impacted adversely if you are doing poorly. A RETROACTIVE WITHDRAWAL MAY BE DIFFICULT TO GET. Please note that Incompletes are only given if: 1. The student already has a passing grade; AND 2. There is evidence of genuinely mitigating circumstances: e.g., serious illness, accidents, family crisis, etc. Incompletes will NOT be given solely to avoid a bad grade. Students are expected to be present for the start of class and present during the whole of the lecture period. Important announcements are often made at the start of the lecture.

3 3 Dates for Tests and Exam Test 1 Thursday 14 th Feb. At scheduled lecture time Room 1059 LSIII. On material presented from Tuesday 15 th Jan Tuesday 12 th Feb in Part 1 (Hardwicke). Test 2. Tuesday 2 nd April. At scheduled lecture time Room 1059 LSIII. On material presented from Tuesday 19 th Feb Thursday 28 th March (Hardwicke and Weilbaecher). Test 3 Thursday 2 nd May. At scheduled lecture time Room 1059 LSIII. On material presented from Thursday 4 th April Tuesday 30 th April in Part 2 (Weilbaecher). Final Exam Room 1059 LSIII Friday 10 th May at am. Covering all material from both parts of the course. ONLY ORDINARY CALCULATORS (MATH FUNCTIONS ONLY) CAN BE USED IN THE TESTS AND EXAMS. USING CALCULATORS ON CELL PHONES, SMART PHONES, BLACKBERRIES, ETC IS ABSOLUTELY FORBIDDEN. HAVING ANY OF THESE TURNED ON DURING AN EXAM WILL BE REGARDED AS CHEATING. Letter grading will be based on: A = % (inclusive) B = 80-89% (inclusive) C = 70-79% (inclusive D = 60-69% (inclusive) F 59% Resources: 1) Voet and Voet, 4 th Edition. 2) Lectures. 3) Notes on Web sites. Students will be issued a 4 digit number for the purpose of identifying their grades in lists posted on the Web Sites. Students who took 451a in the Fall of 2012 will retain the same ID numbers. Keep up - to - date with the course material as it is given. Work steadily through the Problem Sets. There can be a delay in response to an , as we have other duties. Do not postpone asking questions and consulting with us until just before a Test or Exam, particularly on the day of the exam, when we are making preparations and possibly unavailable. The last day of formal instruction is Friday 3 rd May.

4 4 PART 1 Hardwicke This part of 451b assumes that the student has successfully completed 451a. (451a and 451b should be taken in a, b sequence: see p. 173, Undergraduate Catalog.). Material from 451a will not be retaught. Notes, Problem Sets, Answers to Problem Sets, as well as Exam/Test Results for Hardwicke material will be posted at: This is a secure site. The User name and Password for access to it will be given in class at the beginning of the Semester. Do not send s requesting this information. Note down your 4 digit ID number once you have received it. Announcements will be posted on the Notice Board. Tests and exams will be on material covered in the lectures and posted on the Website, and reading related chapters in Voet and Voet. Work systematically through the Problem Sets in good time for the tests and exams. The First Exam (Hardwicke) will be on Topics (See Problem Set 1.) The Hardwicke part of the Second Exam will be on Topics (See Problem Set 2.) The Final Exam will cover all of the material.

5 5 TOPICS PROVISIONAL COURSE OUTLINE 1. Kinetics. First order processes, half-life, relaxation time. 2. Transition state, activation free energy, Arrhenius and Eyring equations. 3. Catalysis. Properties of catalysts. Lowering of activation free energy. Chapter Enzymes are catalysts. Active site. Substrate binding and catalytic sites. Cofactors (coenzymes, prosthetic groups, co-substrates). Lock and key model of Fischer. Proximity and orientation effects, strain, substrate deformation. Induced fit. Channeling. Non-covalent catalysis. Free energy profile. Transition state binds more tightly than substrate. Rate enhancement is proportional to K T* /K S. For catalysis, ΔG binding must not be more negative than the decrease in activation free energy. Role of entropy. Effective concentration. Rate limiting step. Chapters 13, 14 and Types of catalysis by enzymes. General acid catalysis, general base catalysis, concerted acid base catalysis. The Brønsted equations and coefficients. Importance of the imidazole group of histidine. Nucleophilic and electrophilic covalent catalysis. Some examples from the serine esterases. Cofactors for electrophilic catalysis. Metal ion catalysis. 6. Enzyme kinetics. Unisubstrate enzyme kinetics. Steady-state. 'Initial velocity'. Use of steady-state and initial velocity assumptions to derive the Michaelis-Menten equation. Chapter 14, 15 and Meanings and interpretations of K M, k cat and k cat /K M. The Haldane relation. Pre-steady state kinetics. Units of activity. International enzyme unit. Specific activity and its relation to k cat. Chapter Lineweaver - Burke and other data handling plots. 9. Effect of ph on enzyme catalyzed reaction rates. 10. Effect of temperature on enzyme catalyzed reaction rates. 11. Bisubstrate enzyme - catalyzed reactions. Chapter 14, pp Reversible (non-covalent) inhibitors. Substrate - like inhibitors, transition state analogues. Competitive, Non-competitive and Uncompetitive inhibition. Antimetabolites. Chapters 14 and Irreversible (covalent) inhibitors (chemical reagents, affinity agents, suicide substrates). Chapters 14, 15 and K M -type allosteric enzymes. Effects of positive and negative homotropic and heterotropic effector

6 6 15. V max -type allosteric enzymes. Effects of positive and negative homotropic and heterotropic effector 16. Regulatory enzymes. Regulation of metabolic pathways. Chapters 13, 16 and Isozymes FIRST EXAM 18. Oxidation-Reduction, Chapter High Energy Bonds, Chapter Properties of lipid aggregates. Detergents. Role of phospholipids and cholesterol. Biological membranes. Chapters 12 and Transport through membranes. Energetics of membrane transport. Effect of membrane potential. Ionophores. Chapter 12 and Kinetics and mechanisms of transport. Primary active transport. Secondary active transport. The proton-motive 'force' in mitochondria. Chapter 20. PART 2 Intermediary Metabolism and Metabolic Control. R. Weilbaecher. Provisional Course Outline of Topics 1. Introduction to Metabolism (Chapter 16). 2. Glycolysis (Chapter 17). The reactions of glycolysis; fermentations; metabolic regulation and control; metabolism of hexoses other than glucose. 3. Glycogen Metabolism (Chapter 18). Glycogen breakdown; glycogen synthesis; control of glycogen metabolism; glycogen storage diseases. 4. Signal Transduction* (Chapter 19). Hormones; heterotrimeric G proteins; tyrosine kinase-based signaling; the phosphoinositide cascade. 5. Citric Acid Cycle (Chapter 21). Metabolic sources of acetyl-coenzyme A; enzymes of the citric acid cycle; regulation of the citric acid cycle; the amphibolic nature of the citric acid cycle. 6. Electron Transport and Oxidative Phosphorylation (Chapter 22). The mitochondrion; electron transport; oxidative phosphorylation; control of ATP production. 7. Other Pathways of Carbohydrate Metabolism* (Chapter 23). Gluconeogenesis; the pentose phosphate pathway.

7 7 8. Lipid Metabolism (Chapter 25). Lipid digestion, absorption, and transport; fatty acid oxidation; ketone bodies; fatty acid biosynthesis; regulation of fatty acid metabolism; cholesterol metabolism. 9. Amino Acid Metabolism (Chapter 26). Amino acid deamination; the urea cycle; metabolic breakdown of individual amino acids; amino acids as biosynthetic precursors; amino acid biosynthesis. 10. Energy Metabolism: Integration and Organ Specialization (Chapter 27). Major pathways and strategies of energy metabolism; organ specialization; metabolic homeostasis regulation of appetite, energy expenditure, and body weight; metabolic adaptation. 11. Nucleotide Metabolism** (Chapter 28). Synthesis of purine ribonucleotides; synthesis of pyrimidine ribonucleotides; formation of deoxyribonucleotides; nucleotide degradation; biosynthesis of nucleotide coenzymes. * Subject to change in the sequence of topics covered. ** Subject to cancellation in the event of insufficient time. Important! The metabolism lecture notes from 2012 will be posted early and available to review well in advance. You are responsible for the content presented in the 2013 lecture notes, which may include more or less information than the 2012 notes. The 2013 lecture notes will be posted the evening before the lecture. The chapters in Voet & Voet 4 th edition are useful and recommended reading, especially if you have not taken a metabolism course previously. However, the exams will only cover the topics discussed in lecture. I strongly advise attending lectures. Topics will be discussed in greater detail during lecture than the posted lecture notes can provide. Website for lecture notes, prior exams, etc: This is a secure site. The User name and Password for access to it will be given in class at the beginning of the Semester. Do not send s requesting this information.