BCHM3082/3982

Medical and Metabolic Biochemistry

Course Information

These course outlines are a guide only. They are provided for the information of prospective students. Although every effort is made to ensure the most up to date information is provided, timetables often change each semester due to the availability of rooms and resources. Content (including lecture/practical topics, assessment and textbooks) is also regularly reviewed to ensure relevance and effective learning.

General Information
Beginning at the molecular level we explore the biochemical processes involved in the operation of cells, and how they are integrated in tissues, and in the whole human body in normal and diseased states.

Living systems are not possible without some means of catalysing and controlling the myriad reactions that occur in them. The ability to affect a metabolic system in a rational way requires a detailed understanding of the structure of enzymes and the chemical mechanisms of the reactions. Most drugs interfere in selective ways with enzymes or membrane proteins, such as receptors and ion channels. We will answer the following questions: How does aspirin work? How do the cholesterol-lowering drugs exert their effects? What do we need to understand to rationally treat sleeping sickness? How can we decrease the rate of blood clotting? What is the mechanism of the most effective "molecular attack" on HIV? The advanced stream will focus on the unique place NMR spectroscopy occupies for the non-invasive study of enzyme catalysed and membrane transport processes in whole cells.

Moving to the molecule-cellular interface we note that in clinical biochemistry much emphasis is given to chemotherapy of cancer and monitoring the progress of its treatment. The biochemical mechanisms and effects on cells of such "famous" drugs as Tamoxifen, will be described. Adoptive immunotherapy and the use of monoclonal antibodies have recently been supplemented with antisense oligonucleotides and gene therapy, all of which will be discussed.

A potent "molecular genetics" approach has emerged in the understanding and treatment of malaria. A modern understanding of the arrangement of DNA has provided comprehension of the molecular basis of some neurological disorders, and the genetic basis of many cancers. Specific examples will be discussed.

Finally, we will take a whole body approach to understanding metabolism and its regulation. Body energy stores and energy expenditure form part of a "balanced system" that is usually poised around a "set point"; pathological changes in this characteristic lead to obesity. The "metabolic syndrome" involves myriad hormones and cytokines in arcades within arcades of control loops. We will consider conditions such as lipoatrophy in which these control loops are morbidly affected.

The advanced steam will consider the modern theory of metabolic control analysis and how this enables us to make quantitative predictions of the changes in metabolite concentration, when a particular enzyme in a biochemical pathway is inhibited by a drug, or in an inborn error of metabolism.

Mrs Jill Johnston

Room: 410

Telephone: 9351 4248

E-mail: j.johnston@usyd.edu.au

Prof Philip Kuchel

Room: 655

Telephone: 9351 3709

E-mail: p.kuchel@mmb.usyd.edu.au

For BCHM3082
MBLG (1001 or 1901) and 12 CP of Intermediate BCHM/MBLG units (taken from MBLG2071/2971 or BCHM2071/2971 or BCHM2072/2972) or 42CP of Intermediate BMedSc units, including BMED2802 and BMED2804

For BCHM3982
MBLG (1001 or 1901) and Distinction in 12 CP of Intermediate BCHM/MBLG units (taken from MBLG2071/2971 or BCHM2071/2971 or BCHM2072/2972) or 42CP of Intermediate BMedSc units, with Distinction in BMED2802 and BMED2804.

1st Lecture: Monday 9:00am Merewether Lecture Theatre 1

2nd Lecture: Tuesday 9:00 am Merewether Lecture Theatre 1


Pratical: Even weeks, 10:00am - 1:00pm Monday/Tuesday OR 10:00am - 1:00pm Wednesday/Thursday, according to Student Timetable (classes start in Week 2)*
VENUE: All practical classes will be in the Biochemistry 3 lab, Level 4, Biochemistry and Microbiology building, G08

* Note that it is possible to leave practical class to attend a lecture in another subject, in which case the practical class will finish at 2:00pm.

Lehninger Principles of Biochemistry David L Nelson, Michael M Cox, 5th edition, Freeman, 2008

Reference texts

Frayn, K. N. Metabolic regulation : a human perspective (Blackwell Science, 2003)

Weinberg, R. The Biology of Cancer (Garland, 2005)

Mechanistic Basis of Enzyme-Targeted Drugs
C Collyer: 8 lectures

1. Enzyme inhibition and regulation
Case study: Prostaglandins and anti-inflammatory drugs, aspirin and Celebrex

2. Tight binding of transition state analogues, the drug dorzolamide for the management of glaucoma. (background for experiment 4)

3. Mimicry of substrate structural motifs in enzyme-targeted drugs.
Case study: The statin drugs and the treatment of hypercholesterolemia.

4. Covalent and irreversible inhibition of ornithine decarboxylase.
Case study: The treatment of parasites and African sleeping sickness

5. Drugs which covalently attach to cofactors, finisteride and isoniazid.

6. Non-covalent and non-reversible binding of hirudin to thrombin
Case study: Lepuriden and thrombosis

7. Conformational changes induced by non-competitive drugs
Case study: HIV reverse transcriptase and non-nucleoside drugs.

8. Enzymatic mechanisms and inhibitory mechanisms, the discovery of TAMIFLU

Strategies for Treating Cancer (BCHM3082)
R Christopherson: 3 lectures

1. Combination chemotherapy. Treatment of acute lymphoblastic leukaemia (ALL) with mercaptopurine, prednisone, vincristine, methotrexate and cyclophosphamide. Multiple sites of action of methotrexate.

2. Mechanisms of anticancer drugs: fludarabine, taxol, camptothecin, glivec, iressa, tamoxifen and aromatase inhibitors.

3. Adoptive immunotherapy and 'engineered' antibodies. Using the body's immune cells to fight cancer, tumour infiltrating lymphocytes (TILs). Mechanisms of therapeutic antibodies that interact with particular surface molecules on cancer cells.

The Molecular Biology of Disease (BCHM3082)
D Hancock: 5 lectures

1. The genetic response to malaria: It has been estimated that malaria may have been responsible for the deaths of half the people who ever lived! It has had such an impact on survival rates in equatorial regions of the world that certain mutations have persisted, despite being lethal as the homozygote. This lecture will examine the various mutations, how they have increased the survival of the heterozygote and recent directions in malarial research to combat this massive killer.

2. Dynamic Mutations and Trinucleotide Repeats: A number of neurological disorders have been recently found to be the result of dynamic mutations, whereby the phenotype is displayed to greater extent with each generation. The relationship between these mutations and the pathology of the disorder will be examined in this lecture and possible mechanisms to explain the pattern of transmission of the mutation.

3-5. These three lectures will examine cancer at a molecular level, the role of tumour suppressors, oncogenes and the genetic basis for the predispostion of some individuals to certain forms of cancer. The lecture will focus on two cancers as examples: breast cancer and colorectal cancer.

Whole Body Energy Homeostatis: Diabetes and Adiposity
G Denyer 8 lectures

This section of the course will cover the topics described below within the context of recently published research. Each lecture will be based on one or two research journal publications from 2009 with particular emphasis on the techniques used and the results obtained. The background information necessary to understand the research papers will be explained both within the lectures and with the use of online resources.

The topics covered include (but are not limited to):

The concept of the “Weight Set Point.
The regulation of whole body energy expenditure.
Mechanisms of efficiency/inefficiency in fuel oxidation.
Factors controlling food intake. Integration of anorexigenic and orexigenic signals.
Neuroendrocrine regulation of appetite – messages from the periphery.
Role of intestinal signals (gut hormones) in food intake.
The consequences of weight (fat) gain. Obesity and its consequences.
The characteristics of small and large adipocytes.
Hormone production from adipocytes (adipokines and their effects).
Glucose intolerance and insulin resistance.
The metabolic syndrome.
Adipose tissue biology: the role and functions of white adipose tissue and adipocytes.
Adipoctye differentiation growth and development.
Manipulating adipose tissue: Fat transplantation, liposuction, lipodystrophies.
Manipulating adipocytes: transgenic animals, knock-outs, targeted over expression.

NMR spectroscopy of biochemical systems (BCHM3982)
P Kuchel: 8 lectures

Nuclear magnetic resonance (NMR) spectroscopy is a high-tech analytical-(bio)chemical method that has had major impact in both experimental science and diagnostic medicine. NMR spectroscopy is an analytical mainstay of organic chemistry and biochemistry and its underlying physics is the basis of magnetic resonance imaging; this is now widely used in medical diagnosis at the anatomical level. NMR enables the measurement of amounts of metabolites and rates of reactions in living cells, tissues and in whole animals.

Each lecture in the series will address three themes:

(i) Fundamental concepts of NMR. This aspect will be presented to a level sufficient to read articles in popular scientific magazines and to pose questions that are amenable to experimental testing using the methods. This will link in with a practical experiment on the measurement of water transport across red blood cell membranes.
(ii) Biochemical concepts that have been informed by these techniques; and how this information is used in scientific experiments and medical diagnosis.
(iii) Concepts of the molecular basis of selected diseases and how biochemistry and the various forms of high-tech in vivo analysis can lead to disease diagnosis.

1. Introduction; why NMR is useful for studying living systems; electromagnetic spectra; the layout of a modern NMR spectrometer; the magnet; the probe; the computer; model of a spinning magnetic nucleus; the Larmor equation.

2. Quantum mechanical description of NMR; how energy is added to precessing nuclei; Planck’s equation; which nuclides can be studied by NMR?; relaxation of high energy states; relaxation time peak broadening; magnetic saturation; spectral line width; the five features of the NMR spectrum; chemical shift; standard reference compounds.

3. Factors that affect chemical shift; rigorous definition; diamagnetic and paramagnetic effects; ring-current shift; pH effects; examples in proteins.

4. Spectral acquisition; the free induction decay (FID); pulsed NMR; the Fourier transform; basis of spectral line multiplicity; binomial theorem; coupling constants and their range of values; dihedral angles; nomenclature.

5. Peak assignment in spectra; spin decoupling; schematic representation of multiple coupling; heteronuclear coupling; coupling with spin >1/2 nuclei; NMR line shape.

6. Measuring T1; multipulse NMR; the spin echo; measuring T2; measuring translational diffusion with pulsed field gradient NMR.

7. 13C NMR of cells; shift reference; range of chemical shifts; 13C-13C coupling; isotope effects; examples of use with cancer cells.

8. 31P NMR of cells; general overview; peak assignment; pH determination; studies of metabolism; measuring metal ion concentration; saturation transfer to measure reaction rates in living cells on the sub-second time scale.

P1 Structural Analysis of Proteins by Use of Molecular Graphics (1.5 weeks)
P2 Analysis of an inherited Disease using the Yeast Two-Hybrid System (1.5 weeks)
P3 The Diagnosis of Metabolic Disease: Measurement of Hormone and Metabolite Concentrations in Blood Samples (1 week) (BCHM3082)
P4 Adenosine Deaminase Deficiency in Human Lymphocytes (2 weeks) (BCHM3082)
P5 Biological Problem-Solving using NMR (3 weeks) (BCHM3982)

Lecture course: 50% (end-of-semester examination)
Practical course: 50% (25% in-semester practical work, 25% end-of-semester examination)