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.

Course Overview

General Information
Beginning at the molecular level we explore the biochemical processes involved in the operation of cells, and how they are integrated 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 questions such as: How does aspirin work? How do the cholesterol-lowering drugs exert their effects? How can we decrease the rate of blood clotting? What is the mechanism of an effective ‘molecular attack’ on HIV?

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., along with the ‘newer’ strategies such as adoptive immunotherapy and the use of monoclonal antibodies.

We will look at the ‘molecular genetics’ approach to the understanding of conditions such as malaria, some neurological disorders and some cancers, such as breast and colorectal.

Finally, we will take a whole body approach to understanding metabolism and its regulation: how body energy stores and energy expenditure form part of a ‘balanced system’ and the pathological changes in this characteristic which lead to obesity; the ‘metabolic syndrome’ which involves myriad hormones and cytokines in arcades within arcades of control loops.

The advanced stream will focus on the unique role of NMR spectroscopy in the non-invasive study of metabolic processes, including enzyme-catalysed and membrane transport processes, in whole cells.

Course Coordinator Contact Details

Mrs Jill Johnston

Room: 410

Telephone: 9351 4248

E-mail: jill.johnston@sydney.edu.au

Assoc Prof Gareth Denyer

Room: 774

Telephone: 9351 3466

Fax: 9351 4726

E-mail: gareth.denyer@sydney.edu.au

Prerequisites

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 (taken from BMED2801, BMED2802, BMED2803, BMED2804, BMED2805, BMED2806, BMED2807, BMED2808, but including BMED2802 and BMED2804)] OR [18CP of intermediate BMED units (taken from BMED2401, BMED2402, BMED2403, BMED2404,BMED2405, BMED2406, but including BMED2401 and BMED2405) and 6CP of Intermediate BCHM/MBLG units (taken from MBLG2071/2971 or BCHM2071/2971)

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 (taken from BMED2801, BMED2802, BMED2803, BMED2804, BMED2805, BMED2806, BMED2807, BMED2808, with Distinction in BMED2802 and BMED2804)] OR [18CP of intermediate BMED units (taken from BMED2401, BMED2402, BMED2403, BMED2404, BMED2405, BMED2406, with Distinction in BMED2401 or BMED2405) and 6CP of Intermediate BCHM/MBLG units (taken from MBLG2071/2971 or BCHM2071/2971) with Distinction in MBLG2071/2971 or BCHM2071/2971

Timetable

1st Lecture: Monday 9:00am-10:00am, New Law Lecture Theatre 101

2nd Lecture: Tuesday 9:00am-10:00am, Chemistry Lecture Theatre 3

Practical Class Times and Venues

TIMES: Even weeks, 10:00am - 1:00pm Monday/Tuesday OR Wednesday/Thursday 10:00am - 1:00pm, 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 the practical class to attend a lecture in another subject, in which case the practical class will finish at 2:00pm.

Textbooks

Devlin T Textbook of Biochemistry With Clinical Correlations 7th edition. Wiley 2011.

Reference texts

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

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

Lecture Outlines

Lecturer Course section
SA Dr Sandro Ataide/Assoc Prof Charles Collyer Mechanistic Basis of Enzyme-Targeted Drugs
RIC Prof Richard Christopherson Clinical Biochemistry
MH Dr Markus Hofer Molecular Biology of Disease
GSD Assoc Prof Gareth Denyer Whole body Energy Homeostasis: Diabetes and Adiposity
AK RG Dr Ann Kwan,Dr Roland Gamsjaeger BCHM3982
NMR spectroscopy of biochemical systems

Mechanistic Basis of Enzyme-Targeted Drugs
S Ataide & 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: 4 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.

3-4. 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)
M Hofer: 4 lectures


This section will look at the role of gene mutations in human diseases. By looking at specific disorders, we will discuss how mutations can be either protective or causal of diseases:
1 Malaria as a positive selector of genetic mutations: Malaria is a major cause of death in equatorial regions of the world. Despite having a negative impact on key metabolic processes, certain genetic mutations persist in areas in which Malaria is endemic. These mutations confer resistance to Plasmodium, the cause of Malaria, and this lecture will examine how the various mutations have increased the survival of the heterozygote. The lecture will also highlight recent directions in malarial research.

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

3-4 Genetic mutations in brain tumours: Here we will look at genetic causes leading to the development of malignant tumours focussing on brain tumours in children and adults. Despite significant advances in the therapy of many malignant tumours, brain tumours still have a very poor prognosis. However, recent advances in detecting and interpreting genetic and epigenetic changes in these tumours has given us a better understanding of their biology and has led to improved treatment. A focus of this lecture will be on the molecular techniques used in modern diagnostic pathology.

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


This section of the course will cover the topics of obesity and diabetes by reflecting on some selected, recently-published research papers. Each lecture will be based on one or two publications from the last year but the emphasis will be on giving students confidence in their ability to give their own opinion on recent research. The background information necessary to understand the strategies and techniques used in each study will be explained both within the lectures and with the use of online resources.

The topics which may be 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 signalsl; neuroendrocrine regulation of appetite – messages from the periphery
  • Brown adipose tissue and its role in human energy metabolism
  • The role of gut microbes in the cause and effects of obesity
  • The consequences of weight (fat) gain The link between obesity and disease. Hormone production from adipocytes (adipokines and their effects). The characteristics of small and large adipocytes . Interactions between adipocytes and the immune system in obesity
  • Glucose intolerance, Insulin resistance and 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 overexpression

NMR spectroscopy of biochemical systems (BCHM3982)
A. Kwan, R.Gamsjaeger: 6 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.

Practical Classes

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 Characterisation of Metabolic Profile of Adipocytes (2 weeks) (BCHM3082)
P4 Biological Problem-Solving using NMR (3 weeks) (BCHM3982)

Assessment

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