BCH 2022: Metabolic Basis of Human Diseases

Biochemistry and Molecular Biology home Awards and Fellowships Research Phd Program Honours Teaching People Vacation Scholarships

• Coordinator: A/Prof Janet Macaulay
• 6 points
• Monash handbook

A general outline of cellular metabolism is provided, including how energy is produced and used by living organisms. The material presented will illustrate normal human metabolic pathways and their dysfunction in various human diseases and conditions including diabetes, alcoholism, starvation, glycogen storage diseases and juvenile developmental problems. The biochemical basis of hormonal regulation and nutrition, in both famine and disease, is presented. The connection between cellular metabolism and many disease states induced by mutations or deficiencies of critical enzymes in the cell's metabolic pathways is explored.

Lecturing staff

A/Prof Janet Macaulay	Dr Alfons Lawen	Prof Mibel Aguilar	Dr Peter Boag

Organisation of the Unit

BCH2022 consists of 3 lectures per week and one 3 hour practical or small group session per week.

Practical/small teaching group classes are an integral part of BCH2022 and will reinforce concepts from lectures. The specific objectives of the practical/small group teaching program are to enable students to develop problem solving skills through the evaluation of biochemical data, develop skills in the presentation of data and scientific ideas both verbally and in writing, and to provide students with an understanding and hands-on experience of the basic principles of:

1. general biochemical concepts,
2. the applications of radioisotopes in biochemistry,
3. metabolism and its regulation.

The activities include laboratory exercises, computer exercises, oral presentations and case studies.

Topics covered

1. Metabolic Release of Energy: The Body's Power Supply

Introduction to Metabolism: what the cell needs to survive

• General outline of metabolism. The supply of nutrients to living organisms. Autotrophs and heterotrophs. Interconversion of biopolymers, simple intermediate molecules and inorganic compounds. The requirement for cellular energy.

Biological Oxidation: how the cell produces its energy

• Chemical equilibria and changes in free energy. Meaning and use of standard free energy change in cellular reactions. Favourable, unfavourable and coupled reactions.
• Chemistry and reactions of ATP, NAD + and FAD. Group transfer and electron transfer reactions.
• Principles of electron transport and oxidative phosphorylation. Mitochondria, electron carriers, respiratory complexes, redox reactions. Development and consequences of proton gradients. ATP production, control of oxidative phosphorylation. Respiratory control, coupling and uncoupling of mitochondria, brown fat mitochondria, respiratory and oxidative phosphorylation inhibitors. Energy yields. Electron transport in non-mitochondrial systems.

Tricarboxylic Acid Cycle: the energy-harnessing cycle

• Central role of cycle in aerobic metabolism.
• Reactions involved in the oxidation of acetyl-CoA, reduction of electron carriers, energy yields, no net synthesis of oxaloacetate from acetyl-CoA. Other functions of the cycle, replenishment pathways. Sources of acetyl-CoA.

Formation of Acetyl-CoA by Oxidation of Dietary Carbohydrate

• The digestion and fate of dietary starch in mammals. The glycolytic pathway for conversion of glucose to pyruvate. Anaerobic production of lactate/ethanol, oxygen dependent conversion of pyruvate to acetyl-CoA. Mobilisation of glycogen, other feeder pathways for glycolysis. Energetics of carbohydrate oxidation.

Formation of Acetyl-CoA by Oxidation of Dietary Lipid

• Structure, properties and functions of fatty acids, triglycerides, glycerol based phospholipids, sterols. Digestion, absorption and storage of triglycerides. Mobilisation and metabolism of fats in the liver, adipose tissue and muscle. Glycerol metabolism. Transportation of free fatty acids into mitochondria, reactions for the conversion of saturated and unsaturated fatty acids to acetyl-CoA. Fate of acetyl-CoA including ketone body formation. Energetics of triglyceride oxidation.

2. Biosynthesis of Carbohydrates and Lipids

Biosynthesis of Carbohydrates: gluconeogenesis and glycogen synthesis

• The need for gluconeogenesis; tissues involved and substrates. Gluconeogenesis from lactate and pyruvate; enzymes of bypass reactions; Cori cycle. Amino acids as substrates for gluconeogenesis.
• Relationship of gluconeogenesis and glycolysis; some basic concepts in regard to regulation.
• Glycogen synthesis; enzymes involved, relationship to glycogenolysis, glycogen storage diseases.

Biosynthesis of Lipids

• Overview of lipid synthesis. Biosynthesis of fatty acids. Fatty acid synthase complex. Formation of malonyl CoA. Synthesis of palmitic acid. Palmitic acid as precursor of higher and unsaturated fatty acids.
• Cellular generation of NADPH required for lipid synthesis. The pentose phosphate pathway.
• Mechanisms of chain elongation and desaturation of fatty acids. Formation of triacylglycerols. Synthesis of triacylglycerol 3 phosphate and fattyacyl CoA.
• Synthesis of phospholipids, formation of phosphatidyl ethanolamine and phosphatidyl choline from diacylglycerol.

3. Amino Acid Metabolism

• Nitrogen cycle, biological N2 fixation.
• Incorporation of NH₃ into amino acids, glutamate/glutamine synthesis.
• Dietary protein as a N2 source in higher animals, protein turnover, essential and non-essential amino acids.
• Transamination, glutamine/glutamate cycle.
• Summary of amino acid biosynthesis.
• Digestion of dietary protein, amino acid absorption.
• Disposal of NH₃, the urea cycle and its relationship to the citric acid cycle.

4. Intergration and Regulation of Metabolism

Regulation of Enzyme Activity and of Cellular Metabolism

• Regulation of enzyme concentration; constitutive enzymes: induction/repression of enzyme synthesis; isoenzymes; induction of beta-galactosidase activity in E. coli; transcriptional/translational control. Enzyme degradation and protein turnover in cells and tissues.
• Regulation of enzyme activity - inhibition and stimulation. Classical enzymes, Michaelis-Menten kinetics, substrate concentration, product inhibition. Classical activators and inhibitors. Feedback inhibition, allosteric enzymes, allosteric inhibitors and activators. Regulation of glycolysis and gluconeogenesis.
• Regulation of enzyme activity - covalent modifications. Reversible modification, phosphorylation, dephosphorylation, adenylation and disulphide reduction; regulation of glycogen synthesis and degradation. Irreversible modification, partial proteolysis, ubiquitination.
• Regulation of sequential enzyme reactions - rate limiting model vs. distributive control model; enzyme cascades; metabolon.

Communication between Cells and Tissues: Hormones and Signalling

• Overview of cell-cell communication: endocrine, paracrine and autocrine. Neuronal signalling. The endocrine system.
• Chemical nature of the hormones: steroids, proteins, tyrosine derivatives.
• Biosynthesis of the hormones: prohormones.
• Hormone action: specificity, hormone receptor interaction. Cell surface receptors, concept of the second messenger. Intracellular receptors for steroid hormones.
• Mechanisms: effects on protein synthesis; effects on enzymes, adenylate cyclase system, cyclic AMP, GTP binding proteins, activation of cAMP dependent protein kinase, regulation of glycogen metabolism.
• cGMP, insulin receptor signalling, MAP kinase pathway, phosphoinositide signalling, calmodulin, steroid hormone signalling.
• Regulation of blood glucose levels.
• Toxins, tumour promoters and oncogenes.

The Division of Labour: Integrated metabolic activities of mammalian tissues

• Oxygen consumption in man; an index of metabolic activity.
• Biochemical activities and metabolic activities of the red cell. Outline of blood composition, cell biology and function of the red cell. Haemoglobin; basic structure, adult and foetal forms. Glucose metabolism and its role in the maintenance of the red cell: ATP and the Na+/K+ ATPase. Reactions of haemoglobin and oxygen; the generation of metHb. NADH and metHb reduction; NADPH and the disposal of superoxide. 2,3 Bisphosphoglycerate and oxygen binding; comparison of adult and foetal haemoglobins.
• Skeletal muscle and contraction. The major muscle filaments. The sliding filament model. The contraction cycle. Energy sources for contraction; ATP, creatine phosphate, glycogenolysis, oxidative metabolism. Contraction coupling. Severe exercise: recovery from exercise, the Cori cycle, the glucose-alanine cycle.
• Metabolism in brain. Major brain cells. The blood brain barrier. Glucose utilisation; amino acids as a source of neurotransmitters; lipid metabolism.
• Fed and fasted states. Carbohydrate, fat and protein stores in man. Metabolic changes accompanying overnight fasting and prolonged starvation; utilisation of muscle protein; ketone bodies.

5. Biochemistry of Nutrition

Diet as source of energy, materials for biosynthesis and essential molecules.

• The good diet. Dietary recommendations: Core food groups
• Energy considerations. Catabolic pathways involved in energy generation. Calorific value and energy density of food, energy demands in basal and active states; food intake.
• Dietary carbohydrates. Classification and utilisation of simple and complex carbohydrates. Role of dietary fibre and resistant starch in human nutrition; implications for health and disease.
• Alcohol. Absorption and metabolism, effect on NADH/NAD + ratio. Effect of increased NADH/NAD + ratio on metabolism; lacticacidosis, gout, hypoglycaemia; altered lipid metabolism. Positive and negative aspects of alcohol consumption.
• Dietary lipids. Importance of different lipids in our diet. Saturated and unsaturated fats, essential fatty acids, ?-3 and ?-6 polyunsaturated fatty acids, mono-unsaturated fatty acids. Relationships between dietary intake and serum lipid levels.
• Dietary proteins. Nitrogen balance, essential amino acids, high and low quality proteins, limiting amino acids, animal and plant proteins. Assessment in terms of biological value. Protein deficiency and protein requirements in vegetarian diets.
• Mineral elements and water. Maintenance and role of water in the body. A number of minerals will be examined in detail as examples of the functions of the essential minerals. Deficiency states and the effects of excess intake. Fibre-mineral and vitamin-mineral interactions.
• Vitamins. Basic concepts, classification as fat- and water-soluble vitamins. Recommended daily intakes and their limitations. Review of vitamins in terms of dietary sources, metabolic role, deficiency states and effects of excessive intake. "At risk" groups in the community. Factors that effect bioavailability of vitamins.