BCH 2022: Metabolic Basis of Human Diseases

• Subject Convenor: Dr Janet Macaulay
• 6 points
• Monash handbook

How energy is produced and used by living organisms. A general outline of cellular metabolism. The biosynthesis and breakdown of major biological molecules that contribute to energy metabolism of cells and tissues. The regulation and integration of central metabolic pathways in overall cellular metabolism, energy regulation and metabolism of specialised tissues. The biochemical basis of hormonal regulation, and of nutrition.

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

The student composition of practical classes will be made by ALLOCATE and finalised by the FIRST WEEK of semester. Students are to proceed to the Second year Biochemistry teaching laboratories the first Tuesday or Thursday of semester. Allocation of prac class will depend on timetable clashes with other classes. Please finalise the day allocated to you for your practical classes during the first week of semester. Students will be divided up into groups per prac class, each containing 10-12 students. 

Lecturing staff

Dr Janet Macaulay	Dr Alfons Lawen	A/Prof Mibel Aguilar	A/Prof Rob Pike

BCH 2022: Metabolic Basis of Human Diseases Synopsis

1. METABOLIC RELEASE OF ENERGY: THE BODY'S POWER SUPPLY

1.1. 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.
• 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.

1.2. Biological Oxidation: how the cell produces its energy

• 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.

1.2a. The Use of Radioisotopes in Biochemistry

• Radioactive compounds as tracers in the analysis of metabolic pathways. Introduction into practical 5. Detection of radioactivity (Geiger-Müller counter, scintillation counting, autoradiography).

1.3. 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.

1.4. 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.

1.5. 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

2.1. 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.

Synthesis of nucleotide sugars and their role in the formation of glycosidic bonds.
Synthesis/breakdown of galactose, fructose, lactose, sucrose. In born errors of metabolism.

2.2. 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 triacyl glycerol 3 phosphate and fattyacyl CoA.

Synthesis of phospholipids, formation of phosphatidyl ethanolamine and phosphatidyl choline from diacylglycerol.

3. AMINO ACID METABOLISM

• Nitrogen Cycle, biological N 2 fixation.
• Incorporation of NH 3 into amino acids, glutamate/glutamine synthesis.
• Dietary protein as a N 2 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 NH 3, the urea cycle and its relationship to the citric acid cycle

4. INTEGRATION AND REGULATION OF METABOLISM

4.1. 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, phosphor-ylation, 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.

4. 2. Communication between cells and tissues: - Hormones and Signalling

• Overview of cell cell communication: endocrine, paracrine and autocrine. Neuronal signaling. 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 signaling, MAP kinase pathway, phosphoinositide signaling, calmodulin, steroid hormone signaling.
• Regulation of blood glucose levels.
• Toxins, tumor promoters and oncogenes

4.3. 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 (NHMRC, 1995; cereals, dairy products, meat/fish, etc., fruit and vegetables, fats); energy dense and nutrient dense foods; Food pyramids (CSIRO 12345+ pyramid, Mediterranean/Asian pyramids); food variety score. Advantages of breast feeding.

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.