IMMS 1 Revision (part 1)

1. IMMS 1 Revision (part 1) Nick Richards & Byron Haywood-Alexander

2. Topics • Cells • Homeostasis • Molecular building blocks • DNA/RNA • Mitosis/Meiosis • Genetic disease

3. 1. Cells Functional unit of the body, compartmentalised by a cell membrane, containing intracellular organelles and cytoplasm. Many cellular metabolic processes occur here including those that allow molecules into and out of the cell.

4. Require an electron microscope

5. Organelles Nucleus - cell ‘brain’, double nuclear membrane, DNA, nucleolus produce rRNA Mitochondria - cell ‘battery’, oxidative phosphorylation, mtDNA, double membrane (inner highly folded) • Outer membrane - lipid synthesis and fatty acid metabolism • Inner membrane* - Respiratory (electron transport) chain ATP production • Matrix - Tricarboxylic acid (Krebs’) cycle • Intramembranous space - nucleotide phosphorylation Endoplasmic reticulum - flat folded sheets of membrane, nuclear pores • Rough - protein production • Smooth - membrane lipid production, protein processing

6. Organelles Golgi apparatus - parallel membrane sheets - process and modify ER products • Cis (nuclear) face - receive smooth ER vesicles, protein phosphorylation • Medial Golgi - modify products by adding sugars • Trans Golgi Network - proteolysis of peptides into active forms, sorting of molecules into vesicles Vesicles - spherical membrane bound organelles to transport and store material • Cell surface derived: pinocytotic and phagocytic vesicles • Golgi-derived transport vesicles • ER-derived transport vesicles • Lysosomes • Peroxisomes

7. Organelles Lysosomes (waste disposal system) - contain many acid hydrolases. H+ATPase on membrane creates optical pH 5 environment for enzymes. Peroxisomes - contain enzymes that break down long-chain fatty acids D-amino acid oxidase, Catalase, Urate oxidase Cytoskeleton - filament proteins supporting structure of the cell • Microfilaments - Actin forms a mesh (cell cortex) to inner cell membrane • Intermediate filaments - differ from cell to cell - spread tensile forces • Microtubules - Tubulin arise from centromere (2 centrioles) - not RBC

8. Cell membranes • Phospholipid bilayer • Contain glycolipids, glycoproteins, cholesterol and embedded proteins. Proteins: Transmembrane (integral), Catalytic, Structural (pumps, gates, receptors, adhesion molecules, energy transducers).

9. Cell membrane function ? • Barrier the external environment and compartmentalise the cell • Semi-permeable: • absorb nutrients and expel waste • maintain intracellular ionic balance • Cell response to signals • Molecules for intercellular adhesion • Insulate - myelin sheath

10. Cell Junctions Occluding junctions - prevent molecule leakage • Tight junctions Anchoring junctions • Actin filament sites • cell-cell junction (adherens junctions) • cell-matrix junctions (focal adhesions) • Intermediate filament sites • cell-cell junction (desmosomes) • cell-matrix junction (hemidesmosome) Communicating • Gap junctions • Chemical synapses

11. Endocytosis Energetic process to absorb/engulf molecules into cell. Phagocytosis* (eating) - macromolecules/ entire cell to form phagosomes Pinocytosis (drinking) - dissolved solutes Receptor mediated* - specific, depressed areas: coated pits.

12. Exocytosis • Vesicles from the Golgi complex • Fuse with the plasma membrane • Expulsion of waste OR Secretion of enzymes/hormones

13. Movement across membranes Movement types • Passive diffusion • Facilitated diffusion through protein channels with(out) carrier proteins • Active transport Examples • Gaseous exchange along chemical gradient • Glucose - protein assisted which is upregulated by insulin. Voltage gated channels activated by action potentials. • NaK ATPase pump - going against chemical and electrical gradients

14. Receptors Gateway to intracellular signals • open a channel • activate an intracellular enzyme • induce second messenger • migrate to nucleus as receptor-ligand complex

15. 2.Homeostasis ? Control of the internal environment

16. Communication Types • Endocrine - hormones • Nervous - currents and neurotransmitters • Immune - antibodies, cytokines, interleukins Receptor and ligand required

17. Cell to cell signaling Endocrine system - hypothalamus, pituitary, thyroid, parathyroid, thymus, pancreas, kidney, gonads, adrenals Immunity - T lymphocytes secreting IL2, cytokines Neuro synapses, neuromuscular junction, clotting

18. Types of hormone Peptide - insulin, growth hormone, TSH • From short chain of AA to small proteins • Some glycoproteins • Hydrophilic - receptors Steroid - testosterone, oestrogen, cortisol • Synthesised from cholesterol • Different enzymes produce hormones • Lipid soluble - cross membranes but require transport proteins Amino-acid derivative - adrenaline, T4, T3 • synthesised from tyrosine

19. Feedback Positive feedback - amplification of signal Negative feedback loop - centre of homeostasis • Clotting cascade • Oxytocin during childbirth • Blood sugar regulation • Temperature regulation • Blood pressure regulation • Metabolism/thyroid regulation

20. Water Distribution Total body water ~ 42L 60% of body weight Cl- K+ HCO3- 40% of body weight intracellular fluid - 28L 20% of body weight extracellular fluid - 14L Na+ Transcellular - 1L -CSF -Digestive juices -Mucus Interstitial - 10L Plasma - 3L

21. Water Homeostasis • Fluid compartments are in osmotic equilibrium • Solutes (osmotically active) in ICF and ECF create osmotic gradients • Any change in solutes in any compartment results in a water movement ECF ICF K+ Na+ Urea Glucose

22. Regulatory hormones Antidiuretic hormone Aldosterone Atrial natriuretic peptide ? Water Homeostasis Water intake: • Drink - thirst, social • Diet • IV fluid Water loss: • Kidneys • Insensible losses • sweat • breath • vomiting • faeces

23. Definitions Osmosis - net movement of solvent molecules through a semipermeable membrane to a higher solute concentration. Osmolality - measure of the number of dissolved particles per kg of fluid. Osmolarity - measure of the number of dissolved particles per L of fluid. Osmotic pressure - pressure applied to a solution, by a pure solvent, required to prevent inward osmosis. Through a semipermeable membrane. Oncotic pressure - form of osmotic pressure exerted by proteins that tends to pull fluid into its solution.

24. Water homeostasis mechanisms Water loss from ECF • ↑ solute or ↓ fluid results in an ↑ osmolality • Detected by osmoreceptors in hypothalamus • Release of antidiuretic hormone (ADH) from posterior pituitary • ADH acts by increasing water reabsorption in the kidneys • Dilutes solute and returns ECF water to normal Decreased renal blood flow • ↓ water in ECF results in ↓ circulating volume results in ↓ renal blood flow • Kidney release of Renin and activation of RAAS • Angiotensin II and aldosterone increase Na+ reabsorption (exchange K+ and H+) bringing water. Also stimulates ADH.

25. Water deprivation Vomiting Diarrhoea Burns Heavy Sweating Diabetes insipidus Diabetes mellitus Drugs Dehydration • Low intake • Excess loss • Low ADH

26. Hyponatraemia Cerebral over-perfusion headache confusion convulsions Water excess • High intake • Decreased loss • Excess ADH

27. Oedema Oedema - excess water in the intercellular tissue space. • inflammatory (leakage) • Venous (increased end pressure) • Lymphatic (blocked) • Hypoalbuminaemic Serous effusion - excess water in a body cavity.

28. Hyponatraemia Artefactual Sodium loss Diuresis Addison’s disease Excess water IV fluids SIADH Excess water & sodium Oedema (CCF, liver disease) S+S: intracellular overhydration (headache, confusion, convulsions) Sodium Hypernatraemia • Water deficit • low intake • osmotic diuresis • DI • Sodium excess • mineralocorticoid excess S+S: cerebral intracellular dehydration (confusion, tremors, irritability), hypertension, oedema/serous effusion

29. Hyperkalaemia Decreased K+ loss renal failure diuretic/ACE-inhibitors Addison’s Redistribution acidosis S+S: risk of cardiac arrest Hypokalaemia Potassium loss D+V Diuretics Hypomagnesaemia Conn’s and Cushing’s Redistribution Alkalosis Refeeding syndrome S+S: Weakness, dysrhythmia Potassium Excretion from intestines and kidneys (Na/K ATPase pump controlled by aldosterone)

30. Hypocalcaemia Vit D deficiency Mg deficiency Renal disease Parathyroidectomy Intestinal malabsorption S+S: tetany, carpopedal spasm Calcium Hypercalcaemia • Hyperparathyroidism • Malignancy • Skeletal mets • PTH-like hormone from tumours • Vitamin D toxicity • Granulomatous disease (TB) S+S: Metastatic calcification Bones, stone, psychic groans, abdominal moans, thrones.

31. 3. Molecular building blocks Simple molecules form complex, large macromolecules with functions: • Structure • Osmotic • Enzyme • Other specific

32. Carbohydrates/Saccharide/Sugars • Cn(H2O)n Mono, Di, Oligo, Poly • Groups • Hydroxyl • Aldehyde • Ketone • Carboxyl • OH group react with OH/NH = O/N-glycosidic bond • Polysaccharides: 1-4 and 1-6 bonding forming Glycogen, Starch

33. Lipids/Fatty acids • Straight hydrocarbon chain with carboxyl group • Eicosanoids - major biological function • derived from eicosanoic acid

34. Nucleotides • Sugar + nuclear base + single phosphate group • Purine derivative • Pyrimidine derivative

35. Aminoacids • Charge determined by all 3 groups • Change at different pH • Side chain determine polarity and non-polarity • Strong peptide bond CO-NH. Requires proteolytic enzymes.

36. Chiral centres Most sugars in the human body are D form, whereas protein take L-form!

37. Proteins • Long AA chains • Varied function - structure dependent • Structure • Primary • Secondary • Tertiary • Quaternary

38. Enzymes • Biological catalyst - bind but to not get used up • Speed-up and regulate reaction rate • Optimum temperature and pH • Activation, modification, inhibition • Isoenzymes - different structure, catalyse same reaction Disease marker! Drug target!

39. Co-enzymes • Organic structures (nonprotein) that help maximise organic enzyme active site • Cannot catalyse alone • Metal ions (Fe2+, Mg2+, Zn2+), vitamin derivatives (thiamine pyrophosphate) • Activation-transfer coenzymes • Oxidation-reduction coenzymes

40. Forces • Van der Waals - weak attractive/repulsive force between all atoms due to fluctuating electrical charge. • Hydrogen bonds - interaction between polar groups. Important in AA side chains, O/N in main chain and water. • Hydrophobic forces - as uncharged and non-polar side chain repel water, they tend toward a protein core. • Ionic bonds - between fully/partially charged groups • Disulphide bonds - very strong covalent bonding between sulphur atoms.

41. DNA/RNA • Base Nucleotides • Complementary Base Pairing • DNA Polymerase • Sense and Anti-Sense Strands • RNA

42. Maternal Chromosome Paternal Chromosome Gene locus Alleles

43. Replication of DNA • Double stranded -> Single stranded • Topoisomerase • DNA Helicase • DNA polymerase • Semi-conservative replication

44. Transcription ANTI-SENSE DNA • Double stranded -> Single stranded • Topoisomerase • DNA Helicase • RNA polymerase • Messenger RNA (mRNA)

45. Translation • mRNA -> Ribosome • Splicing • Introns • Exons • tRNA • Anticodon

46. Non-Sense Single nucleotide polymorphism (SNP) Premature stop codon Examples? Duchenne’s Muscular Dystrophy Mis-Sense and Non-Sense • Mis-Sense • Single nucleotide polymorphism (SNP) • Different amino-acid • Examples? • Sickle Cell (CAG -> CTG) GOWER’S SIGN