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BI1004 revision notes
Cardiff University
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BI1004 Dynamic Cell Cells and tissue – (Ralphs) Lecture 1 - tissues Organ system = 2+ Organs = 2+ tissue = 2+ cell types PLANT TISSUE: Dermal (epithelium, epidermis/cuticle) : protect/prevent water loss: Epidermis: Made of Pavement cells, differentiate to form guard cells and trichomes (hair cells). Cuticle: waxy layer, prevent H20 loss. Ground tissues (3 types): Parenchyma: most common & versatile, thin walls, large vacuoles, photosynthetic, ONLY dividing cells (meristem), roots/stems/seeds Collenchyma: Structural support, shoot & leaf growth, thickened walls, (can be more thick when demanded) under epidermis of leaves/stems Sclerenchyma: Structural support Long slender, bundles, thick walls, dead, xylem/phloem/cambium Vascular tissue: Xylem: H20 transport, columns of elongate dead cells, woody cells forming tubes called tracheid and vessel elements . Phloem: Organic nutrient (sucrose most), Sieve tubes, end to end by plasmodesmata, kept alive by companion cells. Meristem: Growth cells, Undifferentiated parenchymal cells, stem cells, Apical growth shoots/roots ANIMAL TISSUE: Epithelium: separation internal/external, linings of systems/external covering Connective tissue: support, linking, binding, space-filling, wound healing, infection control, widespread & part of other tissues embedded in extracellular matrix. TYPES: Bone & cartilage = support, & Proper CT = tendons/ligaments. Muscle: movement, skeletal/cardiac/smooth Nerve: Communication, CNS,PNS Lecture 2 – Epithelia Properties: Lining/covering of all surfaces: Avascular, on basement memb, over vascular CT, completely cellular. Controls exit/entry. Forms glands, tubes in underlying tissue. Functions: Protection, Secretion, Absorption, Dialysis, Sensation. Classification: No. layers, Simple (1) or Stratified (2+), Shape of top layer: squamous, cuboidal, columnar. 2 forms not fitting classification: Pseudostratified Pseudostratified ciliated columnar epithelium: cilia/goblet cells Transitional: changes from collapsed - stretched (lines bladder) Common features of epithelia: (4) 1: CELLULARITY – entirely cellular/separation of environment/cellular transfer 2: SPECIALISED INTERCELLULAR CONTACTS – desmosomes, adherens/tight/gap junctions 3: POLARITY – top surface dif. to bottom, top = external environment, bottom = basement memb. 4: BASEMENT MEMBRANCE – 2 parts, (1st) basal lamina = from epithelium & reticular fibres = from CT Functions: Stratified = most common Keratinised = top layer = anucleate cornified = toughest, waterproof, surface cells dead, lost & replaced from underneath Non-keratinised =top layer living nucleated = next toughest, cells alive to surface, inner surfaces, moist by gland secretion. Simple epithelia: small/thin/passive barrier, shape varies = squamous (filters) & columnar/cuboidal (active transport/modification of materials e. golgi/lysosomes) Goblet cells in columnar & lymphocytes found at wounds. Prokaryotes – (Rutherford) Lecture 1 – Cell membrane Importance: disease/ food – preserving & fermenting / Agriculture N2 fixing & rumen of cows etc.. / methanogenic bacteria producting CH4 – global warming & biotech – pharmaceuticals & gene therapy. ARCHAEA & BACTERIA Differences = Bacteria have peptidoglycan wall (archaea don’t), euk vs pro, non membs inside prokaryotes. Properties: Shapes : rod/spirrilum/coccus, single celled, Large SA:V as very small cells, rely on diffusion Structures: flagellum/pilus/nucleoid/ribosomes/plasm memb/cell wall/capsule. CELL MEMBRANE = phospholipid bilayer – hydrophilic heads out/phobic tails in. Fluid/dynamic movement of phospholipids, proteins within membrane peripheral = across, integral=within (carriers/channels/atp synthase) Bacterial cell memb: mono-unsaturated and saturated fats, not normally sterols (cholesterol) (prokaryotes = poly-unsaturated) Gram -ve = 2 membranes. Archaea Memb: Isoprene hydrocarbons (euk & pro = ester linkages fatty acids-glycerol, archaea = ether linkage). PROPERTIES: permeability barrier (H20 fastest, ions slowest), protein anchor, energy production/conservation. Perm barrier: Aquaporins: control H20 across memb. Protein anchors: orientation/concentration/association/recycling/recognition Energy production: movement of H+, ADP + Pi -> ATP, structures are highly conserved in all organisms. Lecture 2 – Cell walls/chromosome/cytoskeleton BACTERIA Gram +ve: 1 layer = Thick peptidoglycan (90%) (10%=teichoic acid) Gram -ve: 2 layers = outer memb = lipopolysaccharide & protein & inner layer = periplasm + thin peptidoglycan (10%) Peptidoglycan = N-acetylglucosamine & N-acetylmuramic acid & (AAs) D-form of Alanine.(peptides) Lipoteichoic acid links cell memb to peptidoglycan Gram +ve = lipoteichoic acid -> peptidoglycan -> cell memb Gram -ve = O-polysac -> core polysac -> lipoteitchoic acid -> peptidoglycan -> cell memb Fimbriae + pili: mobility + cell communication, pili: connect cells/transfer genetic material between cells. – twitching motility Fimbriae: allows bacteria to fix to materials, move to food sources, secretory system = like a syringe penetrating other cells Type IV fimbriae: twitching mobility/mediate genetic transfer Flagella: peritrichous (all over), Polar (1 at end), Lophotrichous (grouped at 1 end) Helically shaped, whipping circular action, =made of flagellin subunits At bottom = hook domain, anchor to cell memb & C/Ms protein rings are polar = create motor for rotation.-H+ through motor protein, Hook = outer memb, motor = inner memb ARCHAEA Paracrystaline cell surface – S-layer (sieve to allow molecule entry) Capsules & slime layer: protective layer, separation from environment. Cell inclusions: build ups in cell, ions,materials,gas (vesicles e. fill with gas = buoyancy or ions = magnetotaxis) BACTERIAL CYTOSKELETON: Helical structure, in long-bacteria Chromosome: nucleotide-concentrated area, circular, not membrane bound (1000xs smaller than in human) Plasmid: Circular piece of Double strand DNA, carry & share genes between organisms (antibiotic resistance – can be taken from other cells) Eukaryote structure – (Watson) Lecture 1 - intro Compartmentalisation : multicellular organisms, allows cell differentiation = uses cell membranes STUDYING: Electron microscopy = cell stain/thin slice/e- microscope, fluorescence microscopy, tag with protein/light microscope, Cell fractionation / centrifuging Nucleus: genetic information: nuclear envelope/pores/nucleus/nucleolus. RNA synthesis in nucleolus. Endoplasmic Reticulum: rough = with ribosomes, make proteins, smooth = lipid synthesis/calcium storage/detoxification, transitional = lipid/protein transport Golgi: stacks of flat vesicles, processes/packages proteins. Secretory Vesicles: contains protein for exocytosis Lysosomes: contains digestive enzymes Mitochondria: site of aerobic respiration (ATP) Peroxisomes: makes/degrades Hydrogen peroxide, detoxification/catabolism (big-> small molecules) CYTOSKELETON: framework, structure/transport Centrosome: 2 barrel shapes, produces microtubules for cytoskeleton Microtubules: Transport system of cell Filaments: location/movement of cell (lots in muslces) Plasma memb: phospholipid bilayer Microtubule growth: added to +ve end (adds onto +ve end) Centrosome: nucleates microtubules, 2 barrel shaped microns. Assists formation of closed microtubules. Microtubule collapse: taken from +ve end Roles: organisation of shape and polatity Intracellular vesicle/organelle transport: motor proteins: KINESIN to +ve end / DYNEIN to -ve end Chromosome movements. MICROFILAMENTS: - polar Subunits : G-actin momoner TOGETHER = F-action (filamentous) – figure of eight shape Functions: Cell locomotion, cell shape INTERMEDIATE FILAMENTS: - non-polar Subunits: dimer multiple proteins – FIBROUS SUBUNIT Dimer -> tetramer -> protofilament -> intermediate filament PRO & EUK SIMILARITIES Genetic info = DNA, translation/transcription, metabolic pathways, synthesis/insertion of memb proteins, protein digestion. PRO & EUK DIFFERENCES Euks can: Organelles/compartmentalisation, cytoskeleton, chromosomes, endo/exo/phagocytosis, cell division with microtubules for chromosomes (mitosis) DEFECTS IN EUKARYOTIC ORGANNELES: - 1 protein has big effect. Lecture 5 – Cell junctions Types: tight/impermeable, gap, anchoring/adherens junctions Analysing: TEM = freeze organism/tissue, surround in plastic, thin slice 2D Freeze fracture = freeze tissue block, hit with hamer – fracture block, top layer with gold, dissolve tissue from gold. = replica in gold 3D TIGHT/IMPERMEABLE JUNCTION – joint at protein rivets Rows of right junction proteins stops leakage between cells Creates dif. cell surface sections ANCHORING/ADHERENS JUNCTION Cytoskeleton = mechanical strength in cells/between cells Links between cells and to extracellular matrix Structure: linker protein -> attachment protein -> cytoskeleton Desmosomes link intermediate filaments Adherens junctions link cytoskeleton/actin in cardiac muscle GAP JUNCTION: communication Aqueous channels between cells Connexions make hexameric cylindrical connexions Allows communication via ion/small molecule passage Cell Cycle (mitosis/meiosis/stem cells) – (Rutherford) Lecture 1 - mitosis Cell cycle phases: M = mitosis/cytokinesis -> G1 = resting/majority of life -> S = DNA replication -> G2 = short rest (repeat). INTERPHASE = G1, S G2 (this can vary e. budding/fission yeast) M sub-phases (PMAT): inter = chromosomes condense, nuc env dissolves, centrosomes replicat Pro = chromosomes fully condense, spindle forms Pro-meta = chromosomes attach to spindle Meta = chromosomes at equator Ana = chromatids to poles (separate chromatids and spindle cores Telo/(cytokinesis) = 2 nuclei reform around chromatids, spindle degrades How Chromosomes CONDENSE: via multiple coiling/folding, wrap around histones. (condensed DNA = chromatin) CONDENSIN (prophase), condenses them, 2 sub-units dimerise (join together) 2 models: 1. dimers bind DNA = loop (condensin – DNA) -> 1st 2. Dimers loops around DNA = loop (Condensin - Condensin -> 2nd How chromatids JOIN: COHESIN: similar structure to condensin, 2 models (cohesin-cohesin vs cohesin-DNA) -> SEPARASE = Cohesin breakdown = chromatid separation. APC/C: Anaphase promoting complex – bind to securin = activates separase – degrades cyclin = exit from mitosis SPINDLE: centrioles produce microtubules, spindle = microtubule network, connect poles with each other and cell memb, binds to chromosomes, facilitates chromosome movement 2 centriole at 90˚ to each other = centrosome = produce spindle fibres Spindle interactions: 3 types of microtubule: 1. Astral = bind to plasma memb using Dynein, fix spindle in place. 2. Kinetochore = attacth to chromosomes using kinesin-4/10 (chromsomes to poles). 3. Interpolar = attatch to other microtubules using kinesin 14 (tightens-pull microtubules together) and 5 (expands-push microtubules apart). Microtubules = tubulin dimers. Spindle growth = added to +ve end Centromere = No genes, condensed DNA (centre of chromosome vs telomere = end of chromosome) KINETOCHORES: bind cetromere to spindle, DNA little affinity to spindle Kinetochores = 3 layers: Checkpoint (attatch to spindle) / outer / inner (attatch to DNA) Spindle made of microtubules, +ve end attatch to kinetochore, -Ve end attatch at centriole. Lecture 2 – meiosis After S-Phase = double strand (G1 = single) Meiosis 1 & 2 PMAT occurs twice (meiosis 2 = same as mitosis) 1 –> 4 cells + variation, diploid -> 4 haploid MEIOSIS I; separates homologous pairs Tetrand = bivalent (pair of homologous chromosomes that have crossed-over -> swapped sections = variation) Chiasma = cross-over point, bivalents formed here Prophase 1 – chromosomes condense/cross-over occurs Leptotene = duplocated chromosomes condense, nuc env disintergrates, centrosomes to alterate poles. Zygotene: condense further, homologous chromosomes aliign together, synapsis (cross-over). Cross-over done by formation of Holiday junctions = SYNAPTONEMAL COMPLEX Pachtene: Synapsis - Crossover occurs, genetic info exchanged = (4 dif daughter chromosomes). Diplotene: cross-over occurs, Bivalents formed, synaptonemal complex dissociates Diakinesis: Cross-over occurs, spindle associates with bivalents Metphase 1: homologous pairs at equator, 1 kinetochore per chromosome attatched to spindle (not 2 like in mitosis) Anaphase 1: replicatd pairs of CHROMATIDS (individual chromosomes) move to poles Telophase 1/cytokenesis: nuc memb reforms, chromosome decondenses, interphasestarts MEIOSIS II: = MITOSIS without DNA replication Overall : SUMMARY Mitosis: chromosomes-replicate/condense/line-up/separate/nucmemb-reforms/cytokenesis Meiosis: (I) chromosomes-replicate/condense/homol-pairs/crossover/separate homol-pairs/cytokenesis – (II) chromosomescondense/lineup/separate/cytokenesis N-number: = number of chromosomes C-Value: amount of DNA 1st = mitosis / 2nd = meiosis -> CYTOKINESIS: actin/myoain filmaents form CONTRACTILE RING – cleaves around the cell memb (clamps) In plants a cell plate – new cell wall forms Lecture 3 – stem cells Cell timeline: Gamete – zygote – embryo – germ layers – tissue Undifferentiated cells Potency: toti/omni = all cells(embryo/zygote) pluri = most cells, multi = related cell types, oligo = a few cells, uni = 1 cell Found in EPIDERMAL CELLS = replacement of skin cells Haemopoeitic stem cells = blood cells 3 types: Embryonic (Embryonic tissue) / induced pluripotent (iPS) / somatic (adult (bone marow) foetal (umbilical cord) Amniotic (fluid)) IN PLANTS: Apical shoot/root – meristem cells = undifferentiated dividing cells. Lateral meriste = at end of branch. binds to R subunits causing the C subunits to discotiate so they can activate other proteins (via phosphorylation) – amplifies signal. Production of cGMP: like cAMP, GTP -> cGMP via Guanylyl cyclases, 2 forms – extra/intra cellular, can be activated by internal/external ligands. cGMP -> 5’-GMP by cGMP phosphodiestrase. cGMP activates PKG. PTEN: PIP3 -> PIP2 – deregulates PKB – tumour supressor genes – cancer cure Lipid derived 20 messengers (PIP2): phosoplipids are hydrolyzed into their components by Phospholipases forming 20 messengers. Phosphorylation of PIP2: PIP2 structure (normal phospholipid – 0===)– hydrophobic domain, 2 fatty acid tails + glycerol = DAG, Hyrdophilic domain – IP3 (projects into cytoplasm). Receptors are G protein-coupled receptors (GPCR). Activation of GPCR/G protein – Activates PLC – phospholipase C (Effector enzyme breaks down PIP2), PIP2 -- (PLC-enzyme) IP3 + DAG. IP3 and DAG are 20 messengers which activate PKC. Calcium Ca2+ 20 messenger molecule: Ach = signalling molecule: IP3 triggers release of Ca2+ - triggers Ca2+ channels to open. Conc. Of Ca2+ in cell increased by: movement of Ca2+ inside cell (channel proteins), & release from intraceullar stores: ER/SR – sarcoplasmic/endoplasmic reticulum Conc. Of Ca2+ reduced by: pumping Ca2+ out of cell and back into stores Calmodulin: 4 binding sites for Ca2+, when Ca2+ binds it causes a conformational change in calmodulin. The Ca2+ Calmodulin complex can stimulate a variety of target proteins (CAM kinases & Ca2+ ATpase pumps) NO 20 messenger molecule of ach and smooth muscle relaxation: Ach binds to GPCR which activates IP3 formation, IP3 stimulates Ca2+ release, Ca2+ stimulates NO synthase producing NO, NO activates guanylyl cyclase, this activates cGMP formation which promotes muscle relaxation/vessel dilation. Role of receptors: Kd. – (binding of ligand = conformational change starting cellular response) Kd: messure of affinity of a receptor for a ligand. Lower the Kd – higher the binding affinity of the ligand for the receptor. R = receptor, L = ligand, Receptor & ligand binding is reversible. Lecture 3 – Types of receptor (4 types) (ion-channel linked/G protein coupled) 1. Ion channel linked receptor (ICLR) (Ion Transporter: when activated - coformational change to move ions through memb). Ion Channel: when activated allow passive diffusion of ions across memb. Uniporter: 1 molecules/1 direction, Symporter: 2 molecules/same direction, Antiporter: 2 molecules/dif. Direction. e.: Ach receptor on skeletal muscles: Ach binds Na+ receptor (in synapses), channel opens, Na+ inwards – high -> low conc. Trasnmition ends when Acetylcholinesterase breaks Ach neurotransmitter down 2. G protein coupled receptor (GPCR): Consists of (3 parts): the GPCR, G protein (GTP/GDP), coupled effector molecule. GPCR: 7 intermembrane domains, C-terminus inside on cytoplasmic face, N-terminus on extraceullular face. Ligand binding on N-terminus changes shape of C-terminus exposing a site that the G protein binds to. G protein: 2 types: monomeric-RAS, Trimeric- 3 subunits (α/β/y). Trimeric: Activation of effector: G protein binds to activated receptor, first GDP exchanged for GTP on G protein, GTP causes conformational change of G protein, GTP bound to α-subunit separates from rest of the G protein (β/y-subunit), This then binds to the effector activating it. After activation of effector: GTP bound to G protein hydrolyzed back to GDP inactivating the α-subunit , it seperates from effector and joins back with the other subunits. Cycle can now happen again. Classes – activate…: Adenyl cyclase - Gαs, Adenyl cyclas K+ channel –Gαi, PLC (phospholipase C) - Gαq & Gαo Example: Regulation of glycogen metabolism (glucagon/epinephrine): Glycogen synthase = catalyses glycogen production. Glycogen phosphorylase = catalyses glycogen breakdown/glucose production Glucagon/epinepthrine bind to GPCR: (Causes activation of PKA): epinephrine bind GPCR, G protein activates Adenylyl cyclase (effector)-> produces cAMP -> activates PKA. PKA: phosphorylates the 2 enzymes with opposite effects: Deactivates glycogen synthase – prevents glycogen production, Activates glycogen phosphorylase – causes glycogen breakdown (epinephrine (adrenaline)inceases glucose levels) Lecture 4 – Types of receptor (enzyme-linked/nuclear receptor) Ras – 2 ½ Monometric G protein. (like trimeric G proteins in GPCR) Growth factor receptors. Active when bound to GTP, Innactive GDP, has intrinsic GTPase (GAPs release GDP to add GTP) to turn off activation, requires accessory proteins to cycle between active/inactive states = GAPs (GTP->GDP) and GEFs (swap GDP with GTP) (GTPase activating proteins/Guanine exchange factores). Pathway of Ras by growth factor = Cell growth: (GRB2-SOS-Ras 3 bound in a row) GRB2 binds to RTK receptor & SOS (GEF) binds to GRB2 & Ras binds to SOS removing GDP for GTP = activating Ras, Ras binds to Raf Kinase (effector) activating MAPK cascade, This cascade reaches nuceus where it phosphorylates Transcription Factors which stimulate cell growth. A GAP then deactivates it (GTP->GDP). 3. (enzyme-linked receptors) Receptor tyrosine kinases: RTKs Structure: extracellular domain binds ligand n-terminus, transmembrane domain, intracellular domain cterminus – contains tyrosine residues = tyrosine kinase region – (only adds phosphate groups from ATP to tyrosine residues on proteins.) 2 Monomers: ligand binds to each inactive monomer = conformational change of external part, so the 2 monomers can bind together = dimerize toether. This induces conformational change in intracellular region. This make intracellular kinase domain undergo autophosphorylation – the phosphates are added to the tyrosine residues on the opposite monomer of the domain from ATP (trans-autophophorylation). These phosphates then phosphorylate other proteins in signal pathway. Insulin signalling: (PI-3) Using RTKs Decreases blood glucose (stored and made In beta-cell) Unliked most RTKS is is a Tetrameric RTK when inactive (not a monomer) – 4 subunits: 2 x α and 2 x β. α-subunits = extracellular + insulin binding sites, β-subunits = intracellular, Tyrosine kinase activity site. When stimulated trans-autophophorylation occurs of β-subunit -> activates IRS-1 protein (phosphoryates it – by more than 1 tyrosine site), IRS-1 (acts as a relay protein) binds and activates PI-3 Kinase (effector), PI-3 Kinase converts PIP2 -> PIP3, PIP3 (20 messenger) activates PDK1 (next messenger) which activates PKB – promotes GLUT-4 vesicles to translocate and fuse with membrane to take up glucose insulin also deacreases glycogen breakdown and decreases glucose synthesis Cytokine Receptors: (JAK (RTK)-STAT) : (transmitt info to nucleus = mediate DNA transcription in immunity) They lack their own kinases, Cytokine receptors recruit (janus kinase) JAK (a soluble RTK): STATs: Transcription factors that are phosphorylated by JAK, then dimarise & transloacte to nucleus. JAK - activated by cytokine(ligand) binding to receptor, Auto-transphosphorylation of JAK occurs, STATs Phosphorylated by JAK, STAT dimerises and transloactes to nucleus – binding to DNA transcribing a protein. Targeting Kinases with drugs; (receptors and kinases good target for drugs): drugs bind to ATP binding region of a kinase blocking it so they cant phosphorylise anything. 4. Nuclear Receptors: 2 types – 1. Ligand binds to receptor in cytoplasm and translocates to nucleus, 2. Ligand binds receptor already in nucleus 1. Soluble Ligand/hormone is able to diffuse though plasma membrane and bind to Nuclear Receptors (in cytosol or Nuc memb.), Nuclear receptors dimerize (like RTKs), translocate to region on DNA called Response element, binding to Response Element allows binding of co-activator proteins, this promotes gene expression. 2. ligand into nuc memb – bind TR/RXR dimer directly on DNA = RNA polymerase + Co-activator join/Corepressor off = transcripion occur. Anti-Hormone drugs = block CcoActivator binding site Lecture 5 – Plant hormones Auxins: Produced in: Seed embryo, meristems of apical buds, young leaves Transport: active transport between cells (unidirectional) Receptor: In nucleus (– ubiquitin ligase) Cellular effect: Promotes Ubiquitinylation/degrades repressor protein, Auxin related gene transcribed.(pretty much for all) Function: Stem elongation, inhances apical dominance, Fruit development Gibberelin: Produced in: meristems of apical buds, roots, seeds, young leaves Transport: paracrine/endocrine - cell to cell Receptor: cytoplasm (– ubiquitin ligase) Cellular effect: Promotes Ubiquitinylation/degrades repressor protein, Gibberelin related gene transcribed. Function: promotes seed germination (growth of roots/stem), flowering/fruit development, break winter dormacy. Cytokinin Produced in: Apical buds, roots, leaves, seeds Tansport: paracrin/endocrine – cell to cell Receptor: Plasmamembrane/cell surface (-AHK receptor) Cellular effect: Cytokinin related gene transcribed and activation of ARR transcription factor Function: promote cell division, axuillary (side) bud growth, stops leaf ageing (sensecence), chloroplast differentiation Ethylene: Produced in: tissues of rippening fruit, nodes of stems, ageing flowers/leaves Proteins that activate receptors: have death domains – interact with receptor death domains, Effectors: have death domains that interact with initiator pro-caspases. TNF activation of pathway: TNF binds with receptor, causes 3 receptors to trimerize, FADD, TRADD and procaspase-8 molecules bind to receptor, 2 procaspase-8 molecules activate each other to initiate caspase cascade. EXCITABLE / CARDIAC / SKELETAL muscles / cells – Amici-Dargan Lecture 1 – Excitable cells/AP Excitable cells: Generare a potential difference across a plasma-memb How PD arrises: Passive – permeability/gradients, Active – Against conc/using atp Permeability and driving forces: impermeable (non)/slightly-large DF/readily permeable-small DF Cell at rest: Permeable to K+ and Cl-, Impermeable to Na+ and large ions. Na+ higher outside/K+ higher inside. Typical conc of ions (inside-outside): Na+ 15:145, K+ 150:5, Cl- 5:100 (mM) INDISE more -ve than OUTSIDE Electrochemical/chemical grads – High to low/+ve->-ve down conc grad. Nernst Equation When both electro/chemical grad:: Tells us: Magnitute of electrical gradient that would balance chemical grad of an ion = equilibrum potential (Vm) -> Resting Potential: formed by:Unequal distribution of Na+/K+ - by Na+/k+ pumps & a selectively permeable memb – more permeable to K than Na Calculation: GHK equation – tells you resting membrane potential. Action potential mV: caused by changes in memb-potential – all or nothing. Required for functioning of: BRAIN/HEART/SKELETAL muscles Excitatory neurotransmitters: EPSPs – small changes in memb potentials which add up to 1 big so AP occurs. Inhibitory Neurotransmitters: IPSPs – prevet AP firing Depolarisation: if Threshold is reached by ESPS then AP will occur -Na+ channels open (Na+ in = inside less -ve) Threshold: varies between neurones/positions on neurones – thicker fibres = lower threshold as easier to stimulate Aps. Ligand-gated channels (GPCRs – Ca2+ from pharmacology) : ligand -> receptor -> G protein -> effector(a-subunit) -> 20 messenger produced from effector -> bind ion channel = conformational change/flow across. Voltage gated channels: Na+ has 2 gates: activation (extra)/(intra)inactivation gates, K+ just have 1 (intra) gate Overall ion changes in AP (Voltage gated ion channels): Resting potential – K+ free Channels are open, V-G closed. Na+ activation gate close & innactivation gate are open Stimulus = some Na+ open (rapid). Threshold reached Depolarisation Na+ activation gates open = + opening of K+ (delayed). Repolarisation: (At 30+) Na+ inactivation gates close. K+ channels open = K+ move out of memb. Hyperpolarisation = overshoot of K+ out – K+ close (inside too -ve - too much K+ out) (activation gate and inactivation gate of Na reset) Refractory period = return to resting potential (Na+ out/K+in via Na+/K+ ion pumps using ATP) Refractory period: period where further impulse = no stimulation of AP. Actual: stimulus-> just after depolarisation: No signal, Na+ channels innactive for 2nd stimulus Relative: After actual: A stronger than normal signal needed for 2nd stimulus as Na+ channels recovering Lecture 2 – Cardiac cells Structure: Multinucleate + joined by intercalated disks: made of: gap junctions (electrica-AP crossing pointl), and Adherens / desmosomes (mechanical – hold cells together). Features: Organised contraction, pump blood, AP start at SAN – passes through electrical syncytium (purkyne tissue). Refilling of heart by Relaxation, abnormal activities = bad conditions Cardiac -Pacemaker cells APs: Ca2+/K+/Na+ channels & Gap junctions FAST & SLOW Phases: 0=Depolarisation/threshold 1=Early repolarisation 2=plateau phase 3= repolarisation 4=resting potential Fast response: Myocytes & purkyne tissue(AP) 0: Na+ open & influx. 1: Na+ close & K+ open move out 2: (L-type – long acting) Ca2+ open (in) k+ open (out) = plateau & NXC – (3Na out 1 Ca in) 3: Ca2+ close, K+ open (move out) 4: Resting potential (more -ve) Slow response: SAN & AVN (no phase 0)(contraction) Depolarisation 0: Small influx of Na+ and Ca2+, hits Threshold: 0 Major influx of Ca2+ = AP generated. 3: Ca2+ close, K+ open – k+ flows out. 4: resting potential (less -ve) (Repeat: K+ close/Na+ & Ca2+ open) Channels in slow response: Funny channels: open at hyperpolarised potentials 4 – Na+ influx = cause next slow response K+ channels: allow for k+ out T-type Ca2+ channels: fast acting for rapid influx in 0 of Ca2+ Absolute refractory period: Allows relaxation between beats, Na+ channels are inactive, fibliration occurs if decreased Mechanisms for CONTRACTION of cells (myofilaments) Myosin: Thick , Actin: thin , I-band: actin, A-band: myosin+actin, H-zone: just myosin, Z-line border of sacromeres, titin: prevents over stretching. During contraction I band and H zone shrink. EC-coupling: Mediated by Ca2+ entry into cytoplasm. Ca2+ influx into cytplasm caused by: (L-type) Ca2+ voltage channels open as a result of an AP, NXC channels activated(1Ca in 3 Na out) CICR (calcium induced calcium release) from the SR. Ca2+ binds to RyR on SR and causes MORE Ca2+ to leave the SR. Ca2+ binds to: troponin on tropomyosin, causing contraction Contraction: Ca2+ binds to tropononin exposing myosin-binding site on actin filaments. Myosin head binds to actin. Myosin head flexes using ATP sliding actin filament along it. The myosin releases by ATP and returns back to original position, this is repeated moving Actin filament along, Ca2+ Efflux in cytoplasm: Ca2+ returns to SR and leaves the cytoplasm via Active transport and NCX. (3Na in 1 Ca out) Role of Ca2+ in contraction/relaxation. Contraction : moves into cells via L-Type calcium channels, Activates RYR on SR releasing more Ca2+ Relaxation: SERCA: SR Ca2+ ATPase that moves Ca2+ into SR, NCX transport Ca2+ out, PMCA plasma-memb Ca2+ Atpase moves Ca2+ out of cell. Cardiac muscle very stretch resistant compared to Skeletal, lots of connective tissue prevents muscle overstretching Frank-Starling law More stretching and sympathetic stimulation(exercise) = stronger contraction. (occurs when heart fills – allows any volume to be pumped) Sympathetic stimulation causes: +ve chronotropy (inc heart rate), +ve Inotropy (inc force contraction), +ve Lusitropy (inc relaxtion) Lecture 3 – Smooth muscle (involuntary) Location: walls of vessels, internal/hollow organs, Circ/digestive/reproductive systems Functions: move food/substances, control airway and blood vessel diameter Structure: spindle shaped, uninuclei. Fibres of Smooth muscle embedded in CT matrix, in series + in parrallele with each other. Supplied with Nerves from ANS (automatic nervous system) – Para/sympathetic responses, Excitatory = contraction, Inhibitory = relaxation. Varicosities: Swells on nerves near presynaptic terminals close to smooth muscles, release neurotransmitter. Single unit smooth muscle: causes contraction of all cells (have gap junctions between cells) Multi unit smooth muscle: allows cells to contract seperatey – contraction of 1 cell Muscle twitches: lots short contrac/relax of muscle add up to give big contraction (Ca2+ from small contractions add up) Phasic contraction/peristalsys : AP not always needed, changes in memb-potential can be enough to cause contraction. Ca2+ source: in smooth (and skeletal) is SR, (In cardiac can get it from extraceullular fluid). SR less well organised and is adjacent to membrane in smooth muscle. Ca2+ and Contraction Neutrotransmitter IP3 binds to receptors (similar to RyR), Ca2+ moves out of SR, Ca2+ binds to calmodulin which activates MLCK. (calmodulin-dependent myosin light chain kinase) This phosphorylates the A-M cross bridge. Cross bridges cycle occurs until Dephosphorylated by myosin Phosphoatase Ca2+ removal promotes relaxation of muscle. Latch state: Enables sustained smooth muscle tone(contraction) with low rate A-M cross-bridge cycling (so not much ATP used). Occurs when some Cross-bridges are dephosphorylated (m-phosphotase), slows rate of crossbridge detatchment = filaments remain locked together. Adsorption & Secretion: e. Epithelial cells in renal proximal tube = move glucose from tubule lumen -> blood using Na+/glucose cotransporter (glucose into cell apical memb.) Uses Facilitated diffusion of glucose (GLUT)move glucose out of cell across basolateral memb. Clinical relevance; h2o balance disorders: Hypotonic (+ve h2o balance) – Cells swell, undergo regulatory v. dec. Hypertonic (-ve h2o balance) – cells shrink – undergo regulatory v. inc. (dehydration/hyper-osmolarity/brain malfunction/cerebral edema). Amici-Dargan – Cellular Neuroscience: Lecture 1 - Cells as Circuits Capacitor = Phospholipid bi-layer + ionic solutions either side Battery = Ion channel – Made from an ion conc. Grad across a memb that is selectively permeable to that ion. Resistor = pore. Key biological components for bio-electricity: k+/Na+ pump, Ca2+/K+/Na+ separate pumps NERNST EQUATION – SIMPLE VERSION. [x o] = con of ion X outside cell. [xi] = conc ion X inside cell. Ex = equ potential for X Importance of this: Changes in memb potential = Aps (all or non). Excitatory neurotrassnmitters cause small changes in memb potentials (EPSPs) – add up to give an AP. Aps required for function of – brain/heart/skeletal muscle 10 fold conc dif: = 60mV change. (one side = 1mol/L other = 10mol/L Ohm’s law: V=IR (voltage = current x resistance). Resisrtance: R = 1/C (resistance = 1/conductance). Conductances in parralel add, Resistances in series add. Temportal intergration – adding up signal over time. I = Q/t (Current = Charge/time) Lecture 2 – Neural communication 1 CNS: Brain + Spinal cord PNS: (peripheral) – Somatic – CNS to skeletal muscles, Motor neurones to skeletal muscles - Voluntary Autonomic – CNS to internal organs – neurones to visceral organs (heart) – Involuntary – parasympathetic + sympathetic Afferent sensory neuron: towards CNS (from skeletal). Vs Efferent sensory neuron: away from CNS (to skele..) Interneuron: link spinal cord – relay messages Afferent->efferent Receptor -> afferent -> inter -> efferent -> effector Synapses – pre/post synaptic neurones: (pre-SN and post-SN) Synaptic transmission in the CNS: Excitatory synapses: electrical activity in pre-SN inc excitability of post-SN. Inhibitory synapses – does opposite Chemical synapses; prevent direct electrical proagation of AP from pre->post-SN Electrical Synapses: rare in CNS Synaptic Delay: due to cellular mechanisms, delay at post-SN Removal of transmitter from cleft: Enzymatic breakdown, Active reuptake (pump back to pre-SN), Active uptake (pump into glial cells) e. ACh – removed by Acetylcholinesterase, NA (noradrenaline) is removed by uptake: Monoamine oxidase (enzyme) and Catechol-o-methyl transferase (COMT) Synaptic Transmission: vesicles with neurotransmitter, fuse with pre-SN, release into cleft, bind to receptors on post-SN Vesicle Release + recycling Pathways: Ca2+ in = vesicles move to pre-SN memb and fuse. Recycling:- 2 pathways: 1 and Collapse: vesicles move to memb, interact with proteins and fuse/become part of it. 2 and run: fuses with memb, but released as new vesicle (don’t join memb) On ECG – upward deflection = dec. potential (depolarisation), downward = inc potential (repolarisation/hyperpolarisation) EPSPs – excitatory post synaptic potentials: (depolarisation+ repolarisation) Potential dec, e. -70 -> -50mv Neurotransmitters: Glutamic acid & Ach = Na+ in. IPSPs- Inhibitory post synaptic potentials: (hyperpolarisation) Potential inc, e. -70 -> -90 mv Neurotransmitters: Glycine & GABA, Cl- in, K+ out. Convergence = Many to 1 Divergence = 1 to many Summation: spatial – E/IPSPs from multiple neurons, temportal – 1 neuron with multiple E/IPSPs, Pre-synaptic inhibition: decreases amount of neurotransmitter released – blocks amount that can leave. Lecture 3 – Neural Communication 2 (propagation = spread) Definitions: Neurone – a single nerve cell Nerve fibre – the axon of a single neurone Nerve – bundle of nerve fibres Intracellular recoridng – recording electrical activity across a memb of 1 single cell (1 electrode inside/1 outisde) Extraceullular recording – recording electrical activity from a population of cells (both electrodes outside cell) Intracellular recordings: take slices of brain tissue – keep alive in solution that mimics fluid, record APs/synaptic communication with electrodes 5 concepts: lipid membrances have a Capacitence, Which Stores Charge, Producing a Voltage across the membrane. Charge = current x time, Voltage = charge stored/capacitance. Electrophysiology –( physiology of nervous systems.) Tetrodotoxin (TTX): occurs naturally in puffer fish. Is a poison. Blocks Na+ channels, Binds to extracellular memb side. Tetraethylammonium (TEA+): Potassium channels are the most widely distributed in all living organisms, TEA+ blocks these. Local circuit and AP propagation in non-mylinated cells Slow current flow, Local current flow occurs between active and adjacent inactive areas. During an AP inside becomes +ve compared to outside (-ve), the adjacent areas to the AP are depolarised by this, when the adjacent area reaches threshold a new AP is made… This only occurs in one direction because – recently depolarised area is in absolute refrac period – cant generate a new AP. AP propagation in mylenated fibre. Nodes occur at intervalles 0-2mm, Local circuit currents cause depolarisation of adjacent node of ranvier = new AP, This is Fast, as AP jumps to nodes (gaps) (only these areas can depolarise – ions can only cross in these mylinated sheet breaks) Factors affecting Conduction Velocity: (Mammalian peripherl nerve fibres classified by diamete and conduction velocity) 1 – Good insulator, increases Conduction velocity 2: smaller = inc. internal resisttance. Demyelinating conditions: decrease conducton velocuty in affected axons, result in block of conduction, cause axonal death (long term). Multiple sclerosis: progressive condition, disruption of myelin sheaths in CNS neurones, Leads to weakness and disability Peripheral Neuropathis: e. Guillian barre syndrome Extracellular recording of APs: extracellular electrodes, stimulate whole nerve, biphasic electrical signal, COMPOUND Action potentials,- sum of activity in a number of nerve fibres. sum of potentials change as APs propagate down axons. Graded Phenomenon: AP from a single fibre = ‘all or none’, Compound AP from whole nerve is NOT “all or none”, Graded dependent on size of the stimulus Small stim = few fibres – small potential Large stim = more fibres – larger potential Max stim = all fibres – max potential Accomodation – maintained depolarisation of memb = increased threshold. Due to inactivation of Na+ channels. Threshold: degree of depolarisation = AP, varies between neurones and parts of 1 neurone, THICKER FIBRES = LOWER (easier to stimulate AP in thick fibre – less internal resistance) Local anaesthetics: e. lignocaine – inc. threshold firing, prevent AP initiation, block Na+ voltage channels, fine nerve fibres most sensitive (involved in pain sensing) Ralphs – Extra cellular matrix Materials by cells, released into exterior = 3D structure with functions Plants & Animals: Fibrous framerwork – embedded in gel-like background matrix Plants: polysac fibres (hemi/cellulose + proteins), Matrix = highly charged pectin polymers# Animals: fibrous protien fibres (e. collagens), matrix = highly charger Glycosaminoglycans-GAGs – hyaluronan Plants ECM: Cell wall = specialiased ECM, carbs + small amount of protein, Fibrous: thick Cellulose – crosslinked with thin hemicellulose. Gel-matrix = -ve charged polysacs - Pectins Cell Wall: rigidity + strength, works with turgor H2O pressure, form osmosis – wall resists pressure = stretches – (tyre) Plants without H2O wilt, pressure drop, loss of strength (walls not loaded) (some extra cell wall-not H2O p needed) Cell wall layers: Middle lamela: 1st made, on surface of CM after cytokinesis – pectin glues cells together + plasmodesmata formation. Composition: uniform layer, between adjacent cell walls. Pectins + some protein, - Endochondral ossification: same starting point, mesenchyme – (stem cells) - forms condensation – condenstaiton differentate into cartillage. Becomes shaped, cartillage englarges into bone. In central = primary centre of ossification (diaphysis) – enlarges filling the shaft of bone. At ends of bone (epihysis) secondary centre of ossification – occurs again. Hypertrophy and cartillage calcification occurs in perisoteal bony colar, Vascular invasion of bone brings osteoprogenitor cells = dif into blasts. Bone forms on clacified cartillage, old carillage eroded except articular cartillage and epiphyseal plate. Synovial joints: bones covered in smooth articular cartillage – rich in collagen and GAGs/Pgs – compression resistance/shock absorbance. Capsule: Bone ends joint and iflled with synovial fluid, ligaments support. Synovial memb lines joint capsule, layer of cells supported by CT, secrete synovial fluid, rich in lubricating hyaluronan. It provides nutrition of cartillage. Allows joint movement. OTHER: Fibrous joint: liked by DRCT – lots collagen little movement. Cartillaginous joints – linked carillage – some flexibility. Caterson – stem cells/tissue engineering & regeneration (TE/TR) ex vivo = production, in vivo = regeneration of damaged tissues with natural or synthetic materials Cell Precursors Autologous: From same individual, e. skin biopsy – wound healing/cartillage repair Allogeneic: Donated/genetically disimilar – tissue banks of epithelia – replacement of burnt skin Xeogenic: From another animal species – human ubilical cord -> mouse cornea blindness cure Mesenchymal & embryonic stem cells: (STEM CELLS). – toti/pluri/multipotent cells, dif into new. Embryonic cell source – haemopietic stem cells (blood), mesenchymal – bone marrow. Genetically manipulated cells: cells tranfected with a gene to maintain cellular phenotype or produce important product for tissue engenering – IPS , induced pluripotent stem cells & plant cells – tabacco plants + 5 genes – make Type I collagen Natural Products – fibrinogen/collagen type I, coral, hyaluronan (hyaluronic acid - HA), human placenta/umbilical cord/amniotic fluid. Fibrinogen/Fibrin: biological glue – entrap cells/help implants adhese into a wound/making biodegradable and not immunogenic, can be isolated from patient blood & used in scaffolds in TE/TR. Fibrinogen is; after injury, modified by thrombin (blood protease) to produce Fibrin – insoluble part of blood clots. Fibrin clots are strengthened by the crosslinking of Fibrin fibrils with a transglutaminase, so this is used in synthetic scafolds and holiding implants in place. Natural Scaffolds: collagen/GAG engeneered into variety of dif biodegradable scaffolds – collagen sponge Functions of natural products: Biodegradable scaffold/messwork for cellular infiltration (compatible enviro for CI) Synthetic Biomaterials: PLA, PGA, Carbon Fibres, Hydroxapatite. Synthetic/natural composites – collagen sponges – cartillage chondrocytes infiltrated into collagen sponge, crosslinked HA, crosslinked HA with bioactive peptrides - facilitated migration/attatchment. Advantage: can be moldued and produced on demand for specific Tissure replacement. Knee joints: allogenic used – donated to replace meniscus – undamaged cells migrate in and repair. Osteochondrosis Dessicans (OCD) – fragment of cartilage/bone seperated from rest of bone, joint inflamation/loss of function, left untreated – no repair. Autologous chondroyte implantation: repair cartillage – take chondrocytes from healthy knee section, fibrinogen/thrombin- fibrin glue seals, chondrocytes reimplanted at damaged site Higgins Bioenergetics – 1 – bioenergetics & ATP synthesis First law: energy in uni remains constand Gibbs Free energy change: amount of energy needed for system to work ∆G = ∆H-T∆S enpalthy-entropy changextemp -ve = exo – reactants<products, +ve = endo visa versa, equilibrium = 0, is independent of path taken Energy needed for input as biological processes = endergonic (endothermic) – active transport/musc cont Obtained: phototrophs / chemotrophs, - chemoorganotrophs=get energy organic compounds via oxidation. Extraction from food: Stage 1 – large molecules -> small (no energy obtained) Fatty acids/glycerol, Glucose/sugars, AAs, stage 2 – small into few units used in metabolism – some ATP made Acetyl CoA . Stage 3 – ATP made complete oxidation of simple units – by oxidation of fuel pathways Citric acid cycle/OX phosphory Redox reactions:OILRIG e- donor: reducing agent – is oxidised,e- acceptor: oxidisng agent – is reduced – most common involve dehydrogenation Dehydrogenases: oxidise compounds – taking 2H+ and 2e- - pass to carrier + energy abstraction biodegradation, Reduced compounds – adding 2H+ & 2e- - from carrier – biosynthetic E- carriers: NADH & FADH2(less ATP than NADH) – TCA cycle – making ATP b– Mitrochondria. NADPH – PPP – reductive biosynthesis – FA synthesis – Cytoplasm. ATP – energy of cell: ATP + H20 -> ADP + Pi + energy / AMP + PPi + energy Drives unfavourable reactions: Glucose + Pi – G-6-P, ATP + H20 -> ADP + Pi -> Glucose + ATP -> G-6-P + ADP ATP -> ADP cycle: ATP (biosynthesis/Pi transport) -> ADP , ADP ( oxi of fules/photosynth) -> ATP ATP production: sub lvl phos: phosphoryl group from metabolite to ADP = ADP + Pi -> ATP, OxPhos – etransger via NADH/FADH2 to O2 = final electron acceptor – in mitrochondria. Metabolism: 4 functions – obtain atp/convert nutrient/polymerise mono/synthesis of molecules for uses – messengers CATABOLIC & ANABOLIC : CATA = fuels -> usable energy, makes ATP/Degradative/-ve ∆G/produces reducing potential/Makes NADH + FADH2 ANA = use enegry from cata -> form complex molecules from simple, Opposite / Uses NADPH Lecture 2 – Metabolic Regulation Metabolic pathways are interdependent Storage/release of nut/energy to cells when needed, work at moleculear lvl by modulation of enzyme activities How its regulated: 3 ways: lvls & accessibility of substrates – compartmentation – (thermodynam/compatmentation). Amounts of enzyme – (rate of trancription/degradation). Modulation of catalytic acitivites of enzymes (regulation proteins/covalent modi/allosteric regulation). Enzyme turnover: Synthesis/degratation controlled, numebr of enzyme molecules is a function of this Determined by: alteration transcrip factors/stability mRNA/rate translation/Rate proteing degradation Modulation of enzyme activity Allosteric Regulation: Allosteric enzymes: has a 2nd binding site from active site – ligand bind – allosteric effectors/modulators = conformational change -> changes affinity to substrate/other ligand – acitvator(+ve) or inhibitor(-ve). End product/feedback inhibition: bind to allosteric site – depends conc/affinity – conform change affect active site. some have multiple allosteric site – summation of all ligand = conform change amount Adenylate control (ATP/ADP/AMP) ATP>ADP>AMP. ATP + AMP -> 2ADP (reversible), ATP inc = dec of ADP/AMP – visa versa Energy : AMP = 0, ATP = 1, lots of ATP inhibits synthesis of ATP and inc utilising pathways/use of it Generating: glycogenolysis/glycolysys/B-oxidation (spliting) Utilising: glycogenesis/gluconeogenesis/lipogenesis/purine+pyramidine synth (joining) Covalent Modification: mod of exisiting protein covalent bonds quicker than changing enzyme lvl – adenylation/methylation/phosphorylation-most common (adding groups to side chain – selective & enzyme catalysed -> conformational change. De/phosphorylaiton -/+ Pi -> is reversible triggered by external signal leading to amplification of signal. Kinase add Pi, Phosphatas take Pi Lecture 3 – Glycolysis Stage 1: trapping&destabalising glucose -> 2x3c – 5 steps , 2 ATPs per glucose needed. Stage 2: oxidation 3c -> pyruvate – 5 steps , made: 4xATP & 2NADH per glucose. Glucose + 2NAD+ + 2ADP +Pi -> 2pyruvate + 2NADH + 2ATP + 2H+ + 2H2O. (NAD+ limited – needs replacing – wont continue if pyruvate was final metabolite – equ of cell not balanced CATABOLIC FATES OF PYRIVATE O2 present – e- on NADH -> O2 = H20/ATP/NAD+ made NO O2 = e- on NADH -> Pyruvaye = lactate or ethanol + NAD+. Ethanol: Yeast/microorganisms Anaerobic – Glucose + 2H+ + 2ADP +2Pi -> 2ethanol +2co2 +2ATP +2H2O Lactic acid: Microorganisms/O2 limited enviro – Reg of NAD+ Aerobic: more ATP via TCA cycle & OxPhos – pyruvate enters mitro & Oxidised to Acetyl CoA – NADH from step 6 cant enter mitro – NAD+ regen by OxPhos using 2 shuffles: Malate/Asparate shuffle – Outside: Asparate ->(a-ktoglutarate->glutamate) oxaloacetate -> (NADH+H+ -> NAD+) Malate (outside) -> reverse inside = NAD+ inside Glycerol 3-Pi shuffle: outside: DIP -> (NADH+H+ -> NAD+) G3P . Reverse = E-FADH2 -> FAD – H2 recycled with Q complex. Inside: Lecture 4 – Gluconeogenesis Non-Carb precuror users – seedlings/bacteria/starving animals Glucose: only RBC/brain fuel – 160g req/day Gluconeogenesis: liver – maintain blood glucose PYRUVATE -> GLUCOSE – no reverse of glycolysis, precursors at oxaloacete/DHAP or pyruvate Precursors: Lactate – skeletal muscles exceed OX metab, AAs – diet/starvation – not leucine/lysine, Glycerol – TAG -> glycerol + FFAs Glycerol -> (Glycerol kinase) -> glycerol phosphate -> (glycerol phosphate dehydrogenase) -> DHAP Pyruvate -> (6ATP + 2NADH used) Glucose – not reverse of glycolysis (makes 2ATP + 2NADH) Reversable reactions of Glycolysis need to be bypassed: 3. Glucose + ATP -> G-6-P + ADP 1 2. F-6-P + ATP -> F1,6-bisP + ADP 3 1. Phosphoenolpyruvate + ADP -> Pyruvate + ATP 10 (PEP) Bypass 1 – pyruvate -> PEP 1. Pyruvate -> (ATP/Pyruvate Carboxylase) Oxaloacetate 2. Oxaloacetate -> (GTP/PEP carboxykinase) PEP LEFT: pyruvate = precurose = cystolic (needs low NADH) Cystolic PEP carboxykinase used, Oxaloacetate cant leave mitro, so converted to Malate which can, then back to oxaloacetate with production of NADH RIGHT: Lactate = precursor = mitro enzyme (yields NADH) Mitro PEP carboxykinase – makes NADH – used for 1,3-bisP -> GAP (glyceraldehyde 3-phosphate dehydrogenase – step 6 in glycolysis) later in cycle. Overall: Pyruvate + ATP + GTP + H2O -> PEP + ADP + GDP + 2H+ + Pi Bypass 2: F1,6-bisP -> F-6-P – uses same enzymes glycolysis until this. Enzyme = Fructose 1,6 biphosphatase F1,6-BisP + H2O -> F6P + Pi Bypass 3: in liver/kidney G-6-P -> glucose needed – occurs in ER (endorecticulum) G-6-P -> (H2O/G-6-phosphate) Glucose + Pi CORI CYCLE Lactate -> glucose in liver form muscle O2 to muscles < than whats needed for NADH oxidation, occurs via e- form Pyruvate -> (lactate dehydrogenase/NAD+) Lactate. Oxygen debt reduced by Lactic acid -> glucose via gluconeogenesis – mostly in larger animals Lactate enters oxy cells -> pyruavte enters TCA cycle Excess lactate enters live -> glucose – maintains blood glucose Glyoxylate Cycle: Plants/microorgs FFAs-> Glucose Acetyl CoA made by B-oxidation -> glucose via this cycle/gluconeogenesis Makes succinate -> TAC cycle -> gluconeogenesis -> Sucrose Acetyl-CoA stimulates Pyruvate carboxlase -> inc in gluconeogenesis for energy
BI1004 revision notes
University: Cardiff University
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