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Flashcards in Metabolism / Bioenergetics Deck (31)
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What are pathways and how are they regulated

- Pathways: Series of related enzymatically catalysed reactions form a pathway
- Metabolic Pathway: Produces energy or valuable materials
- Signal Transduction Pathway: Transmits information throughout the body
- Regulation: Controlled in order to regulate levels of metabolites, feedback inhibition


What is cellular metabolism and respiration

- Sum of all chemical reactions that occur in the body, anabolic (synthesis of molecules) and catabolic (breakdown of molecules)
- Regulated by enzymatic activity
- Respiration relates to O2 utilisation and CO2 production by the cellular tissues


What is the role of high energy transporters such as ATP, NADH and FADH2

- Electrons from reduced fuels (carbohydrates, lipids, AA) are transferred to reduced cofactors NADH or FADH2
- Transport H and E, to mitochondria for ATP generation (aerobic) or convert pyruvic acid to lactic acid (anaerobic)
- NADH: Produced in glycolysis / TCA to facilitate ATP synthesis (2.5), in ETC, converted back to NAD
- FADH2: Produced in glycolysis / TCA, 1.5 ATP
- ETC utilises reduced co-enzymes to produce ATP via oxidative phosphorylation


Why is ATP the universal energy currency of the cell and how is it required

- Frequently the donor of phosphate in biosynthesis of phosphate esters
- ATP hydrolysis has very high negative  ΔG = - 30.5kJ/mol (very favourable)
- Cellular ATP concentration is usually far above equilibrium concentration, ATP = potent source of = energy


What is anaerobic vs aerobic metabolism

- Anaerobic: Formation of ATP without the use of O2 (ATP-PC and glycolysis), cytoplasm, shorter energy production
- Aerobic: Production of ATP using O2 as the final electron acceptor (TCA, ETC), oxidative, mitochondria, longer energy production (60sec)


What is the pentose phosphate pathway

- Alternative use to glucose, cells generate pentose phosphates and NADPH
- Pentose phosphates can be generated into glucose-6-phosphate and inserted into TCA cycle (no ATP required)
- Or ribose-5-phosphate (precursor for DNA / RNA / coenzyme synthesis)


What is glycolysis and the steps involved

- Anaerobic, ubiquitous, substrate level phosphorylation
- Sarcoplasm, breakdown of glucose to pyruvate
Preparatory Phase:
- Energy investment, phosphorylation of glucose (6C)
- Glucose-6-phosphate (via hexokinase, use ATP)
- Fructose-6-phosphate
- Fructose-1,6-biphosphate (via PFK, use ATP)
- Glyceraldehyde-3-phosphate (3C)
- Used: 2 ATP molecules, 1 glucose and 2 NAD+
Payoff Phase:
- Energy production, glyceraldehyde-3-phosphate (3C) converted to pyruvate (3C) via pyruvate kinase
- Glucose + 2 NAD+ + 2 ADP + 2 Pi — 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP


What are the fates of pyruvate

- Pyruvate formed in glycolysis can serve as a precursor in anabolic reactions or become
- Acetyl CoA: 2 acetyl CoA, aerobic, CAC to produce 4CO2 + 4H2O), animal plant and many microbial
- Ethanol: 2 ethanol + CO2, anaerobic, fermentation
- Lactate: 2 lactate, anaerobic, fermentation, via lactate dehydrogenase in vigorously contracting muscle, regenerates NAD for glycolysis to continue, favourable


What is the function of gluconeogenesis

- Allows generation of glucose from AA, lactate and glycerol when glycogen stores are depleted
- Reverse pathway of glycolysis
- Pyruvate to oxaloacetate (pyruvate carboylase)
- Oxaloacetate to PEP (PEP carboxykinase)
- Fructose 1-6 biphosphate to fructose 6 phosphate (fructose biphosphatase-1)
- Glucose 6 phosphate to glucose (glucose 6 phosphatase)
- 2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 4 H2O — Glucose + 4 ADP + 2 GDP + 6 Pi  + 2 NAD+


Compare and contrast regulation of glycolysis and gluconeogenesis and key regulatory steps

- Opposing pathways both thermodynamically favourable
- End product of one is starting product of the other
- Reversible reactions used in both, prevents futile cycle
- No ATP generated during gluconeogenesis
- Different key regulatory enzymes
- Glycolysis (muscle and brain) and gluconeogenesis (liver)
- Regulatory enzymes correspond to points that have same substrate and product but different enzyme


What is the role of fats as fuel

- 1/3 of energy comes from triacylglycerols
- Carry more energy than polysaccharides per C, they are more reduced, complex and carry less water (non-polar)
- Long term energy needs, good storage, slow delivery


Explain the process of B oxidation of saturated fats

- Mitochondria, small saturated (<12 C) FA diffuse freely across mitochondrial membranes, larger FA transported via carnitine transporter / fatty acyl-adenylate (exergonic)
- Series of reactions, oxidative conversion of FA chain 2 C units at a time into acetyl CoA
- Reduce FAD and NAD+
- Acetyl CoA enters CAC and further oxidises into CO2, makes more GTP, NADH, and FADH2
- Or acetyl CoA is converted to ketone bodies (oxaloacetate depletion), taken up by heart, muscles, brain


Describe process of fatty acid synthesis

- Occurs when NADPH levels are high (adipocytes / hepatocytes), requires malonyl-CoA and acetyl-CoA
- Synthesis of fatty acids is a multistep process
- Step 1: Acetyl-CoA is carboxylated to form malonyl-CoA, catalysed by acetyl CoA carboxylase (ACC)
- Step 2: FAS1 catalyses sequential addition of 2C units to malonyl CoA
- Final Product is Palmitate, uses a lot of ATP and NADPH, palmitate can be extended further and also desaturated


How is fatty acid synthesis regulated

- Citrate Anabolism: Excess energy / acetyl CoA is transported into cytosol so FA synthesis can use it up
- RLE: Acetyl CoA to Malonyl-CoA via acetyl-CoA carboxylase (ACC), palmitoyl CoA inhibits, citrate activates
- Gene Expression: FA bind to transcription factors
- Malonyl-CoA: Inhibits FA import into mitochondria, ensure FA synthesis and b oxidation don't occur simultaneously


What are the fates of nitrogen

- Ammonia: Plants conserve almost all N, aquatic vertebrates release NH3 to environment (passive diffusion from epithelial cells or active transport via gills)
- Urea: Terrestrial vertebrates / sharks excrete nitrogen in form of urea (less toxic than NH3, high solubility)
- Uric Acid: Birds and reptiles excrete N as uric acid (insoluble, excretion as paste)
- Both: Humans excrete both urea (from AA) and uric acid (from purines)


What are the processes of amino acid metabolism

NH3 (Ammonia)
- Transfer of one amine to a-ketoglutarate (transamination)
- Transfer of second amine to l-glutamine
- L-glutamine is a temporary storage of N (2 fates)
- 1: Glucose alanine cycle
- 2: Converted to carbamoyl phosphate to enter urea cycle and secreted by sweat / urine
Carbon Skeleton
- Ketogenic AA: Converted to ketone bodies via acetyl CoA
- Glucogenic AA: Converted to glucose and enter glycolysis (pyruvate, acetyl-CoA, α-ketoglutarate, succinyl-CoA, oxaloacetate)


What are the principles of amino acid synthesis

- Synthesised from a-ketoglutarate, 3-phosphoglycerate, oxaloacetate, pyruvate, phosphoenolpyruvate, erythrose 4-phosphate, and ribose-5-phosphate


How are amino acids used as precursors for biological macro molecules

- Porphyrin rings (e.g., heme)
- Phosphocreatine
- Glutathione
- Neurotransmitters and signalling molecules
- Cell-wall constituents
- Metabolic precursor of nucleic acids


What is the role of acetyl CoA in metabolism

- Allows carbohydrates, fats and proteins to enter aerobic metabolism to form ketone bodies or enter TCA / ETC or become FA
- Glycogen (glycogenolysis) glucose (glycolysis) pyruvate (oxidation) acetyl CoA
- Triglyceride (lipolysis) FFA (b oxidation) acetyl CoA
- Protein (proteolysis) AA (deamination / oxidation) acetyl CoA


Describe the TCA cycle and high energy carriers

- Priming and oxidation of pyruvate (3 C) to create acetate (2 C), binds with coenzyme A to produce acetyl CoA, CO2 and 2 NADH
- 1: Acetyl CoA (2 C) combines with oxaloacetic acid (4 C) to produce citrate / citric acid (6 C), favourable, irreversible
- 2: Isomerisation of citrate to isocitrate, unfavourable, reversible
- 3-4: Oxidative decarboxylations to produce 2 NADH and CO2, dehydrogenase converts isocitrate to a-ketoglutarate (5C) to succinyl CoA (4C), favourable, irreversible
- 5: Phosphorylation of succinyl CoA (4C) to succinate (4C) and GTP, favourable, reversible
- 6: Dehydrogenation to FADH2, reversible, succinate (4C) to fumarate (4C)
- 7: Hydration of double bond, favourable, reversible, fumarate to l-malate via fumarase
- 8: Dehydrogenation to NADH, unfavourable, reversible, l-malate (4C) to oxaloacetate (4C)
- Transfers high energy e- to carriers, harvested e- directed to ETC to drive ATP synthesis


Explain the importance of compartmentalisation of metabolic processes and regulation of opposing anabolic / catabolic pathways

- Metabolic processes must be coordinated, opposing pathways are not operating simultaneously, cell must respond to constant changes (external and internal conditions)
- In multi-cellular organisms cells must co-operate, simplified by division of labour between tissues
- Different pathways operate in different tissues
- RBC: Utilises PPP, no mitochondria no TCA
- Brain: Glucose main fuel
- Muscle: Glucose, FA, ketone, anaerobic and anaerobic
- Adipose: FA, affected by insulin / glucagon
- Liver (G): Glycolysis, gluconeogenesis
- Liver (FA): Degrade FA, synthesise ketones
- Liver (AA): Completely oxidised or converted to glucose to ketones


What is the ETC and what does it produce

- Inner mitochondrial membrane, series of specialised acceptor / donor molecules (cytochromes)
- Phase 1 (create proton gradient) phase 2 (chemiosmosis / synthesis of ATP)
- 1: Reduced coenzymes (NADH and FADH2) deliver e to respiratory complexes I and II
- 2: E are transferred from one complex to another in membrane, each complex is reduced and then oxidised, releasing energy that is used to pump H+ into inter membrane space
- 3: Creation of electrochemical gradient between matrix and inter membrane space
- 4: At respiratory enzymes complex IV, E pairs combine with two protons (H+) and a half molecule of O2 = water
- 5: Complex V (ATP synthase) harnesses energy of proton gradient


What is the physiological relevance of the cori cycle

- Anaerobic glycolysis in muscle, pyruvate → lactate (transported in blood) → liver → pyruvate → glucose / glycogen, reuse lactate and recovery of glucose
- Re-oxidise NADH and permit continued ATP production from glycolysis
- Muscles produce ATP via glycolysis but during anaerobic contraction produce lactate
- Lactate exported into the blood
- Liver takes up lactate from the blood and then converts it to pyruvate to glucose via gluconeogenesis
- Glucose then recycled into blood


How is metabolism regulated differently in various tissues

- Regulation of metabolism is a coordinated event across the whole organism
- Availability of substrates, allosteric activation & inhibition of enzymes, covalent modification of enzymes, induction & repression of enzyme synthesis
- When Glycolysis is switched on GNG is switched off – but may occur in different organs eg Cori Cycle


Explain the regulation of movement of fuels during starvation

- Liver makes increased acetyl CoA when fat is mobilised and glucose is decreased
- Increased acetyl CoA normally causes TAG synthesis but if glucose is low, TAG is also low
- Excess acetyl CoA to ketones, leads acidosis in starvation
- The liver maintains glucose output using AA for gluconeogenesis that come from muscle


What is the flow chart of catabolism and anabolism

- Energy containing nutrients (CHO, fats, proteins)
- Use ADP, NAD, FAD to catabolise
- Produce energy depleted products, ATP, NADH, FADH2, NADPH
- Precursor molecules for anabolism (AA, sugar, FA)
- Use ATP, NADH, FADH2, NADPH to undergo anabolism
- Produce Cell macromolecules (proteins, lipids, nucleic acids), ADP, NAD and FAD


Provide an overview of metabolism of lipids proteins and ketones

- Lipids: Triglycerides undergo lipolysis to FFA which undergo β oxidation to acetyl CoA (catabolic), acetyl CoA can also undergo fatty acid synthesis (anabolic)
- Protein: Undergo proteolysis to AA which undergo deamination / oxidation to acetyl CoA (catabolic), acetyl CoA can also undergo amino acid synthesis (anabolic)
- Ketones: Acetyl CoA undergoes catabolism to form ketone bodies


How are unsaturated fatty acids metabolised

- Contain cis double bonds, not a substrate for enoyl-CoA hydratase and cannot undergo β oxidation, slightly lower yield of FADH2, different enzymes for odd numbered PUFAs
- Isomerase: Converts cis double bonds starting at carbon 3 to trans double bonds (monounsaturated and polyunsaturated)


How is TCA cycle regulated

- Steps 1, 3, 4: Highly thermodynamically favourable and irreversible steps, PDC (pyruvate to acetyl CoA), citrate synthase, IDH and KDH
- Activated by substrate availability and inhibited by product accumulation


What is chemiosmosis and proton motive force

- ATP: ADP + Pi → ATP is highly thermodynamically unfavourable
- Chemiosmotic Theory: Transfer of electrons down an electron transport system through a series of oxidation-reduction reactions releases energy
- Chemiosmosis: Movement of ions across semipermeable membrane, down electrochemical gradient, energy needed to phosphorylate ADP provided by flow of protons down electrochemical gradient
- PMF: The inner mitochondrial membrane separates two compartments of different [H+], resulting in differences in chemical concentration and charge distribution across the membrane


What is the glucose alanine cycle

- Similar to cori cycle
- Pyruvate binds with glutamate to produce a-ketoglutarate and alanine
- Transfer to liver
- Binds with a-ketoglutarate to form pyruvate and glutamate
- Glutamate enters urea cycle
- Pyruvate undergoes gluconeogenesis to glucose, regenerated for glycolysis