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MIMS > Bioenergetics and Metabolism > Flashcards

Bioenergetics and Metabolism Flashcards

1
Q

what is enthalpy change related to?

A

how much energy is released by a reaction

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2
Q

what is Gibbs Free Energy?

A

enthalpy change - temperature(change in entropy)

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3
Q

what is needed for a spontaneous reaction?

A

must either be exothermic, have large increase in entropy or both, ∆G < 0

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4
Q

what is ∆G for a reaction at equilibrium?

A

∆G = 0

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5
Q

what conditions are needed for standard changes in Gibbs free energy?

A

pH 7, 1atm of pressure, 298K

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6
Q

how does coupling work?

A

endergonic reaction (won’t occur spontaneously) coupled to exergonic reaction

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7
Q

what reaction is one of the main driving forces for other thermodynamically unfavourable reactions?

A

ATP hydrolysis

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8
Q

why is ATP hydrolysis so exothermic?

A

phosphate and ADP have more resonance stabilisation than ATP. negative charge is dissipated over more of the molecule thereby stabilising the structure- ATP has 4 negative charges at pH 7 so P-O-P bonds weakened by electrostatic repulsion, more water can bind and stabilise ADP and Pi than ATP

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9
Q

what is the phosphorylation potential of ATP hydrolysis?

A

free energy of ATP hydrolysis

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10
Q

order of phosphorylation potentials of biologically important phosphorylated molecules, least to most?

A

PEP, 1,3-bisphosphoglycerate, phosphocreatine, ATP, G-6-P, 3-phosphoglycerate

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11
Q

what molecules will phosphorylate ADP?

A

PEP, 1,3-bisphosphoglycerate, phosphocreatine

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12
Q

examples of ATP hydrolysis coupling?

A

used to phosphorylate glucose to provide enough energy to prime the molecule to be broken down to pyruvate, used to stabilise peptide chains so they can be made longer, provides energy to join 2 nucleic acids at start of DNA synthesis

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13
Q

what group do NADH, NADPH, FADH2 and FMNH2 carry?

A

electrons

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14
Q

what group does coenzyme A carry?

A

acyl

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15
Q

what is the main redox system for energy producing pathways?

A

NAD+/NADH

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16
Q

what is the main redox system for biosynthesis?

A

NADP+/NADPH

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17
Q

when are reactions catalysed by acetyl-CoA important?

A

activation of fatty acids and at start of CAC

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18
Q

overview of liver role in bioenergetics and metabolism?

A

central role in glucose homeostasis. ‘fat factory’ in terms of synthesis and export of triglycerides to adipose tissue. liver partially oxidises fats to produce ketone bodies- central to N recycling and excretion/amino acid metabolism

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19
Q

why can heart be called ‘dustbin’ of body?

A

will metabolise wide variety of substrates left over from other metabolic processes

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20
Q

overview of what brain uses for metabolism?

A

largely uses glucose, can use ketone bodies during fasting

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21
Q

why is control needed in metabolic pathways?

A

to avoid uncontrolled substrate cycle, link energy production to energy usage, to respond to physiological changes

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22
Q

how can amount of enzyme present be changed? (2 general ways)

A

altering rate of synthesis or altering rate of destruction- long term changes or metabolically controlled changes

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23
Q

when is glucagon produced, when is insulin produced?

A

glucagon in response to low blood glucose, insulin in response to high blood glucose

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24
Q

2 broad types of metabolic pathway?

A

catabolic and anabolic

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25
Q

what happens in anabolic pathways?

A

more complex biomolecules synthesised from simpler smaller units. pathways consume energy

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26
Q

what happens in catabolic pathways?

A

larger molecule broken down to smaller units to generate energy- units may become building blocks for anabolic pathways

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27
Q

what is the overall reaction of glucose metabolism?

A

C6H12O6 + 6O2 -> 6CO2 + energy as ATP

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28
Q

what are the 2 pathways involved in carbohydrate metabolism?

A

glycolysis, citric acid cycle, oxidative phosphorylation

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29
Q

other names for the citric acid cycle?

A

Krebs cycle, tricarboxylic acid cycle

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30
Q

how is glucose transported into most cells?

A

GLUTs (glucose transporters)

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31
Q

products of CAC?

A

CO2, NADH, FADH2, GTP

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32
Q

products of oxidative phosphorylation?

A

ATP, NAD+, FADH

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33
Q

which tissues take up glucose in an insulin independent manner? why do they do this?

A

brain (needs constant flow of glucose), liver cells (mop up excess glucose), erythrocytes

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34
Q

which tissues take up glucose in an insulin dependent manner?

A

fat and muscle cells

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35
Q

what are the insulin independent GLUTs?

A

GLUT 1, 2, 3

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36
Q

what is the insulin dependent GluT?

A

GluT4

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37
Q

how do GluT4 molecules respond to insulin?

A

prior to cells being exposed to insulin the GluT4 proteins are trapped in intracellular vesicles, insulin recruits these vesicles to the cell membrane to allow transport of glucose

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38
Q

products of glycolysis?

A

pyruvate, 2ATP, NADH

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39
Q

what are the 2 fates for NADH produced in glycolysis?

A

can be transported into mitochondria for oxidation or used to reduce pyruvate to lactate to regenerate NAD+

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40
Q

difference in carbohydrate metabolism in anaerobic conditions?

A

glycolysis still used (important in RBCs, cells in retina and fast-twitch white muscle), oxygen debt then repaid by increasing CAC rate to oxidise lactate produced by pyruvate conversion by LDH

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41
Q

what are the 2 halves of glycolysis?

A

first half which involves chemical priming and consumes ATP, second half which involves energy (ATP) generation

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42
Q

what are the 3 stages in the overall pathway of glycolysis?

A

glucose prepared for lysis then split into 2 3C-monosaccharides, one of these (glyceraldehyde-3-phosphate) is then oxidised to produce 2ATP and 2NADH per glucose, then rearrangement to produce pyruvate

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43
Q

2 examples of cells with no mitochondria?

A

RBCs and cells within retina

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44
Q

what happens in the first stage of glycolysis?

A

glucose-> glucose-6-phosphate -> fructose-6-phosphate -> fructose 1,6-phosphate-> glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. consumes 2 ATP

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45
Q

what happens in the second stage of glycolysis?

A

glyceraldehyde-3-phosphate oxidised to produce 2 ATP and 2 NADH per glucose. aldehyde in the glyceraldehyde converted to a carboxylic acid. NAD+ and inorganic phosphate incorporated to form 1,3-bisphosphoglycerate- has high energy acyl bond which supplies phosphate to convert ADP to ATP. 2ATP and 2NADH produced overall

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46
Q

what happens in the 3rd stage of glycolysis?

A

rearrangement, dehydration and loss of phosphate to produce pyruvate and 2 ATP

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47
Q

what are the ways NAD+ are regenerated in mammalian tissues?

A

NADH can be oxidised in mitochondria, NADH can be oxidised by lactate dehydrogenase during conversion of pyruvate to lactate

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48
Q

fates of lactate produced in anaerobic glycolysis?

A

exported to bloodstream (Cori cycle) or converted back to pyruvate for oxidation of carbon backbone in CAC

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49
Q

effect of excess lactate in blood?

A

overpowers buffering capacity of blood, makes blood more acidic

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50
Q

what is the pentose phosphate pathway?

A

operates alongside glycolysis, ensures supply of reducing potential in form of NADPH and important intermediates such as ribose 6-phosphate for anabolic pathways

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51
Q

where does the pentose phosphate pathway operate?

A

in liver and other cell types heavily involved in biosynthesis of fats and other biomolecules such as mammary glands, adipose tissue and adrenal cortex

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52
Q

overall product of pentose phosphate pathway?

A

for every 3 molecules of glucose 6-phosphate diverted from glycolysis into PPP 2 molecules of fructose 6-phosphate and 1 molecule of glyceraldehyde 3-phosphate are returned back to the glycolysis pathway

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53
Q

why is gluconeogenesis important?

A

brain always requires glucose as fuel even if part of requirement can be met by other fuels. some organs in body have little oxidative capacity so need to recover the lactate produced by anaerobic glycolysis in these tissues in for other organs can use or re-cycle carbon chain back to anaerobic organs such as glucose

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54
Q

which 3 reactions in glycolysis aren’t readily reversible?

A

glucose -> glucose 6-phosphate; fructose 6-phosphate ->fructose 1,6-bisphosphate; phosphoenolpyruvate->oxaloacetate->pyruvate

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55
Q

reaction converting pyruvate -> phosphoenolpyruvate?

A

2 steps. first= pyruvate carboxylase catalyses reaction of pyruvate, ATP, bicarbonate to form oxaloacetate, second= PEP carboxykinase catalyses conversion of oxaloacetate to PEP using GTP

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56
Q

how is fructose 1,6-bisphosphate converted back to fructose 6-phosphate?

A

hydrolysis of a phosphate group by fructose 1,6-bisphosphatase

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57
Q

how is glucose 6-phosphate converted back to glucose?

A

hydrolysis by glucose 6-phosphatase

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58
Q

what GluTs does the liver use?

A

GluT

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59
Q

which has a higher Km. glucokinase or hexokinase?

A

glucokinase

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60
Q

effect of the different Kms of glucokinase and hexokinase?

A

liver can’t take up glucose at low blood glucose levels due to higher Km of glucokinase but can deal with high glucose concentrations. when glucose 6-phosphate builds up muscle tissue can still produce glucose 6-phosphate for glycogen or lipid synthesis

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61
Q

what is the substrate/allosteric inhibitor of PFK-1? what potentiates this?

A

ATP, potentiated by citrate

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62
Q

where is hexokinase?

A

muscle

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63
Q

where is glucokinase?

A

liver

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64
Q

effect of PFK-1 in inactive state? (high citrate and ATP)

A

glycolysis in muscle

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65
Q

effect of exercise on [AMP]?

A

causes large rise in [AMP] as adenylate kinase catalyses the reaction 2ADP <-> ATP + AMP

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66
Q

why does [AMP] rise rapidly as [ADP] rises during muscle contraction?

A

[AMP] is only around 2% [ATP] so 10% decrease in [ATP] will result in 400% increase in [AMP]

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67
Q

how is PFK-1 controlled in muscle?

A

by [AMP] (AMP increases, glycolysis increases)

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68
Q

how is PFK-1 controlled in the liver?

A

fructose 2,6-bisphosphate causes decreased gluconeogenesis and increased glycolysis. potent activator of PFK-1

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69
Q

how is fructose 2,6-bisphosphate formed?

A

phosphorylation of fructose 6-phosphate by separate kinase PFK-2

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70
Q

why do futile cycles such as the one between fructose 6-phosphate and fructose 1,6-bisphosphate (via PFK-1 and fructose 1,6-bisphosphatase) exist?

A

serve important regulatory process of signal amplification in tissues such as skeletal muscles, at cost of expending some ATP the system is made more sensitive to small changes in concentration of regulatory muscles

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71
Q

what enzyme controls the conversion of fructose-6-phosphate to fructose-2,6-bisphosphate to control the flux through glycolysis and gluconeogenesis?

A

bifunctional enzyme with domain containing PFK-2 and domain containing fructose 2,6-bisphosphatase

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72
Q

how is hormonal control of balance between glycolysis and gluconeogenesis exercised in the liver?

A

by controlling concentration of fructose 2,6-bisphosphate by controlling production of PFK-2 and fructose 2,6-bisphosphatase (recycles it to fructose 6-phosphate)

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73
Q

action of glucagon in liver?

A

acts when [glucose] is low, activates PKA which phosphorylates the bifunctional enzyme so that simultaneously PFK-2 decreases, fructose 2,6-bisphosphatase increases- so gluconeogenesis favoured over glycolysis

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74
Q

how is hormonal control of balance between glycolysis and gluconeogenesis exercised in cardiac muscle?

A

hormonal action of adrenaline causes phosphorylationn of PFK-2 via PKA on different site increasing its rate so fructose-2,6-bisphosphate increases, glycolysis increases

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75
Q

how is hormonal control of balance between glycolysis and gluconeogenesis exercised in skeletal muscle?

A

PFK-2 isoform not phosphorylated, enzyme responds to increase in [fructose-6-phosphate] and therefore fructose-2,6-bisphosphate increases reinforcing effect of AMP increase, increasing glycolysis

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76
Q

what does fructose 1,6-bisphosphate stimulate?

A

pyruvate kinase

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77
Q

how is glucose stored?

A

as glycogen

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78
Q

structure of glycogen?

A

polymer of glucose predominantly joined at α(1->6), one end joined to protein glycogenin

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79
Q

when is the CAC active, fed or fasted state?

A

in the fed state

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80
Q

effect of products of CAC- citrate and ATP- on glycolysis?

A

act as allosteric inhibitors of glycolysis so allow conversion of glucose to glycogen in fed state when CAC is active

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81
Q

where is there more glycogen, the liver or muscle?

A

more in muscle

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82
Q

why is UTP needed to produce glycogen?

A

glucose-1-phosphate isn’t a powerful enough donor to form a glucose-glucose bond so needs energy input from UTP

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83
Q

enzyme required for glucose 6-phosphate -> glycogen?

A

glycogen synthase

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84
Q

enzyme and cofactor required for glycogen -> glucose 6-phosphate?

A

glycogen phosphorylase and AMP

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85
Q

how is glycogen metabolism controlled?

A

hormonal and electrical stimulation- stimulated by adrenaline which binds to receptor to activate adenylate cyclase to make cAMP which activates PKA which activates phosphorylase kinase and inhibits glycogen synthase. phosphorylase kinase activates glycogen phosphorylase b to make glycogen phosphorylase a.

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86
Q

what opposes the action of AMP stimulating phosphorylase b?

A

ATP

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87
Q

during exercise is glycogen being produced or broken down to glucose 1-phosphate? so is glycogen synthase or glycogen phosphorylase active?

A

being broken down, so glycogen phosphorylase is active

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88
Q

effect of glucose 6-phosphate on glycogen metabolism?

A

inhibits conversion of glycogen to glucose 1-phosphate

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89
Q

what enzyme breaks down cAMP to AMP?

A

cAMP phosphodiesterase

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90
Q

what stimulates cAMP phosphodiesterase to convert cAMP to AMP?

A

insulin

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91
Q

what inhibits cAMP phosphodiesterase conversion of cAMP to AMP?

A

caffeine

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92
Q

effect of Ca2+ on glycogen metabolism in muscle?

A

activates phosphorylase kinase which activates glycogen phosphorylase b to make glycogen phosphorylase a which is used to convert glycogen to glucose 1-phosphate

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93
Q

how is signal to break down glycogen turned off in well fed state?

A

cAMP hydrolysed to 5’AMP and protein phosphatases remove phosphates from proteins, insulin acts through glycogen synthase kinase 3 (GSK3) which is inhibited and turns on glycogen synthase thus glycogen formed

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94
Q

what is the Cori cycle?

A

muscle tissue generates lactate during explosive exercise, would cause acidosis if not exported into blood. lactate converted back to glucose via gluconeogenesis in liver, after exercise glucose transported back to muscle tissue and stored as glycogen

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95
Q

importance of gluconeogenesis?

A

maintaining normal function in brain where glucose is the primary fuel

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96
Q

what can the brain use as fuel?

A

glucose and ketone bodies

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97
Q

what does the body do to proteins in long term starvation?

A

converts them to glucose via amino acids and citric acid cycle

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98
Q

what are the excess products from adipose tissue and skeletal muscle during type 2 diabetes? what happens to them?

A

lactate, alanine, glycerol. serve as substrates for gluconeogenesis with energy required for ATP coming from beta-oxidation of FAs

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99
Q

role of PEP-CK under normal circumstances?

A

partial control (stimulation) of gluconeogenesis- negatively regulated by insulin

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100
Q

effect of type 2 diabetes on PEP-CK?

A

expression of PEP-CK rises as negative regulation by insulin lost, increased production of glucose adds to hyperglycaemia

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101
Q

function of metformin?

A

suppresses liver gluconeogenesis, treatment for type 2 diabetes

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102
Q

what is the CAC involved in?

A

generation of energy from metabolic fuels that are broken down to acetyl-CoA, provision of building blocks for metabolic processes, co-ordination of fuel use to physiological demands, control of PDH to ensure glucose supplies to brain, connection to oxidative phosphorylation

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103
Q

overall is the CAC a reduction or oxidation reaction?

A

oxidation

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104
Q

where does the CAC take place?

A

in the matrix of the mitochondria

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105
Q

what is produced by each turn of the CAC?

A

3 NADH, 1 FADH2, GTP (readily converted to ATP), CO2 (2 for each acetyl group entering cycle)

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106
Q

what conditions are required for the CAC?

A

oxidative

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107
Q

how is pyruvate converted to acetyl-CoA to enter the CAC?

A

using CoASH and NAD+ and pyruvate dehydrogenase to produce acetyl-CoA, CO2 and NADH

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108
Q

what happens to acetyl-CoA in the CAC?

A

combines with oxaloacetate to form citrate, uses citrate synthase, releases CoASH. high energy sulphur bond broken

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109
Q

what happens to citrate in the CAC?

A

uses aconitase to form isocitrate. rearrangement reaction

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110
Q

what happens to isocitrate in the CAC?

A

uses isocitrate dehydrogenase and NAD+ to form oxoglutarate, releases CO2 and NADH. oxidation and decarboxylation.

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111
Q

what happens to oxoglutarate in the CAC?

A

uses α-ketoglutarate dehydrogenase, NAD+ and CoASH to form succinyl CoA, CO2, NADH.

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112
Q

what happens to succinyl CoA in the CAC?

A

uses succinyl CoA synthetase, GDP, phosphate to form succinate, CoASH, GTP. GTP can then be converted to ATP (GTP + ADP -> ATP + GDP)

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113
Q

what happens to succinate in the CAC?

A

uses FAD to form fumarate and FADH2

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114
Q

what happens to fumarate in the CAC?

A

uses fumarase and H2O to form malate. hyddration reaction

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115
Q

what happens to malate in the CAC?

A

uses malate dehydrogenase and NAD+ to form oxaloacetate and NADH

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116
Q

what happens to oxaloacetate in the CAC?

A

uses acetyl CoA and citrate synthase to form citrate and CoASH

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117
Q

order of intermediates in the CAC?

A

oxaloacetate + acetyl-CoA -> citrate -> isocitrate -> oxoglutarate -> succinyl CoA -> succinate -> fumarate -> malate -> oxaloacetate

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118
Q

where do glycolysis, the PPP and FA synthesis take place? (have their enzymes)

A

in the cytosol

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119
Q

where do the CAC, beta-oxidation and the respiratory chain take place? (have their enzymes)

A

in the mitochondria

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120
Q

overall stoichiometry of CAC?

A

2 carbons enter (as acetyl-CoA) and 2 carbons leave as CO2

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121
Q

why is an anaplerotic pathway needed alongside the CAC, what is this pathway?

A

to return carbon to the cycle. pyruvate carboxylase converts pyruvate + CO2 + H2O + ATP to oxaloacetate + ADP + Pi + 2H+

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122
Q

how many ATP molecules are generated from 1 NADH?

A

2.5

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123
Q

how many ATP molecules are generated from 1 FADH2?

A

1.5

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124
Q

overall ATP generated from oxidative glycolysis (including from NADH entering ETC)?

A

5

125
Q

total number of ATP molecules generated from CAC (including NADH and FADH2 entering ETC)?

A

8NADH + 2FADH2 + 2GTP = 25 ATP

126
Q

total number of ATP molecules generated from aerobic glycolysis + the CAC?

A

30

127
Q

structure of PDH?

A

multienzyme complex of 3 enzymes

128
Q

function of PDH kinase?

A

phosphorylates PDH and deactivates it

129
Q

what are the regulatory enzymes for PDH?

A

PDH kinase and PDH phosphatase

130
Q

function of PDH phosphatase?

A

dephosphorylates PDH which activates it

131
Q

what inhibits PDH kinase? what does this ensure?

A

pyruvate- ensures PDH converts pyruvate to acetyl CoA when lots of pyruvate present

132
Q

what activates PDH phosphatase?

A

Ca2+, and insulin in adipocytes

133
Q

why does Ca2+ activate PDH phosphatase?

A

stimulates PDH during exercise

134
Q

why does insulin activate PDH phosphatase in adipocytes?

A

stimulates PDH during feeding for lipid synthesis

135
Q

ratio of what substances is used to regulate PDH?

A

ratio of NADH/NAD+ and acetyl CoA/CoA so PDH turns off if lots of NADH and acetyl CoA (products of PDH catalysed reaction)

136
Q

inhibitor of citrate synthase? when is this important?

A

allosterically inhibited by ATP. important for gluconeogenesis and ketogenesis during starvation to supply brain

137
Q

effects of citrate synthase inhibition by ATP?

A

oxaloacetate used in gluconeogenesis,
acetyl-CoA used to generate ketone bodies instead of being used to produce citrate in the CAC

138
Q

what inhibits isocitrate dehydrogenase (ICDH)

A

high NADH/NAD+ ratio and ATP - conditions typical of fed state

139
Q

what stimulates isocitrate dehydrogenase?

A

ADP

140
Q

what inhibits α-ketoglutarate dehydrogenase?

A

its products succinyl-CoA and NADH

141
Q

what stimulates α-ketoglutarate dehydrogenase?

A

Ca2+

142
Q

why do tumours have a high oxidative glycolytic rate even when oxygen available?

A

running glycolysis at higher flux helps promote flux through PPP which produces ribose for nucleotide synthesis, NADPH for FA synthesis and glutathione reduction- products used for making more DNA and lipids in cell membranes- give cancer competitive replicative advantage

143
Q

where and how are fats stored in the body?

A

stored in adipocytes + less healthily in liver,
as triacylglycerols (also called neutral fats/triglycerides)

144
Q

why are fats an efficient way to store energy?

A

require less water than glycogen and produce more energy following complete oxidation

145
Q

how are TAGs mobilised?

A

converted into glycerol and FFAs by lipases which progressively hydrolyse ester bonds via diacylglyceride (DAG) and monoacylglyceride (MAG)

146
Q

role of hormone sensitive lipase?

A

converts TAG to DAG to MAG to FFA

147
Q

what is adipose TAG hydrolysis highly dependent on?

A

adipose triglyceride lipase (ATGL)

148
Q

effect of insulin on HSL and ATGL?

A

inhibitory

149
Q

effect of PKA on HSL?

A

activates it by phosphorylating it

150
Q

how does insulin act in opposition of cAMP raising hormones?

A

activates phosphodiesterase enzyme to break down cAMP

151
Q

things that raise fatty acid levels?

A

fasting, prolonged exercise, stress

152
Q

how does cAMP activate HSL?

A

activates protein kinase, PKA then involves ATP to activate HSL

153
Q

where are FFAs released and where are they taken up? where are most taken up in exercise?

A

released from adipose tissue, taken up by liver and muscle to be oxidised. in exercise most taken up by cardiac and skeletal muscle

154
Q

what acts as a carrier molecules of FAs? what does this binding to the FA result in?

A

CoA-SH. binding results in ATP conversion to AMP

155
Q

what happens in β-oxidation? where does this take place?

A

takes place in mitochondria. converts aliphatic fat into set of activated acetyl units (acetyl CoA) that can be used in the CAC

156
Q

stages of β-oxidation?

A

FAs activated using Coenzyme A to form acyl-CoA by fatty acyl CoA synthase. AMP produced by CoA-SH binding to a FA. overall reaction favourable as PPi formed is hydrolysed to Pi

157
Q

does all β-oxidation use the same enzyme?

A

no, different enzymes for short, medium and long chain FAs

158
Q

where does activation of β-oxidation occur?

A

at outer mitochondrial membrane

159
Q

how does the fatty acyl CoA produced in β-oxidation get across the inner mitochondrial membrane?

A

modified by carnitine acyltransferase I, carried across attached to carnitine, transferred back to CoA-SH once inside by carnitine acyltransferase II

160
Q

how is a fatty acid converted into acetyl CoA units?

A

oxidised to introduce double bond, double bond hydrated to introduce an oxygen. alcohol from the water added is hydrolysed to ketone. 4 carbon fragment cleaved by CoA to yield acetyl CoA, process repeated on FA chain.

161
Q

products generated by β-oxidation?

A

FADH2, NADH, acetyl-CoA, AMP, PPi

162
Q

how many ATPs are produced from palmitate?

A

around 106- 8 acetyl CoA for CAC, 7FADH2, 7NADH, 7H+ = 108, and 2 molecules of ATP consumed in palmitate activation

163
Q

what happens to the fat-derived acetyl CoA produced for the CAC?

A

can’t be used to synthesise glucose, is completely oxidised to CO2

164
Q

what happens when the liver produces mor acetyl-CoA than can be metabolised via the CAC? when might this happen?

A

ketone bodies formed in liver and released into blood. happens in starvation or diabetes when oxaloacetate levels drop during gluconeogenesis

165
Q

what are the FAD dependent acyl-CoA dehydrogenases? (4)

A

very long chain (VLCDH), long chain (LCDH), medium chain (MCDH/MCAD) and short chain acyl-CoA dehydrogenase (SCAD)

166
Q

effects of MCAD (medium chain acyl-CoA dehydrogenase) deficiency?

A

associated with cot death as babies can’t oxidise FAs as readily so die at night when glycogen depleted.

167
Q

when is FA oxidation needed, fed or fasted state?

A

fasted state when glycogen depleted

168
Q

what causes Jamaican vomiting sickness?

A

unripe ackee contains inhibitors of acyl-CoA dehydrogenases, depletes glycogen reserves

169
Q

effect of insulin of fatty acid oxidation/metabolism?

A

inhibits it

170
Q

what are the 3 ketone bodies?

A

acetoacetate, β-hydroxybutyrate and acetone

171
Q

which ketone body is exhaled on the breath?

A

acetone

172
Q

what happens to acetoacetate in the muscle?

A

cleaved to 2 acetyl-CoA which enters CAC

173
Q

why can’t liver cleave acetoacetate to acetyl-CoA?

A

doesn’t have the tranferase required to transfer CoA from succinyl-CoA to form acetoacetyl-CoA

174
Q

what is the issue with ketoacidosis?

A

the low pH- not the increase in ketone bodies itself

175
Q

effect of diabetes on ketogenesis?

A

increases it

176
Q

what happens to the glycerol produced from TAGs?

A

circulated to liver for recycling (since adipose tissue doesn’t have glycerol kinase)

177
Q

what is an important source of gluconeogenic precursors in ruminants?

A

conversion of propionate into succinyl-CoA

178
Q

how is fatty acid oxidation regulated?

A

lipolysis of TAG, re-esterification of FAs, transport into mitochondria, availability of NAD+ and FAD

179
Q

why aren’t FAs re-esterified under fasting conditions?

A

insulin concentration low so Glut4 isn’t recruited to membrane of adipose cells so little glucose uptake, depletes glycerol and prevents FFAs from re-esterification, so FAs released from adipose cells

180
Q

what prevents FA synthesis and degradation occurring alongside each other?

A

malonyl-CoA produced during FA synthesis, inhibits carnitine shuttle in liver (and maybe skeletal muscle + pancreas)

181
Q

where are very long chain FAs oxidised?

A

in peroxisomes

182
Q

what are peroxisomes?

A

rounded oxidising organelles found in the cell (especially liver cells) which chew up fats to shorter chain FAs

183
Q

where does fatty acid synthesis take place?

A

cytoplasm

184
Q

steps of fatty acid synthesis?

A

acetyl-CoA + CO2 + ATP -> malonyl CoA + ADP + Pi, catalysed by acetyl-CoA carboxylase

185
Q

why does fatty acid synthesis use NADPH not NADH?

A

allows 2 different reducing potentials at the same time in the cell- high NADPH/NADP ratio to favour reduction in FA synthesis at same time as high NAD/NADH ration to favour oxidation in glycolysis

186
Q

what process produces the majority of NADPH in cells?

A

pentose phosphate pathway

187
Q

how is the acetyl group from Acetyl-CoA generated in the mitochondria exported to the cytosol for FA synthesis?

A

carried out as citrate (produced by CAC)

188
Q

reaction converting citrate back to oxaloacetate and acetyl-CoA in cytoplasm after export from mitochondria?

A

ATP + citrate + CoA -> oxaloacetate + acetyl-CoA + ADP + Pi, catalysed by ATP citrate lyase

189
Q

what enzyme adds acetyl-CoA to the growing FA chain?

A

fatty acid synthase

190
Q

what conditions favour fat synthesis/lipogenesis?

A

high carbohydrate diet and insulin

191
Q

3 key steps of regulation of FA synthesis?

A

control of malonyl-CoA synthesis, control by AMP and citrate, uptake of glucose controlled by insulin, control of TAG synthesis

192
Q

how do AMP and citrate control FA synthesis?

A

AMP increases phosphorylation of ACC via AMPK. citrate activates ACC allosterically. feed forwards signal that acetyl-CoA is abundant- inhibited by acyl-CoA

193
Q

how is TAG produced?

A

3 fatty acyl-CoA + glycerol 3-phosphate -> TAG. glycerol 3-phosphate is produced from glyceron-phosphate + NADH

194
Q

where is TAG produced?

A

liver, adipose, lactating mammary glands

195
Q

how does insulin stimulate TAG production?

A

stimulates the enzymes that add acyl groups to glycerol- possibly by altering the phosphorylation of them. stimulates glucose metabolism to provide glycerol backbone for TAG synthesis

196
Q

what are the 2 ‘halves’ of amino acid metabolism and what are their fates?

A

nitrogen metabolism and the carbon backbone metabolism, N collected in liver for excretion as urea, C backbone enters CAC and is metabolised

197
Q

what are the ketogenic amino acids and what does this mean?

A

leucine and lysine- must be metabolised as ketone bodies, can’t enter CAC directly

198
Q

what does glucogenic amino acid mean?

A

can enter the CAC directly so could be used to make glucose via gluconeogenesis

199
Q

where is amino acid metabolism most intensive? where else does it take place?

A

liver, also takes place in muscle

200
Q

where is the urea cycle focused?

A

liver

201
Q

what happens to ammonia generated by amino acid metabolism in the muscle?

A

captured as glutamate to form glutamine for export to the liver

202
Q

how is N excreted in mammals?

A

as urea from the liver into the blood, then transported to kidney for disposal

203
Q

why is urea ideal for N excretion?

A

water soluble, not basic or acidic, ideal for detoxification

204
Q

what are responsible for transfer of amino groups between amino acids? what amino acids are they transferred to?

A

2-oxo acids, courtesy of amino transferases. transferred to glutamate, alanine and aspartate

205
Q

what is the prosthetic group of amino transferase?

A

vitamin B6

206
Q

what is the glucose-alanine cycle?

A

alanine = carrier of ammonia and carbon skeleton of pyruvate from skeletal muscle to liver. in liver ammonia excreted, pyruvate used to produce glucose which is returned to muscle

207
Q

what catalyses glutamate -> glutamine?

A

glutamine synthetase, also requires ATP hydrolysis

208
Q

what happens to the glutamine produced in the muscle?

A

transported to liver, NH4+ liberated in mitochondria by glutaminase,

209
Q

what happens to glutamate in the liver?

A

N in glutamate released as ammonia via oxidative deamination using glutamate dehydrogenase in mitochondria

210
Q

what makes glutamate dehydrogenase unusual?

A

can use either NAD+ or NADPH as cofactor, allosterically regulated by GTP and ATP

211
Q

what is the N input into the urea cycle in the form of?

A

aspartic acid and ammonia

212
Q

what happens to ammonia in first step of urea cycle?

A

reacts with bicarbonate to form carbamoylphosphate, requires 2 ATP

213
Q

what happens to carbamoylphosphate in the urea cycle?

A

added to ornithine to make citrulline

214
Q

what happens to citrulline in the urea cycle?

A

condenses with aspartate and uses ATP to form arginosuccinate

215
Q

what happens to argininosuccinate in the urea cycle?

A

cleaved to form fumarate and arginine

216
Q

what happens to fumarate produced in the urea cycle?

A

used in the CAC

217
Q

what happens to arginine in the urea cycle?

A

hydrolysed by arginase to release urea and ornithine ready to restart cycle

218
Q

how are enzymes catalysing the urea cycle reactions distributed in the cell?

A

distributed between the mitochondrial matrix and the cytosol

219
Q

what is the Krebs bicycle/aspartate-arginosuccinate shunt?

A

the interactions between the CAC and the urea cycle

220
Q

effects of ammonia toxicity (large excess of ammonia)?

A

can produce hepatic encephalopathy whereby ammonia accumulates in brain drawing water in and damaging brain as it tries to expand. also detrimental effects on brain of depleting CAC of α-ketoglutarate by first converting it to glutamate and then glutamine

221
Q

overview of the chemiosmotic hypothesis?

A

reducing potential generated by β-oxidation and the CAC (+ a little from glycolysis). the NADH and FADH2 generated are then oxidised by O2 to produce water- process pumps H+ across mitochondrial membrane- force generated used to make ATP from ADP and phosphate, this fuels the cell. process takes place in mitochondria

221
Q

mitochondrion structure?

A

cristae of inner mitochondrial membrane provide very large SA. inner membrane of single liver mitochondrion has over 10000 sets of respiratory chains and ATP synthase molecules

222
Q

how many mores sets of electron transfer systems in heart mitochondria than liver?

A

3x

222
Q

what % of the protein of heart tissue is found in mitochondria?

A

30%

223
Q

what pumps protons out of the mitochondria? what supplies the energy for this?

A

the PMF, energy from oxidation of NADH and FADH2

224
Q

what gradients does the PMF work against?

A

pH gradient and charge gradient

225
Q

how are ATP synthesis and the proton motive force coupled?

A

protons travel through ATP synthase which forms ATP by the condensation of ADP and Pi

226
Q

how can oxygen consumption in mitochondria be measured?

A

by an oxygen electrode: mitochondria placed in buffer, oxygen electrode records decrease in oxygen level

227
Q

what is state 4 respiration?

A

ADP not present, mitochondria respire slowly to compensate for leakage of protons across inner mitochondrial membrane

228
Q

what is state 3 respiration?

A

oxygen consumption increases markedly when ADP present- demonstrates that system is coupled- protons can only flow across IMM when ADP present so oxygen used to oxidise reducing agents

229
Q

what do uncouplers such as protein ionophores and 2,4-DNP do?

A

promote H+ re-entry so dismantle the PMF. when present O2 consumed even when no ATP produced

230
Q

how many redox centres, different polypeptides and supramolecular complexes are there in the ETC?

A

20 redox centres, 70 different polypeptides, in 4 supramolecular complexes

231
Q

how are electrons shuttled between complex I + II to complex III?

A

by ubiquinone (Q) being reduced to QH2

232
Q

how are electrons shuttled from complex III to IV?

A

cytochrome c

233
Q

what does complex 4 transfer electrons to?

A

O2

234
Q

what is NAD?

A

nicotinamide adenine dinucleotide

235
Q

what is FMN?

A

flavin mononucleotide

236
Q

what is FAD?

A

flavin adenine dinucleotide

237
Q

where is the redox centre in FAD?

A

the isoalloxazine ring

238
Q

what prosthetic group does complex I use for oxidation?

A

FMN

239
Q

what prosthetic group does complex II use for oxidation?

A

FAD

240
Q

what do complexes I, II, and III use to carry out redox of flavins and Q?

A

iron-sulphur proteins

241
Q

what makes ubiquinone membrane soluble?

A

long lipophilic side-chain

242
Q

how is Q reduced to QH2?

A

2 steps: transports electrons from complex I and II to III

243
Q

how do cytochromes transfer electrons?

A

transfer single electrons by Fe2+/Fe3+ redox

244
Q

what are the cytochrome categories?

A

a, b and c

245
Q

where are cytochromes b and c1 found?

A

in complex III

246
Q

where are cytochromes a and a3 found?

A

in complex IV

247
Q

how can cytochrome c be tracked?

A

by its spectroscopic properties

248
Q

experimental evidence for order of the ETC?

A

redox states within proteins can be monitored by variety of spectroscopies: visible (cytochromes), UV (Q) or electron spin resonance (Fe and Cu). if deprive mitochondria of O2 all of the respiratory chain components reduced. as O2 introduced oxidation occurs in order: cyt a, cyt c, cyt b, flavins and the NADH. can also order complexes according to redox potential as measured by electrochemical methods. redox potential of individual reactions give their order, differences in energy tell us there are 3 spans with sufficient energy to synthesise ATP- correspond to proton pumping by complex I, III and IV

249
Q

complex I donor and acceptor?

A

NADH donor, ubiquinone acceptor

250
Q

complex II donor and acceptor?

A

succinate donor, ubiquinone acceptor

251
Q

complex III donor and acceptor?

A

reduced Q donor, cyt c acceptor

252
Q

complex IV donor and acceptor?

A

reduced cyt c donor, O2 acceptor

253
Q

how many protons are pumped out by complex I for every 2 electrons?

A

4

254
Q

how many protons are pumped out by Q/complex III for every 2 electrons passing through?

A

4

255
Q

how many protons are pumped out by complex IV for every 2 electrons it passes to O2?

A

2

256
Q

how many protons are pumped out for each package of 2e- that passes from NADH to O2?

A

10

257
Q

describe complex I?

A

uses NADH to reduce ubiquinone. largest of the protein complexes- around 40 polypeptides. NADH reduces FMN, electrons pass through 8-9 FeS centres, this reduces Q to QH2. proton pumping driven by conformational changes

258
Q

describe complex II?

A

succinate dehydrogenase (important part of CAC). has bound FAD that is reduced by succinate in mitochondrial matrix. 3 FeS centres pass electrons to Q to produce QH2

259
Q

describe complex III

A

uses Q to reduce cyt c. contains FeS protein, cyt c1 and cyt b so often called bc1 complex. cyt c1 receives electrons from the FeS centre, transfers them to cyt c. cyt c loosely associated with outer surface of mitochondria. cyt b in complex spans mitochondrial membrane, has 2 haems at opposite sides of protein. complex III releases 4H+ to intermembrane space when electrons transferred fro QH2 to cyt c. acts as electron wire as part of proton motive Q cycle.

260
Q

what does antimycin inhibit?

A

complex III

261
Q

describe complex IV

A

cytochrome oxidase. reduces O2 to H2O using cyt c. 4 redox centres: cyt a, cyt a3, CuA (2 Cu ions) and CuB, all work together to ensure O2 reduced to O2^2-, prevents formation of superoxide. 2 more e- cleave O-O, with 4H+ used to make water

262
Q

reaction catalysed by ATP synthase?

A

ADP + Pi -> ATP + H2O

263
Q

structure of ATP synthase?

A

2 parts, F0 and F1. F1 on its own just hydrolyses ATP and Pi together. initially ATP strongly bound to ensure it’s formed, then released by further conformational change which requires the binding change mechanism. F0 is complex of 10 subunits, which translocate H+s to the γ subunit of the F1 core. protons flow through F0, generates rotation of the subunits, in turn drives the γ subunit. as the γ subunit moves it drives the binding change mechanism. 3H+ used for each ATP produced

264
Q

what are the 3 conformations that each site of the ATP synthase cycle through?

A

O (open- low affinity for ADP and Pi), L (loose- binds ADP and Pi loosely), T (tight- tight binding required to squeeze out the water)

265
Q

steps of ATP synthesis by ATP synthase?

A

ADP and Pi binds to L site, energy in to convert L to T (ADP + Pi -> ATP + H2O), energy in to convert T to O, ATP released

266
Q

what can be used to transport metabolites into and out of the mitochondrion?

A

ATP and ADP exchange courtesy of charge gradient, phosphate enters courtesy of pH gradient

267
Q

danger posed by reactive oxygen species in mitochondrion?

A

if rate of e- entry into respiratory chain greater than rate of e- transfer through chain, partially reduced Q radical can be produced, in turn donates electron to O2. superoxide (O2-) acts on aconitase (4Fe-4S protein) to release Fe2+, Fe2+ leads to formation of hydroxyl free radical

268
Q

function of reduced glutathione (GSH)?

A

opposes formation of hydroxyl free radical by Fe2+ caused by superoxide in mitochondria

269
Q

how much of circulating glucose does brain use at rest?

A

25%

270
Q

how much of brain fuel requirement can be met by ketone bodies?

A

50%

271
Q

what can’t the brain use as fuel?

A

fat

272
Q

major fuels of muscle?

A

glucose from glycogen, FAs, ketone bodies.

273
Q

what can’t the muscle do?

A

store glycogen, carry out gluconeogenesis

274
Q

what sort of metabolism does heart muscle use?

A

relies entirely on aerobic metabolism

275
Q

favoured fuel of muscle at rest?

A

fatty acids

276
Q

organs that use GluT4 transporters?

A

muscle, adipose tissue

277
Q

role of liver in metabolism?

A

acts as buffer of blood glucose

278
Q

metabolic processes liver can carry out?

A

FA synthesis, TAG metabolism (beta oxidation), ketogenesis, gluconeogenesis, glycolysis, amino acid metabolism, urea cycle

279
Q

function of adipose tissue in metabolism?

A

stores FAs, releases them according to demand, releases hormones that regulate metabolism. no glycerol kinase so if low glucose uptake (no insulin) then low glycerol 3-phosphate concentration, free FAs not re-esterified, so will be exported

280
Q

pancreas involvement in metabolism?

A

blood glucose level sensed by glucokinase, all G6P goes straight to oxidative phosphorylation, linked to insulin synthesis and release

281
Q

role of kidney in metabolism?

A

disposes of urea, maintains blood pH, carries out gluconeogenesis

282
Q

long term adaptive changes to fed state (high carb diet)?

A

insulin stimulates enzymes necessary for fat synthesis. arises directly by stimulating PFK and ACC, indirectly by increasing NADPH production and acetyl-CoA transport into cytosol

283
Q

VLDL and the liver?

A

TAGs made in liver, not stored there in healthy individuals. TAGs packed with Apo B-100 (apoprotein) and packaged into VLDL. VLDL then exported to blood, most TAG ends up in adipose in healthy individuals

284
Q

digestion of dietary triacylglycerol?

A

dietary TAG churned and emulsified by bile acids from gallbladder in SI. makes small fat micelles with large total SA. lipase from pancreas hydrolyses TAG at surface of micelles. FAs and MAGs from TAG hydrolysis absorbed into brush border, converted into TAG, packaged into chylomicrons- contain Apo B-48 and phospholipids to stabilise the structure, secreted into lymph system and enter bloodstream at thoracic duct

285
Q

how is TAG removed from blood?

A

adipose and aerobic muscle have lipoprotein lipase (LPL) on outer surface, binds VLDL and chylomicrons by recognising surface apoproteins. LPL hydrolyses TAG at tissue surface, FAs released into cells. adipose makes TAG, muscle oxidises FAs

286
Q

control of lipolysis in adipose tissue?

A

TAG lipase activated by phosphorylation catalysed by PKA. caused by glucagon, adrenaline, noradrenaline raising cAMP. insulin opposes by breaking down cAMP with a phosphodiesterase. adipose triglyceride lipase (ATGL) antagonised by insulin (enzyme needed for TAG hydrolysis to DAG). fasting, prolonged exercise, stress raise blood FA content

287
Q

metabolic changes in short term exercise?

A

in 100m sprint muscle phosphocreatine lasts 4 secs, glycogen would last 80s but exhaustion after 20s. adrenaline and Ca2+ stimulate phosphate produced from ATP breakdown to be used by phosphorylase to produce glucose 1-P from glycogen. middle distance runners partly use aerobic ATP production. AMP formed by adenylate kinase, deaminated to IMP which stimulates glycogenolysis. IMP degraded to adenosine, stimulates vasodilation. both allow continued glycolysis during longer bursts of anaerobic metabolism, mid term + after exercise recycle lactate as glucose (Cori cycle)

288
Q

metabolic changes in long term exercise?

A

glycogen and FAs oxidised, FAs mainly released from adipose courtesy of HSL and ATGL. small amount of FA released from breakdown of muscle triglyceride. FAs and glycogen-derived pyruvate produce acetyl-CoA, produces ATP by oxidative phosphorylation and CAC. oxaloacetate supply can be outstripped by acetyl-CoA supply- so cell converts Iso and Val to succinyl-CoA to add into CAC.

289
Q

what is ‘hitting the wall’ in long distance running?

A

when glycogen is depleted and start to rely on fat which is slower at generating ATP

290
Q

role of AMPK?

A

recognises ATP depletion and limits further depletion by inhibiting synthesis of glycogen, and FA and cholesterol biosynthesis. at same time initiates compensating changes that boost or maintain ATP levels

291
Q

regulatory events mediated by AMPK?

A

upregulates SNS, FA oxidation + glucose uptake in muscle, glycolysis in heart, downregulates lipolysis, glucose uptake, FA synthesis + FFA esterification in adipose, cholesterol, FA and glycogen synthesis in liver, insulin secretion in pancreas

292
Q

what increases AMP levels activating AMPK?

A

nutrient or exercise-induced stress

293
Q

early stages of type II diabetes?

A

reduced insulin secretion, subsequent insulin resistance, raised glucose

294
Q

effects of insulin resistance in type 2 diabetics?

A

raised glucose, GluT4 not transported to membrane so excess glucose can’t enter muscle or adipose, elevated non-esterified FAs (NEFAs) further inhibits glucose uptake in these tissues, promotes VLDL-TAG secretion. activates HSL so more FAs and glycerol produced and released + acetyl-CoA and NADH produced which inhibit PDH so turns of CAC. glycogen synthesis impaired, rate of glycolysis is low. alanine and lactate produced by muscle for gluconeogenesis in liver.

295
Q

how does type 2 diabetes prevent VLDL uptake?

A

produces low activity of adipose tissue lipoprotein lipase extracellularly

296
Q

lipotoxicity?

A

in liver excessive malonyl-CoA levels promotes de novo FA synthesis, inhibits CPT1. long chain CoAs diverted from TCA cycle to biosynthetic enzymes that produce TAGs, DAG, ceramide. in muscle FA influx promotes beta-oxidation without increase in TCA cycle, so metabolic byproducts of incomplete fat oxidation accumulate in mitochondria

297
Q

why is proline used in collagen/why is it special?

A

no H on N of amino acid so can’t form H bonds with anything else + backbone has slight curvature. can form sharp bends in collaged, and can form polyproline helix which doesn’t have stabilising H bonds.

298
Q

what is the conformational change when a Hb subunit binds O2?

A

iron pulled upwards, moves the His the iron attaches to up, which moves the alpha helix this is a part of so alpha helix bond to other alpha helix breaks, forms bond with another alpha helix it is brought into proximity with initiating conformational change in beta subunits

299
Q

substrate specificity for chymotrypsin?

A

small hydrophobic amino acids in selectivity pocket select proteins with large hydrophobic Trp and Phe

300
Q

substrate specificity for trypsin?

A

favourable for positively charged Lys/Arg

301
Q

substrate specificity for elastase?

A

alanine in specificity pocket interacts with Leu, Iso, Val, Phe, Trp

302
Q

FMN structure?

A

has triple ring structure

303
Q

hexokinase as example of importance of proximity in pathways?

A

in skeletal muscle hexokinase close to ATP/ADP pump so ATP pumped out is used in glycolysis, produced ADP which returns via pump to mitochondrial matrix

303
Q

effect of ischaemic damage to tissue on metabolism?

A

causes hypoxia so will have same effect as oxygen deprivation

304
Q

Warburg metabolism in cancer?

A

to start with cells are hypoxic in cancer proliferation, to synthesis new nucleotides need ribose- PPP used to synthesise ribose

304
Q

where is glucose produced in liver transported to primarily?

A

brain and erythrocytes (RBCs)

MIMS (15 decks)

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