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MTM > Metabolism And Control > Flashcards

Metabolism And Control Flashcards

1
Q

How is energy metabolised

A

Via
Glycolysis
TCA
Electron transport chain & oxidative phosphorylation

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2
Q

What are catabolic pathways

A

break down complex molecules into
simple molecules and release energy

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3
Q

What are anabolic pathways

A

build complex molecules from simple molecules and require energy usually in form of ATP

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4
Q

What metabolic pathways cytosolic

A

Glycolysis, PPP & fatty acid synthesis

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5
Q

Where are most enzymes for TCA cycle

A

located in the mitochondrial matrix, except succinate dehydrogenase, which is linked to the respiratory chain in the inner membrane

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6
Q

What are perxisomes

A

a small organelle present in the cytoplasm of many cells, which contains the reducing enzyme catalase and usually some oxidases

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7
Q

What are types of metabolic reactions

A

❖ Oxidation: loss of electrons
❖ Reduction: acquisition of electrons
❖ Usually coupled in a reaction where electrons are transferred from molecule to another
❖ hydrolysis - dehydration: add/remove water
❖ (de)phosphorylation: removal/addition of a phosphate group
❖ (de)carboxylation: removal/addition of a CO2 molecule
❖ Ligation reactions

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8
Q

An example of hydrolysis

A

hydrolysis - dehydration: add/remove water

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9
Q

Purpose of energy metabolism

A

❖ Primary purpose of energy metabolism is to provide a
constant supply of ATP to maintain cell growth

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10
Q

How can ATP be produced

A

either through substrate-level phosphorylation, a process which doesn’t require oxygen

or through oxidative phosphorylation, which uses oxygen

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11
Q

What bonds do ATP have

A

ATP molecule stores energy in 2 phosphoanhydride bonds

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12
Q

Hydrolysis of ATP releases

A

Inorganic phosphate
And (at physiological pH) releases 7.3 kcal as energy

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13
Q

4 different steps for ATP production

A

❖ Glycolysis (1 glucose —> 2 pyruvate)
❖ Oxidative decarboxylation of pyruvate to form acetyl-CoA (one per pyruvate) loss of one CO2 per pyruvate
❖ TCA cycle <— introduction of 2 carbon atoms in the form of acetyl-CoA, subsequent loss of 2 CO2 per acetyl- CoA
❖ Electron transport chain: energy which was stored in the form of energy rich H- (e.g. NADH) is converted to water (H2O) and ATP

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14
Q

Equation for ATP production

A

❖ C6H12O6 + 6O2 —> 6CO2 + 6H2O + 31ATP

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15
Q

What is the overall yield of glycolysis

A

Glucose = 2 x Pyruvate
2ADP = 2ATP
2NAD+ = 2NADH

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16
Q

Pathway of glycolysis

A

❖ Ordered series of enzymatic reactions in the cytosol
❖ Glucose is primed with two phosphorylation steps (energy investment) and one isomerisation to form F-1,6-bp
❖ F-1,6-bp is split to form GA-3-P
❖ GA-3-P is converted to Pyruvate

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17
Q

What can lactate cause

A

Exercising skeletal muscle
Increase in lactate
Muscle pain

Coronary arteries blocked by artherosclerosis
Insufficient O2 supply for heart
Increase Lactate
Chest pain (Angina pectoris)

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18
Q

Anaerobic respiration

A

NAD+ must be regenerated for glycolysis to continue, so lactate is formed

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19
Q

What is the cori cycle

A

Liver provides glucose for tissue glycolysis. The lactate produced is used by the liver to make glucose.

Lactate converted to Pyruvate then glucose 6 phosphate in the liver

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20
Q

Pathway of gluconeogensis

A

Synthesis of glucose from pyruvate
Some reactions in common with glycolysis
‘Irreversible’ steps use different enzymes
Costs energy:
2 Pyruvate + 4ATP + 2GTP + 2NADH makes one glucose
(Glucose makes 2 Pyruvate +2ATP + 2NADH)

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21
Q

What is pyruvate decarboxylation

A

❖ This is mediated by a large enzyme complex (pyruvate dehydrogenase) that converts pyruvate to acetyl-CoA
❖ Occurs within the mitochondria
❖ NAD+ is reduced to NADH
❖ One CO2 is produced (note: this is the first carbon which is lost from glucose in the process of converting glucose to CO2, H2O and energy)

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22
Q

What is the PDH complex (link reaction)

A

catalyzes the oxidative decarboxylation of pyruvate with the formation of acetyl-CoA, CO2 and NADH

increases the influx of acetyl-coA from glycolysis into the TCA cycle

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23
Q

PDH complex regulation

A

The pyruvate dehydrogenase complex is regulated by covalent modification through the action of a specific kinase and phosphatase; the kinase and phosphatase are regulated by changes in NADH, acetyl-CoA, pyruvate, and insulin.

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24
Q

What is carbon flux

A

???

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25
Q

How does pyruvate enter the TCA cycle

A

To enter the TCA cycle, pyruvate is used
to make Acetyl CoA

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26
Q

What process does gluconeogensis reverse

A

Glycolysis
Turns pyruvate into glucose
In the liver

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27
Q

Which steps in glycolysis are irreversible

A

Steps 1, 3, 10

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28
Q

What enzyme regulates glycolysis

A

Phosphofructokinase

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29
Q

What enzyme regulates gluconeogenesis

A

1,6, bisphosphatase

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30
Q

What happens when ATP is low

A

❖ When ATP is low phosphofructokinase and glycolysis are switched on to generate ATP

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31
Q

What happens when ATP is abundant

A

❖ When ATP is abundant phosphofructokinase is switched off and 1,6, biphosphatase is switched on driving ATP through gluconeogenesis to glucose

32
Q

What happens when oxygen levels are low

A

❖ Pyruvate is converted to lactate when oxygen levels are low. Produces 2 ATP rapidly but much more is produced by TCA cycle. (Anaerobic respiration)

Lactate produced to regenerate NAD+
NADH oxidised to NAD

33
Q

What is the Cory cycle

A

❖ Lactate from skeletal muscle is taken up by the liver to go through gluconeogenesis (Cory cycle)

34
Q

What is the cyclic acid cycle

A

❖ Also known as the Tricarboxylic acid cycle
❖ Accounts for 2/3 of total oxidation of carbon
in most cells
❖ Takes place in the mitochondrial matrix
❖ Oxygen is required for the downstream electron transport chain as O2 is a final acceptor for NADH to lose electrons and NAD returns to the cycle

35
Q

What does TCA cycle breakdown

A

❖ The TCA cycle is involved in the breakdown of all three major food groups (carbohydrates, proteins and lipids)

36
Q

Mechanism of TCA cycle

A

❖ Through a series of reaction oxidise pyruvate to CO2
❖ Each cycle adds 2 carbon atoms as acetyl group and releases them in the form of CO2
❖ However, the carbons lost originate from oxaloacetate, not acetyl-CoA
❖ The energy of acetyl-CoA is stored in NADH and FADH2

37
Q

Overall products of TCA cycle

A

Acetyl CoA - CoA and 2 CO2
3NAD+ - 3NADH
FAD - FADH2
GDP + Pi - GTP

38
Q

Where is NAD derived from

A

NAD+ is derived from the vitamin niacin (B3)

39
Q

What is NAD

A

❖ It acts as a coenzyme in several redox reactions
❖ It’s oxidation in the respiratory chain generates 2.5 molecules of ATP

40
Q

Where is FAD derived from

A

vitamin riboflavin (B2)

41
Q

What is FAD

A

❖ FAD attaches covalently to it’s enzyme (prosthetic group)
❖ Succinate dehydrogenase contains FAD and is bound to the inner membrane of the mitochondria and is an integral part of the respiratory chain
❖ FAD’s oxidation in succinate dehydrogenase generates 1.5 molecules of ATP

42
Q

What kind of reaction is TCA cycle

A

Anaplerotic reaction
“fill in” missing metabolites for important metabolic pathways

43
Q

Examples of Anaplerotic reactions

A

❖ Direct conversion of pyruvate to oxaloacetate (PC reaction)
❖ Oxaloacetate/aspartate conversion
❖ Glutamate/a-ketoglutarate
conversion
❖ Malate to pyruvate conversion (malic enzyme)

44
Q

How many coenzymes are produced at the end of TCA cycle

A

10 NADH and 2 FADH2 molecules

45
Q

Where are enzymes for ETC located

A

located in the inner mitochondrial membran

46
Q

How much ATP does each coenzyme produce

A

Each NADH produces indirectly approx. 2.5 ATPs, whereas FADH2 will produce approx. 1.5 ATPs (lower energy content of the electrons compared to NADH)

47
Q

What happens when NADH gets oxidised

A

loses a proton and 2 electrons:
❖ NADH —>NAD+ +2H+ +2e-

48
Q

What is the last step in the ETC

A

2e- +2H+ +1/2O2 —>H2O

49
Q

What happens when electrons leave NADH

A

❖ When the electrons leave NADH they are high in energy
❖ Each time they are passed on to one of the complexes, they lose energy
❖ This energy is used to pump protons from the mitochondrial membrane into the inter membrane space
❖ The proton gradient is then used to produce ATP

50
Q

Where are the electrons transported

A

❖ the transport of 2 electrons through complex I and III will extrude 4 H+ each into the inter membrane space

51
Q

What is set up when protons move across the intermembrane of the mitochondria

A

Electrochemical potential of 150-250mV and possible concentration gradient

52
Q

What does the potential difference provide

A

provides the energy for ATP synthesis
❖ 3 H+ ions are needed to make 1 ATP (plus 1 H+ to translocate the ATP to the cytosol)

53
Q

What is cytochrome c oxidase

A

catalyses the transfer of the electrons to molecular oxygen

can be inhibited by cyanide, carbon monoxide and azide

54
Q

What is substrate level phosphorylation

A

transfer of phosphate from a substrate to ATP (GTP)

55
Q

What is oxidative phosphorylation

A

formation of ATP coupled to oxidation of NADH or FADH2 by O2

56
Q

How is energy converted to ATP

A

Energy from electron transport drives efflux of H+ from mitochondrial matrix

Proton electrochemical gradient formed

Proton gradient drives ATP synthase

57
Q

Chemi osmotic coupling hypothesis

A
58
Q

What is ATP synthase

A

The electrochemical gradient is used to drive synthesis of ATP via conformational change in ATP synthase

59
Q

Location of NADH molecules

A

formed during glycolysis and located in the cytosol

60
Q

Where is NADH oxidised

A

NADH can only be oxidised inside the mitochondria and NADH are unable to cross the mitochondrial membrane

61
Q

What are the 2 mechanisms which enable ‘reducing equivalents’ (NADH) to be transferred from the cytosol into the mitochondrion

A
  • Glycerol phosphate shuttle
  • Malate/aspartate shuttle
62
Q

What is the glycerol phosphate shuttle

A

(important in insects) uses cytosolic NADH to reduce DHAP to form glycerol-3-phosphate which then diffuses into the mitochondria and is oxidised by the mitochondrial glycerol-3- phosphate dehydrogenase to form DHAP and FADH2

63
Q

What is the malate/ aspartate shuttle

A

❖ starts with cytosolic oxaloacetate
❖ malate dehydrogenase reduces OAA to form malate, which is then transported into the mitochondria
❖ inside the mitochondria the reaction is reversed by mitochondrial malate dehydrogenase

❖ Then to transport OAA back to cytosol it needs to be able to cross the inner mitochondrial membrane
❖ it has to be transaminated to aspartate which then can be transported into the cytosol, where it is converted back into OAA by the cytosolic aspartate aminotransferase

64
Q

What is lost in the malate/ aspartate shuttle

A

while usually 10 H+ per NADH can be pumped across the membrane to form ATP, in this case the glutamate aspartate carrier (to maintain glutamate and aspartate concentrations) uses 1 H+. Hence the ATP production is only 2.25 molecules of ATP per cytosolic NADH

65
Q

What is the ATP yield for insects

A

❖ Insects use the glycerol phosphate shuttle, where 2 cytosolic NADH yield 2 mitochondrial FADH2, hence the yield in insects would be 36 ATP

66
Q

What is the yield for ATP for humans

A

Using the modern non-integer P/O ratios yield a total of 31 ATP for eukaryotes using the malate/aspartate shuttle and 29.5 ATP using the glycerol phosphate shuttle

67
Q

Why is brown adipose tissue important

A

❖ Mitochondria largely uncoupled, so energy released as heat rather than captured as ATP

❖ Important for maintaining body temp, especially in neonates (hibernation)

68
Q

What are UCP

A

Uncoupling proteins
Provide proton channel
Dinitrophenol is also an uncoupler

69
Q

How is metabolism controlled

A

Primary control - the level of ATP
❖ Levels of intermediates affect local rates
❖ 3 major control strategies:
❖ Enzyme levels
❖ Enzyme activities
❖ Substrate availability
❖ Many points of control, mostly at steps unique to the pathway

70
Q

What are the three control points of TCA cycle

A

Enzymes:
Pyruvate dehydrogenase
isocitrate dehydrogenase
𝛼 - ketoglutarate dehydrogenase

are all control points are they are inhibited by ATP, NADH and acetyl CoA

71
Q

What are the different metabolic profiles of different organs

A

❖ Brain - consumes ~60% of body glucose at rest. Can use ketone bodies in starvation
❖ Muscle - resting muscle uses fatty acids. Anaerobic muscle draws on glycogen stores (75% of glycogen stored in muscle)
❖ Kidneys - 0.5% of body mass, use 10% of body glucose (Na+- K+ ATPase)
❖ Liver - major site of conversion (Cori cycle)

72
Q

What diseases are associated with defects in carbohydrate metabolism

A

❖ A range of diseases resulting from mitochondrial defects (neuro/visual symptoms) - eg Leber hereditary optic neuropathy (complex I)
❖ Beriberi (VitB1, Pyr DeH, a-ketoglut DeH), mercury & arsenic poisoning (Pyr DeH and GAP -> 3PGA conversion)
❖ Diabetes, glucosuria
❖ Glycogen storage disease (eg von Gierke’s - absence of glucose 6- phosphatase; McArdle’s - myophosphorylase deficiency; Tarui - PFK; Cori; others)
❖ Cancer (Metabolomics; PKM2)

73
Q

How do atp levels control insulin secretion

A

Insulin controls carbohydrate metabolism
Imbalance between insulin and glucagon
If theres high glucose or excessive ketone body production it stimulates insulin

74
Q

The Warburg effect in cancer

A

Tumour cells carries out aerobic glycolysis and still produces lactate and then continues into the TCA cycle
Only 6 ATP compared to usual 31 ATP

75
Q

What is oxaloacetate

A

4 carbon molecule
Feeds back into TCA cycle to combine with a 2 carbon molecule forming citric acid

76
Q

What can be used to produce ATP

A

Lactate
Fatty acids
Amino acids

77
Q

Are fatty acids oxidised quickly

A

Beta oxidation pathway is slow

MTM (12 decks)

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