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protein control in cellular regulation > metabolism > Flashcards

metabolism Flashcards

1
Q

what is the role of phosphofructokinase-1?

A

catalyses the transfer of a phosphoryl group from ATP to fructose-6-phosphate to yield fructose-1,6-bisphosphate in the first committed step of glycolysis

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2
Q

how is PFK-1 allosterically regulated?

A

it is activated when ATP concentration is low or ADP/AMP accumulates
it is inhibited when cellular ATP concentration is high and other fuel substrates are present

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3
Q

how does fructose-2,6-bisphosphate regulate PFK-1?

A

binds to an allosteric site of PFK-1, increasing the affinit of the enzyme for fructose-6-phosphate. F26BP activates glycolysis and inhibits gluconeogenesis

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4
Q

in which way does fructose-2,6-bisphosphate regulate PFK-1?

A

mediates hormonal regulation of gluconeogenesis and glycolysis

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5
Q

what are PFK-2 and FBPase-2?

A

two separate enzymatic activities of a single, bifunctional protein

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6
Q

how does glucagon regulate PFK-2/FBPase-2?

A

glucagon stimulates adenylyl cyclase to produce cAMP, which phosphorylates PFK-2/FBPase to enhance FBPase activity and decrease PFK-2. glucagon lowers cellular F26BP, inhibiting glycolysis and stimulating gluconeogenesis

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7
Q

how does insulin regulate PFK-2/FBPase-2?

A

insulin stimulates phosphatase activity, increasing level of F26BP, which stimulates glycolysis and inhibits gluconeogenesis

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8
Q

what are the mechanisms of regulaton of glycolysis by phosphofructokinase?

A

1- allosteric modulation by multiple modulators
2 - indirect regulation by phosphorylation and dephosphorylation
3 - transcriptional regulation - upregulationn by insulin

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9
Q

which isoform of pyruvate kinase is subject to phosphorylation?

A

liver

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10
Q

how is pyruvate kinase regulated by phosphorylation in the liver?

A

low blood glucose -> glucagon -> cAMP-dependent PK phosphorylates the kinase -> slows glycolysis

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11
Q

what happens to pyruvate in: aerobic vs anaerobic conditions?

A

aerobic - used in citric acid cycle and OXPHOS

anaerobic - used for reoxidation of NADH as part of glycolysis

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12
Q

why is the reoxidation of NADH necessary?

A

NAD+ must be regenerated due to its role as electron acceptor

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13
Q

how is NAD+ regenerated?

A

pyruvate is oxidised by lactate dehydrogenase to produce NAD+ +H (using NADH) and lactate as product

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14
Q

what is the Cori cycle?

A

the process where metabolites from glycolysis in skeletal muscles are converted to glucose in glyconeogenesis by different isoenzymes of lactate dehydrogenase in the liver

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15
Q

which non-carbohydrate substrates are there for gluconeogenesis?

A

1 - pyruvate
2- glycerol
3- glucogenic amino acids

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16
Q

which reactions in glycolysis are irreversible?

A

hexokinase - glucose -> G6P
phosphofructokinase - fructose-6-phosphate to F16BP
pyruvate kinase - phosphoenolpyruvate -> pyruvate

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17
Q

how does gluconeogenesis achieve synthesis of glucose despite irreversible reactions in glycolysis?

A

uses different enzymes to replace irreversible ones

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18
Q

what are the three principle ways in which metabolic pathways are controlled?

A

1- controlling amount of enzyme
2- restricting availability of substrates
3- controlling catalytic activity of enzymes

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19
Q

what occurs in the fed state?

A

transient increase in plasma glucose, amino acids and triacylglyerides in the 2-4 hours following a meal
insulin is released from the pancreas and fuel stores are created

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20
Q

what occurs in the fasted state?

A

if no further food is ingested following the fed state, plasma levels of glucose, amino acids and TAGs fall. there is a fall in insulin secretion and an increase in glucagon release

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21
Q

what is glucagon?

A

a small peptide secreted by pancreatic a-cells. it is a hormone of fasted state and its action is catabolic. it signals through GPCRs, activating adenylyl cyclase and causing an increase in cAMP

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22
Q

what is insulin?

A

a peptide synthesised in pancreatic B-cells. a hormone of fed state, its action is anabolic and it signals through tyrosine kinase receptors

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23
Q

what are the two phases of insulin release?

A

1- release from granules

2- synthesis

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24
Q

how is insulin post-translationally modified?

A

preproinsulin has N-terminal signal sequence cleaved out to form proinsulin, from which the C-peptide is cleaved to form insulin

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25
Q

what are the major pathways of glucose utilisation?

A
  • storage of glucose, starch and sucrose
  • synthesis of structural polymers
  • oxidation via pentose phosphate pathway
  • oxidation of pyruvate via glycolysis
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26
Q

how are dietary carbohydrates processed?

A
  • digestion in mouth and lumen
  • breakage of glycosidic bonds to produce monosaccharides
  • absorption and release of monosaccharides by glucose transporters
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27
Q

what is the location, Km and role of GLUT1?

A

all mammalian tissues
Km - 1mM
basal glucose uptake

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28
Q

what is the location, Km and role of GLUT2?

A

liver and pancreatic B cells
km - 15-20 mM
in the pancreas, regulates insulin, in liver, removes excess glucose from the blood

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29
Q

what is the location, km and role of GLUT3?

A

all mammalian tissues
1mM
basal glucose uptake

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30
Q

what is the location, km and role of GLUT4?

A

muscle + fat cells
5mM
amount in muscle plasma membrane increases with endurance training

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31
Q

what is the location, km and role of GLUT5?

A

small intestine

primarily a fructose transporter

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32
Q

how does insulin enhance transport of glucose into myocytes? (write it)

A

1 - glucose transporters are stored within the cell in membrane vesicles
2 - when insulin interacts with the receptor, vesicles move to the surface and fuse with the plasma membrane, increasing the number of glucose transporters in the plasma membrane
3- when the insulin level drops, glucose transporters are removed from the plasma membrane by endocytosis, forming small vesicles
4- smaller vesicles fuse with a larger endosome
5- patches of endosome enriched with glucose transporters bud off to become small vesicles, ready to return to the surface when insulin levels rise again

33
Q

why is glucose-6-phosphate important?

A

the phosphorylation of glucose traps it in the cell, this is why this is the starting point for many pathways

34
Q

what are the total and NET products of the oxidation of glucose-6-phosphate in glycolysis?

A

2 molecules of pyruvate
2NADH
4ATP (2NET)

35
Q

what does hexokinase do?

A

phosphorylates glucose by hydrolysis of ATP, driving the reaction forward

36
Q

what feature of glucokinase allows it to be active only in the fed state?

A

high km, low affinity for glucose means that plasma glucose must exceed the normal concentration of 4-5mM to activate glucokinase

37
Q

how does glucokinase regulatory protein interact in fed state?

A

glucose binds GKRP, blocking interaction with GK, GK is present in the cytosol with high activity

38
Q

how does glucokinase regulatory protein interact in fasted state?

A

F6P binds GKRP, promoting interaction with GK, GK is targeted to the nucleus with low cytosolic activity

39
Q

why does phosphofructokinase-1 have sigmoidal kinetics?

A

it is an allosterically regulated enzyme

40
Q

how does glucagon stimulate glycogenolysis?

A

stimulates adenylyl cyclase to produce cAMP, which phosphorylates PFK2/FBPase2 to enhance FBPase activity and decrease PFK2 activity, therefore, glucagon lowers cellular F26BP. this inhibits glycolysis and stimulates glycogenolysis

41
Q

how can PFK-2 and FBPase2 be two separate enzymatic activities of a single bifunctional protein?

A

the balance of the two activities in the liver is regulated by insulin and glucagon

42
Q

how does insulin cause glycolysis to be stimulated?

A

stimulates phosphatase activity to increase levels of F26BP

43
Q

what forms of regulation are there on glycolysis by phosphofructokinase?

A

1 - allosteric via multiple modulators
2- indirect by phosphorylation/dephosphorylation mediated by insulin and glucagon
3- transcriptional regulation, unregulated by insulin

44
Q

how is liver pyruvate kinase regulated?

A

phosphorylation
when blood glucose is low, there is a release of glucagon. this facilitates cAMP dependent protein kinase mediated phosphorylation of pyruvate kinase, inactivating it. the effect of this is slower usage of glucose as a fuel in the liver

45
Q

what is substrate level formation of ATP?

A

the transfer of a phosphorylation group from phosphoenolpyruvate to ADP, catalysed by pyruvate kinase requiring Mg2+

46
Q

how is pyruvate used in aerobic conditions?

A

in citric acid cycle and OXPHOS

47
Q

how is pyruvate used in anaerobic conditions?

A

deoxidation of NADH as part of glycolysis

48
Q

what is the role of lactate dehydrogenase?

A

oxidation of pyruvate following glycolysis to generate NAD+ and H+ from NADH

49
Q

what happens during the cori cycle?

A

isoenzymes of lactate dehydrogenase are used to convert lactate to glucose via gluconeogenesis

50
Q

in the fed state, which of gluconeogenesis or glycolysis dominates?

A

glycolysis dominates, gluconeogenesis is downregulated

51
Q

in the fasted state, which of gluconeogenesis or glycolysis dominates?

A

gluconeogenesis dominates, glycolysis is downregulated

52
Q

where in the cell does glycolysis take place?

A

cytoplasm

53
Q

how are glucokinase and hexokinase isozymes?

A

they both phosphorylate glucose by hydrolysis of ATP, but have different structures

54
Q

what are the differences between the isozymes of hexokinase?

A

hexokinase I, II and III have high affinity for glucose, but glucokinase is only present in the liver, and has a high value for km, plasma [glucose] must be high to activate it, it is therefore, only active n the fed state

55
Q

what is the effect of ATP binding to the inhibitor site of phosphofructokinase-1?

A

shifts equilibrium towards the T state

56
Q

how is ATP a homotropic allosteric regulator of phosphofructokinase 1?

A

can activate or inhibit the enzyme based on location of binding

57
Q

how is pyruvate kinase allosterically regulated?

A

inhibited by high concentrations of ATP, acetyl-CoA, and long chain fatty acids

58
Q

where does the citric acid cycle happen?

A

matrix of mitochondria

59
Q

what is the importance of the pentose phosphate pathway?

A

generates NADPH and 5C sugars

ribose can be used to make nucleic acids and NADPH is useful due to its reducing power

60
Q

what is the key regulatory step in the pentose phosphate pathway?

A

glucose 6-phosphate dehydrogenase

61
Q

what happens in the oxidative phase of the pentose phosphate pathway?

A

oxidative decarboxylation of 1 glucose-6-phosphate occurs, carbon is lost as carbon dioxide and 2NADPH and 1 ribose sugar is made

62
Q

why do red blood cells require high pentose phosphate pathway activity?

A
  • RBCs contain lots of O2 binding Hb
  • side effect of this is production of reactive oxygen species - can cause Hb to aggregate
  • ROS are removed via the glutathione reductase system, which requires NADPH
63
Q

what does glucose 6-phosphate dehydrogenase deficiency cause?

A

haemolytic anaemia

  • ROS damage membranes
  • low levels of reduced glutathione cannot reduce disulphide bonds
  • cross-linking of Hb leads to formation of Heinz bodies and lysis of RBCs
64
Q

what is the structure of glycogen?

A

storage molecule made up of glucose units in the form of long chains with a-1,4-linkages and a-1,6-linkages to make branch points

65
Q

why is glycogen useful as a storage molecule?

A

enables glucose to be stored in a compact way that has lower osmotic pressure than glucose (which can be harmful to cell)

66
Q

what is the key enzyme for glycogen synthesis?

A

-glycogen synthase (makes a-1,4-glycosidic bonds)

a branching enzyme later adds on the a-1,6- branches

67
Q

what is the key enzyme for glycogen breakdown?

A

glycogen phosphorylase

68
Q

what does glycogen synthase do?

A

takes an activated glucose and adds it onto a non-reducing end of a pre-existing glycogen molecule
producing a new linkage with non-reducing end

69
Q

what does glycogen phosphorylase do?

A

clips off the last glucosyl unit on a glycogen chain, producing glucose-1-phosphate

70
Q

how is glycogen stored?

A

liver - provides glucose for the blood

skeletal muscle - provides g6p to power muscle contraction

71
Q

how is glycogen phosphorylase regulated in the fasted state?

A

glucagon receptors in liver (Gas- type GPCRs) -> AC -> PKA -> phosphorylase kinase -> phosphorylase a
phosphorylase b converts to active phosphorylase a

72
Q

how does phosphorylation modulate the activity of glycogen phosphorylase?

A
  • serines are phosphorylated, causes a movement of active sites
  • promotes the high affinity form (R state)
73
Q

how do the roles of glycogen differ in the liver and skeletal muscle?

A

in the liver, it permits release of glucose into the blood to maintain blood glucose concentrations during fasted states
in the muscle, it produces G6P to permit ATP production for contraction

74
Q

what is muscle glycogen phosphorylase stimulated and inhibited by?

A

stimulated: AMP + Ca2+
inhibited: ATP +G6P

75
Q

what does effect does phosphorylation by glycogen synthase kinase-3 have?

A

inactivates glycogen synthesis

76
Q

what does protein phosphatase 1 do?

A

binds to glycogen binding protein

77
Q

what effect does increased blood glucose have on glycogen synthesis and how?

A

increases
insulin activates PKB -> phosphorylation of glycogen synthase kinase-3 (inactivates it) -> glycogen synthase becomes dephosphorylated over time, assisted by PP1 -> increased activity of glycogen synthase

78
Q

outline regulation of protein phosphatase 1 in the fed state

A

1- glucose binding to GPP exposes phosphoserines
2- insulin-stimulated activation of PP1 causes dephosphorylation of GP
3- T-state form of GP is stabilised, lowering activity
4- PP1 dephosphorylates GS, raising activity

protein control in cellular regulation (10 decks)

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