Bull section Flashcards

1
Q

How many reactions take place in glycolysis?

A

10

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2
Q

What is the product of glycolysis for one glucose molecule?

A

2 pyruvate

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3
Q

What is the first step in glycolysis?

A

Glucose enters the cell
-phosphorylated by hexokinase to form glucose-6-phosphate
- step uses ATP
- irreversible

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4
Q

What is the second step in glycolysis?

A

Glucose-6-phosphate is converted to fructose-6-phosphate via the enzyme phosphoglucose isomerase
- isomerization reaction

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5
Q

What is the third step in glycolysis?

A

Fructose-6-P is phosphorylated to form fructose-1,6-bisphosphate by the enzyme phosphofructokinase (PFK)
- this step is irreversible
- this step uses ATP

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6
Q

What is the fourth step in glycolysis?

A

Cleavage of fructose-1,6-bisphosphate to two different 3 carbon molecules.
Cleaved by enzyme aldolase
- produces one dihydroxyacetone phosphate and one glyceraldehyde 3 phosphate

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7
Q

What is the 5th step in glycolysis?

A

The dihydroxyacetone phosphate produced in step four is converted to glyceraldehyde 3 phosphate by triose phosphate isomerase - resulting in TWO total glyceraldehyde 3 phosphate (one from step 4 one from step 5)

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8
Q

What is the 6th step in gylcolysis?

A

glyceraldehyde 3 phosphate is oxidized by glyceraldehyde 3 phosphate dehydrogenase to form 1,3-bisphosphoglycerate

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9
Q

What is the 7th step in glycolysis?

A

1,3-bisphosphoglycerate undergoes substrate level phosphorylation by the enzyme phosphoglycerate kinase to form 3-phosphoglycerate AND ATP

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10
Q

What is the 8th step in glycolysis?

A

3-phosphoglycerate is converted to 2-phosphpoglycerate by phosphoglycerate mutaseW

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11
Q

What is the 9th step in glycolysis?

A

2-phosphoglycerate is converted to phosphoenolpyruvate (PEP) by the enzyme enolase

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12
Q

What is the 10th step in glycolysis?

A

Phosphoenolpyruvate is converted to pyruvate via pyruvate kinase, generating ATP , this reaction is irreversible

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13
Q

Is pyruvate production from glycolysis a spontaneous reaction? what is the delta G for the net pathway?

A

Yes it is spontaneous in cellular conditions, deltaG is -22kcal/mol

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14
Q

What are the three fates of pyruvate?

A

Can be converted into ethanol, lactate or acetyl CoA depending on the cells needs

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15
Q

Why would pyruvate be converted into ethanol? What are the two steps in this process?

A

Happens anaerobically in some organisms, fermentation- NAD+ is regenerated in the second step of the conversion - loses a CO2
Pyruvate is converted into acetaldehyde via pyruvate decarboxylase
- Acetaldehyde is converted into ethanol via alcohol dehydrogenase

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16
Q

Why would pyruvate be converted into lactate? What is the step in this pathway?

A

NADH is used to reduce pyruvate to lactate, regenerating NAD+
Pyruvate is converted into lactate via lactate dehydrogenase

This reaction also occurs in muscles when oxygen supply is limited requiring the muscles to function anaerobically for a short period of time

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17
Q

What happens when lactate builds up in the muscle?

A

Lactate lowers the ph of muscle which inhibits PFK which is the main regulatory point of glycolysis - slowing the ability for muscle to metabolize glucose and fatigue sets in

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18
Q

Why would pyruvate be converted to Acetyl CoA? What is the step in this pathway?

A

Because this is the pathway where the most energy is obtained from pyruvate - NAD+ not directly regenerated but is in the TCA cycle
- Pyruvate is converted to acetyl coa via the pyruvate dehydrogenase complex

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19
Q

Where do galactose and fructose enter glycolysis?

A

Galactose enters as glucose 6-p
Fructose enters IN LIVER as dihydroxyacetone phosphate and glyceraldehyde 3 phosphate

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20
Q

Why can high fructose consumption lead to diabetes?

A

because fructose enters glycolysis via the liver it bypasses the main regulatory enzyme of glycolysis - PFK, so excess acetyl coa is synthesized and converted into fats

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21
Q

What are the three regulatory enzymes in glycolysis?

A

Hexokinase, PFK and pyruvate kinase

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22
Q

What is special about glycolysis in the muscle?

A

Muscle glycolysis provices ATP used for muscle contraction - highly controlled by the energy state of the cell - ATP:AMP ratio
- More ATP available inhibits glycolysis
- heavily regulated by PFK which is controlled allosterically - ATP is allosteric inhibitor and decreases PFKs ability to bind to fructose 6p
- a drop in ph also inhibits PFK

  • hexokinase is inhibited by its product - glucose 6p

-pyruvate kinase is allsterically inhibited by ATP and ACTIVATED by fructose-1,6-bisphosphate
- why? because fructose16bisphosphate is the product of PFK, meaning a rise in fructose16bisphosphate means that the cell is getting ready to be more active and produce more ATP

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23
Q

Why isn’t hexokinase the control point in glycolysis?

A

because glucose 6-p can enter other pathways and not just glycolysis

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24
Q

What is special about glycolysis in the liver?

A

main function is different than that of muscle- liver is needed to maintain blood glucose levels in the blood stream - does not need to contract
- PFK is still main point of regulation - however it is not regulated by ATP and pH like in muscle - instead uses Citrate as a major inhibitor of PFK in liver (since citrate is formed from acetyl coa, which is a product of pyruvate metabolism means that high level of citrate = biosynthetic porecusors are suffiencent)

  • PFK needs to be activated to handle rise in blood glucose after a meal - turns some fructose 6p into fructose 26bisphosphate which is an allosteric activator of PFK accelerating glycolysis after a meal
  • instead of hexokinase, liver uses glucokinase which has a 50fold higher Km (can handle a higher load) - glucokinase is NOT inhibited by glucose 6p meaning the liver does not waste glucose

-

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25
Q

What are the three non carbohydrate precursors for gluconeogenesis?

A

Lactate
amino acids
glycerol

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26
Q

When is gluconeogenesis important?

A

during periods of fasting to keep blood sugar levels high

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27
Q

Where does gluconeogenesis occur in animals?

A

only in liver and kidney, mainly liver

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28
Q

How is lactate used as a gluconeogenic precursor?

A

Because pyruvate can be converted into lactate and the reaction is reversible, most of the lactate winds up in the liver and is converted back to pyruvate via lactate dehydrogenase and can enter gluconeogenesis

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29
Q

Where does glycerol enter the gluconeogenic pathway?

A

is taken up by the liver and converted into dihydroxyacetone phosphate

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30
Q

How does pyruvate get moved to the next step in gluconeogenesis? What are the enzymes and products?

A

Pyruvate is converted to phosphoenolpyruvate - cannot be the same as glycolysis because it is exergonic and not reversible
- pyruvate is instead converted to oxaloacetate via pyruvate carboxylase
- oxaloacetate gets stuck in the mitochondria and has to be converted to malate via malate dehydrogenase and then back to oxaloacetate after entering the cytosol
-oxaloacetate is converted to phosphoenolpyruvate via phosphoenolpyruvate carboxylase

31
Q

How does the conversion of fructose 1,6 bisphoshphate work in gluconeogenesis?

A

In glycolysis fructose 6p - fructose 16bisp is irreversible
- instead Fructose-1,6bisp is hydrolased by fructose 1,6bisphosphatase to form fructose 6p

32
Q

How is glucose 6p converted into free glucose in the last step of gluconeogenesis?

A

glucose 6p is converted into free glucose by glucose 6 -phosphatase (hexokinase in glycolysis)
- this occurs in the ER

33
Q

How is gluconeogenesis made possible?

A

via energy coupling - simple reversal of glycolysis is +22kcal/mol which is not possible
- with energy coupling becomes -38kcal/mol

34
Q

How are glycolysis and gluconeogenesis regulated in relation to each other?

A

They are reciprocally regulated - when glucose is abundant, glycolysis is favoured
when glucose is scarce, gluconeogenesis is favoured

35
Q

What is the main regulatory step and enzyme in gluconeogenesis?

A

Same step as in glycolysis (swapped order) the conversion of fructose 1,6 bisp to fructose 6p catalyzed by fructose 1,6 bisphosphatase

36
Q

Describe the reciprocal effects of 3 allosteric regulators on the main rate limiting step in both glycolysis and gluconeogenesis

A

AMP - low energy state in cell - increases glycolysis, decreases gluconeogenesis

Fructose 2,6 -bisp - increases glycolysis, decreases gluconeogenesis

Citrate - decreases glycolysis, increases gluconeogenesis

37
Q

What molecule is the main indicator to adjust blood glucose levels in liver?

A

Through production of fructose 2,6 bisp - activates glycolysis and inhibits gluconeogenesis at the same point

38
Q

How is fructose 2,6 bisphosphate made?

A

by PFK2 and fructose 1,6 bisphosphatase2 (?)

39
Q

What determines the concentration of fructose2,6 bisp in the cell?

A

The relative activities of 2 enzymes, PFK2 and FBPase2 which in turn regulates activities of glycolysis and gluconeogenesis

these enzymes are on the same protein

40
Q

How does blood sugar levels regulate PFK2 and FBPase2 activities?

A

Via a single serine residue.
-Serine is phosphorylated when glucose is low during fasting - glucagon is secreted when blood sugar drops- stimulates cAMP signal leading to phosphorylation - activates phosphatase activity domain and inhibits kinase domain - results in lowering fructose 2,6 bisp - favours gluconeogenesis

-conversely, after a meal glucagon drops and insulin increases - leads to less phosphorylation of serine - activates kinase activity and inhibits phosphatase activity - increases production of fructose 2,6 bisp - favours glycolysis

41
Q

When does insulin NOT inhibit gluconeogenesis?

A

In people with type 2 diabetes - keep producing glucose even when glucose levels are sufficient

42
Q

What is the purpose of the cori cycle?

A

The cori cycle is a process that converts lactate formed in the muscle to glucose in the liver

  • in the muscle glucose is used in glycolysis to produce 2 ATP, and convert glucoe to pyruvate, which is then converted to lactate in the form of lactic acid
  • this lactate is taken up from the blood into the liver where it is converted into pyruvate and then uses 6 ATP to form glucose which goes back into the blood to the muscle to repeat the cycle
43
Q

What is the main role of the pentose phosphate pathway?

A

The main role of the PPP is to produce NADPH which is used as reducing power in most reactions
- PPP also generates ribose 5 phosphate which provides the sugar component for nucleotides
- shares intermediates with glycolysis which means the pathways are regulated together

44
Q

What is the first phase of the PPP? What are the reactions in the first phase?

A

The oxidative phase - glucose 6p is oxidized and NADP+ is reduced to NADPH
- glucose 6p is oxidized via glucose 6 phosphate dehydrogenase to form one NADPH and 6-phosphogluconobetalactone
-6phosphogluconobetalactone is converted to 6-phosphogluconate via lactonase
-6-phosphogluconate is converted to ribulose 5 phosphate via 6-phosphogluconate dehydrogenase - producing another NADPH

45
Q

For every glucose 6p in the PPP how many NADPH are made?

A

2 NADPH

46
Q

What is the second phase of the PPP?

A

The non-oxidative phase - ribulose 5p is converted to ribose 5p via phosphopentose isomerase
-excess ribose 5p can be converted to other 3,4,5,6,7,C glycolytic intermediates

47
Q

How is the PPP regulated?

A

Remember, because glucose 6p can be used in either the PPP or glycolysis, and both reactions take place in the cytosol, there is only one pool of glucose to pull from
- the cytosolic concentration of NADP+ plays the biggest role in regulation
- rate limiting step is catalyzed by glucose 6p dehydrogenase which produces NADPH, meaning that NADP+ will be low, since NADP+ is a substrate for glucose 6-p dehydrogenase, low NADP+ means low rate
- additionally, NADPH competes with NADP+ to bind to glucose 6p dehydrogenase - competitive inhibitor - when NADPH levels are high (NADP+ is low) there is no need to be active

48
Q

How do we determine which pathway glucose 6p enters? What are the four options?

A

By concentration and needs for ribose5p or ATP
- 1. if cell needs ribose 5p and no NADPH, glucose 6 p goes into glycolysis until becoming glyceraldehyde 3p which goes into the reversible reactions of PPP to make ribose 5p but skips making NADPH
2. if need for NADPH and ribose 5p are the same - glucose 6 p only goes into PPP - metabolized thru oxidative portion to produce NADPH and ribose5p
3. NADPH is needed more than ribose 5p - OCCURS IN LIVER - goes thru oxidative portion of PPP to make NADPH and ribulose 5p - converted to ribose5p and then into glyceraldehyde 3p in switchy reactions of PPP - used then in gluconeogenesis
4. both NADPH and ATP are needed - same as 3 where it starts in PPP and goes till glyceraldehyde 3p and fructose 6p in switchy reactions that then go into glycolysis to generate ATP

49
Q

What is glyocgen?

A

polymer of glucose that acts as a storage form
- degraded by liver to release glucose to maintain blood sugar levels
- in muscle - glucose released from glycogen is used to satisfy muscles needs during contraction

50
Q

What are the two chemical linkages present in glycogen?

A

a1-4 glycosidic bonds
a1-6 glycosidic bonds (branch points)

51
Q

At what ends does glycogen synthesis and breakdown occur?

A

non reducing ends

52
Q

in the conversion of glucose 1p to glycogen, which pathway uses an additional intermediate?

A

in glycogenolysis, glycogen goes right to glucose 1p, but in glycogenesis it uses activated UDP glucose to form glycogen

53
Q

What is the activated precursor molecule for glycogenesis?

A

UDP glucose

54
Q

What are the steps and enzymes to convert glucose into glycogen?

A

Glucose is phosphorylated by hexokinase to make glucose 6p
- glucose 6p is converted to glucose 1p via phosphoglucomutase
-glucose 1p is converted to UDP glucose via UDP glucose pyrophosphorylase
-UDP glucose is added to the chain as glycogen via glycogen synthase

55
Q

Where does glycogen synthesis add a new glycogen molecule?

A

on carbon 4 of terminal glucose

56
Q

What is the requirement for glycogen synthase to be able to add a glucose unit?

A

oligosaccharide has to be at least 4 glucose units

57
Q

How does glycogen get started? explain this molecule

A

Via glycogenin
- dimer of 2 identical subunits
- can synthesize an oligosaccharide using UDP glucose as a substrate of around 10-20 glucose units long attached to a tyrosine residue
- acts as both the catalyst and substrate - serves as a primer for glycogen synthase to act on

58
Q

How are branch points formed in glycogenesis?

A

The Branching enzyme hydrolyzes an 1-4 linkage of about 7 units and then moves it to a 1-6 linkage to form a branch point

59
Q

What are the rules for when a branch point can be formed in glycogen?

A

branch point must be 4 residues away from an existing branch - usually 10 residues

60
Q

What is the regulatory step in glycogen synthesis?

A

glycogen synthase
- glucose 6p is allosteric activator of synthase b
- also regulated via phosphorylation (unphosphorylated A form is active- phosphorylated b form is inactive)

61
Q

How is glycogen broken down in glycogenolysis?

A

glycogen phosphorylase cleaves off glucose by catalzying a phosphorolysis reaction (using inorganic phosphate instead of water)
- products are glucose 1p and a glycogen molecule 1 unit shoter
- stops working 4 glucose units away form branch point

62
Q

Why is glycogen broken down using phosphorolysis instead of hydrolysis?

A

because the released sugar glucose 1p is already phosphorylated, doesn’t need to use an ATP to do it so there is an energy advantage

63
Q

What happens when glycogen phosphorylase stops working as it approaches a branch point?

A

transferase will move 3 glucose to another branch leaving a single glucose
- then, debranching enzyme (a1,6-glucosidase) hydrolyzes 1-6 linkage releasing free glucose instead of glucose 1p

64
Q

What is the fate of glucose 6p produced by glycogenolysis in liver and muscle?

A

in liver - glycogen breakdown happens when blood sugar is low - glucose 6p produced is acted on by glucose 6 phosphatase (gluconeogenesis) which removes phosphate group and enters blood as free glucose

  • in muscle - because glucose 6 phosphatase is absent in muscle and muscle needs atp, glucose 6p goes into glycolysis to make ATP
65
Q

How is glycogen phosphorylase regulated IN THE LIVER?

A

Glycogen phosphorylase is regulated by both allosteric interactions and reversible phosphorylation
- each of the two subunits can be phosphorylated by phosphorylase kinase to convert the enzyme to the more active A form
- can be phosphorylated by phosphorylase phosphatase to convert glycogen phosphorylase to the less active B form
-allosterically regulated by glucose which inhibits the enzyme (adequate level of glucose means no more needs to be broken down) - can bind to either a or b form

66
Q

How is glycogen phosphorylase regulated in the muscle?

A

regulated by covalent phosphorylation and allosteric regulation
- reversible phosphorylation same concept as liver
- AMP is an allosteric activator of muscle phosphorylase B
-ATP is an allosteric inhibitor of muscle phosphorylase B - makes sense - if ATP is plenty don’t need to break down glycogen to glucose for atp synthesis
- Glucose 6p is an inhibitor - levels are high meaning adequate amounts of glucose are present for energy

  • IN MUSCLE - only glycogen phosphorylase B is sensitive to allosteric regulator - A form is always fully active
67
Q

What do epinephrine and glucagon signal?

A

They both signal the need for glycogen breakdown
- epinephrine acts in muscle when a quick burst of energy is needed - uses for atp
- glucagon acts in liver (secreted by pancreas) in response to low blood sugar for the liver to release more glucose
- work similarly to activate glycogen phosphorylase

68
Q

Explain the regulatory cascade for glycogen breakdown when glucagon or epinephrine bind to receptors?

A

An enzyme called adenylate cyclase becomes activated
- adenylate cyclase converts ATP to cAMP
-cAMP binds to protein kinase A causing a conformational change so the catalytic subunit can phosphorylate proteins (can phosphorylate phosphorylase B to convert it to phosphorylase a stimulating glycogen breakdown

  • results in amplification of initial hormone signal
69
Q

What is cAMP termed as?

A

a second messenger since it acts inside the cell as a messenger of the signal that the hormone brought to the cell initially

70
Q

What is an additional point to make about the regulatory cascade for glycogen breakdown in muscle specifically?

A

Phosphorylase kinase is activated when Ca binds to a subunit called calmodulin
- means that when muscle contraction is stimulated, glycogen breakdown is also stimulated to provide fuel for ATP generation

71
Q

How are glycogen synthesis and degradation reciprocally regulated?

A

When protein kinase A is activated by cAMP it phosphorylates phosphorylase B to the A active form
- at the same tie it converts glycogen synthase from the A active form to the B inactive form
- thus when degradation is stimulated, synthesis is inhibited

To go the other way - PP1 removes phosphate from phosphorylase kinase and glycogen phosphorylase a which inactivated both and inhibits glycogen breakdown
- at the same time it removes phosphates from glycogen synthase which increases activity and increases glycogen synthesis

72
Q

How does insulin stimulate glycogen synthesis?

A
  • Increases GLUT4 which increases glucose uptake by cells - converted to glucose 6p which is an allosteric activator of glycogen synthase B
  • binding of insulin forms IRS-P which activates protein kinases that phosphorylate glycogen synthase kinase which inactivates it. this reduces the phosphorylation state of glycogen synthase which increases its activity - A form
73
Q

How does glucose regulate liver metabolism?

A

glycogen synthase activity does not increase until all phosphorylase is in B form
-happens because glucose binds to phosphorylase A which causes it to be dephosphorylated by PP1 and converted to phosphorylase b
- PP1 cant bind to phosphorylase B which means it can bind to synthase instead which activates it

74
Q

Where do most glycogen storage diseases affect?

A

defects in glycogenolysis rather than glycogen synthesis
- results in abnormal swelling of affected area often liver
- issues with releasing glucose into the blood leading to hypoglycemia