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Biochemistry > Chapter 21- Glycogen metabolism > Flashcards

Chapter 21- Glycogen metabolism Flashcards

1
Q

Glycogen

A

Glycogen is a highly branched homopolymer of glucose present in the cytoplasm of all tissues. The largest stores of glycogen are in liver and skeletal muscle

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2
Q

Glycogen in the liver

A

The liver breaks down glycogen and releases glucose into the blood to provide energy for the brain and red blood cells

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3
Q

Glycogen in skeletal muscle function

A

Muscle glycogen stores are mobilized to provide energy for muscle contraction

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4
Q

3 steps of glycogen degradation

A
  1. Release of glucose 1-phosphate from glycogen
  2. Remodeling of glycogen to allow continued degradation
  3. Conversion of glucose 1-phosphate into glucose 6-phosphate
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5
Q

3 fates of glucose 6-phosphate

A
  1. Processing by the glycolytic pathway
  2. Conversion into free glucose for release into the blood
  3. Processing by the pentose phosphate pathway
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6
Q

UDP-glucose

A

Glycogen synthesis requires an activated form of glucose, uridine diphosphate glucose (UDP-glucose), formed by the reaction of UTP and glucose 1-phosphate. Glycogen must be remodeled to allow continued synthesis

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7
Q

Glycogen degradation and synthesis are

A

Reciprocally regulated.

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8
Q

Glycogen phosphorylase

A

Degrades glycogen from the nonreducing ends of the molecule. The phosphorylase catalyzes a phosphorolysis reaction that yields glucose 1-phosphate

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9
Q

Phosphoglucomutase

A

Glucose 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase; no ATP is expended.

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10
Q

Pyridoxal phosphate (PLP)

A

Glycogen phosphorylase requires pyridoxal phosphate (PLP) as a cofactor. PLP forms a Schiff base with a lysine residue at the active site of the phosphorylase.

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11
Q

The phosphate substrate of PLP promotes

A

Cleavage of an α-1,4-linkage in glycogen by donating a proton to the departing glucose. This results in the formation of a carbocation intermediate. The carbocation and phosphate combine to form glucose 1-phosphate.

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12
Q

PLP–Schiff-base linkage

A

Schiff bases are also called imines. A Schiff base is formed by the reaction of a primary amine with an aldehyde or a ketone

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13
Q

Which bonds can glycogen phosphorylase cleave?

A

Glycogen phosphorylase cannot cleave near branch points and can only cleave α-1,4-glycosidic bonds

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14
Q

Transferase

A

Shifts a small oligosaccharide near the branch point to a nearby chain, thereby making the glucose moieties accessible to the phosphorylase. A debranching enzyme (α-1,6-glucosidase) then cleaves the α-1,6 bond at the branch point, releasing a free glucose. This is necessary for the breakdown of glycogen

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15
Q

How does phosphoglucomutase convert glucose 1-phosphate into glucose 6-phosphate? (3)

A
  1. A serine at the active site of phosphoglucomutase is phosphorylated.
  2. Phosphoglucomutase forms a glucose 1,6-bisphosphate intermediate by donating its bound phosphoryl group to glucose 1-phosphate.
  3. The phosphoryl group is restored to the enzyme with the formation of glucose 6-phosphate
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16
Q

Glucose 6-phosphatase

A

Generates free glucose from glucose 6-phosphate in the liver. The free glucose is released into the blood for use by other tissues such as the brain and red blood cells

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17
Q

Why is glucose 6-phosphatase not found in other tissues?

A

Glucose 6-phosphatase is absent in most other tissues. Muscle tissues retain glucose 6-phosphate for ATP generation. In contrast, glucose is not a major fuel for the liver.

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18
Q

Glycogen phosphorylase

A

The key regulatory enzyme for glycogen degradation

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19
Q

2 forms of glycogen phosphorylase

A

Phosphorylase exists in two forms: a less active b form and a more active a form. The a form differs from the b form in that a serine residue is phosphorylated. Both the a form and the b form display an equilibrium between the R and T states. In the b form, the T state is favored, whereas in the a form, the R state is favored.

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20
Q

Liver phosphorylase

A

A key role of the liver is to maintain adequate blood glucose levels. As a result, the default state of liver phosphorylase is the a
form in the R state. In essence, liver phosphorylase is prepared to generate blood glucose unless signaled otherwise

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21
Q

What is a negative regulator of liver phosphorylase?

A

Glucose is a negative regulator of liver phosphorylase, facilitating the transition from the R state to the T state

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22
Q

Isozymes

A

Liver phosphorylase and muscle phosphorylase are isozymes.

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23
Q

What is the default form of phosphorylase in the muscle?

A

In muscle, the default form of the phosphorylase is the b form in the T state

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24
Q

Function of phosphorylase in the muscle

A

When energy is needed, as signaled by an increase in the concentration of AMP, the phosphorylase binds AMP, which stabilizes the R state. The T state of the phosphorylase is stabilized by ATP and glucose 6-phosphate

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25
Q

Types of skeletal muscle fibers (3)

A

Type 1, type 2a, type 2b

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26
Q

Type 1 skeletal muscle fibers

A

Slow-twitch fibers, use cellular respiration, powered by fatty acid degradation, to generate ATP. Glycogen is not an important energy source for these fibers. High fatigue resistance and mitochondrial density

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27
Q

Type 2a skeletal muscle fibers

A

Fast-twitch fibers, generate energy by aerobic glycolysis and perform little cellular respiration. Mitochondria are rare and glycogen is the primary fuel for these fibers

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28
Q

Type 2b skeletal muscle fibers

A

Possess properties intermediate between the other two fiber types

29
Q

Phosphorylase kinase

A

The regulatory enzyme that converts glycogen phosphorylase b to phosphorylase a with the addition of a phosphate. This covalent modification removes a peptide loop from the active site of the b form, rendering the enzyme more active.

30
Q

Phosphorylase kinase structure

A

Subunit composition of (αβγδ)4, with the active site on the γ subunit

31
Q

How is phosphorylase kinase activated?

A

Phosphorylase kinase itself is activated first by Ca2+ binding and then by phosphorylation- it’s maximally activated when bound to calcium and phosphorylated. The δ (delta) subunit of phosphorylase is the calcium sensor calmodulin. Phosphorylase kinase is phosphorylated by protein kinase A

32
Q

The isozyme of glycogen phosphorylase in the brain is stimulated by

A

Like muscle phosphorylase, the brain isoform is stimulated by AMP.

33
Q

The isozyme of glycogen phosphorylase in the brain is regulated by

A

A redox switch- two cysteines that form a disulfide bond. Reactive oxygen species such as hydrogen cause the formation of the
disulfide bond, which then prevents AMP activation of the enzyme without altering its regulation by phosphorylation

34
Q

The isozyme of glycogen phosphorylase in the brain may be a target of

A

Brain glycogen phosphorylase may be a target of dithiocarbamates, such as the pesticide thiram. Thiram is believed to disrupt the functioning of the redox switch, explaining its neurotoxic side effects

35
Q

Which molecules signal the need for glycogen breakdown?

A

G proteins transmit the signal for the initiation of glycogen breakdown. The hormones epinephrine and glucagon bind to specific seven-transmembrane (7TM) receptors in the plasma membranes of target cells.

36
Q

Which receptors do epinephrine and glucagon bind to?

A

Epinephrine binds to the β-adrenergic receptor in muscle; glucagon binds to the glucagon receptor in the liver. This causes Gs protein activation

37
Q

When G proteins are activated, what happens next in glycogen breakdown? (3)

A
  1. The GTP-bound subunit of Gs adenylate cyclase, catalyzes formation of the second messenger cAMP from ATP.
  2. The elevated cAMP concentration activates protein kinase A.
  3. Protein kinase A phosphorylates phosphorylase kinase, which activates glycogen phosphorylase, leading to glycogen degradation
38
Q

Which mechanisms can turn off glycogen degradation? (4)

A
  1. The hormones that stimulate glycogen breakdown are no longer present.
  2. The inherent GTPase activity of the Gα subunit inactivates G protein signaling.
  3. Phosphodiesterase converts cAMP into AMP, which does not stimulate protein kinase A.
  4. Protein phosphatase 1 removes phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, thereby inactivating the enzymes
39
Q

How has glycogen phosphorylase become more sophisticated as it evolved?

A

Examination of the primary structure of glycogen phosphorylase from a variety of organisms revealed that the catalytic mechanism has been maintained throughout evolution. By contrast, regulation by phosphorylation was a later adaptation.

40
Q

Which monomer extends the glycogen chain?

A

UDP-glucose is the monomer that is used to extend the glycogen chain in synthesis.

41
Q

Glycogen degradation yields

A

glucose 1-phosphate

42
Q

Which molecule donates glucose in glycogen synthesis?

A

Uridine diphosphate-glucose (UDP-glucose) is the glucose donor in glycogen synthesis.

43
Q

How is UDP-glucose synthesized?

A

UDP-glucose is synthesized by UDP-glucose pyrophosphorylase in a reaction that produces a pyrophosphate (PPi).

44
Q

Why is the synthesis of UDP glucose irreversible?

A

The reaction, like many biochemical reactions, is subsequently rendered irreversible by the hydrolysis of pyrophosphate.

45
Q

Glycogen synthase

A

The key regulatory enzyme in glycogen synthesis, transfers a glucose moiety from UDP-glucose to the C-4 terminal residue of a glycogen chain to form an α-1,4-glycosidic bond

46
Q

Glycogen synthase primer

A

Glycogen synthase requires a polysaccharide of glucose residues as primer. The primer is synthesized by glycogenin, a dimer of
two identical subunits. Glycogen synthase then extends this primer

47
Q

Glycogenin

A

The primer of glycogen synthase is synthesized by glycogenin, a dimer of two identical subunits. Each subunit of glycogenin generates an oligosaccharide of glucose residues 10–20 glucose units in length

48
Q

How does glycogen synthase generate linkages?

A

Glycogen synthase can only synthesize α-1,4-linkages. A branching enzyme generates branches by cleaving an α-1,4-linkage, moving a block of approximately seven glucoses and synthesizing an α-1,6 linkage. Glycogen synthase can then extend the branched polymer

49
Q

Why do protein kinase A and glycogen synthase kinase modify glycogen synthesis?

A

Glycogen synthase is usually inactive when in the phosphorylated b form and is usually active when in the unphosphorylated a form

50
Q

How is the b form of glycogen synthase converted?

A

Another regulatory process for glycogen synthase is the conversion of the b form in the T state to the active R state by binding glucose 6-phosphate. Phosphorylation has opposite effects on glycogen synthase compared to glycogen phosphorylase.

51
Q

Why is glycogen an efficient storage form of glucose?

A

Only one molecule of ATP is required to incorporate glucose 6-phosphate into glycogen. The complete oxidation of glucose 6-phosphate derived from glycogen yields about 31 molecules of ATP

52
Q

How are glycogen breakdown and synthesis reciprocally regulated?

A

Glycogen synthesis is inhibited by the same glucagon and epinephrine signaling pathways that stimulate glycogen breakdown

53
Q

Which 2 pathways reciprocally regulate glycogen breakdown and synthesis?

A
  1. Phosphorylation of glycogen synthase a by protein kinase A to form glycogen synthase b inhibits glycogen synthesis.
  2. Glycogen synthase kinase also phosphorylates and inhibits glycogen synthase
54
Q

Protein phosphatase 1 (PP1)

A

Shifts glycogen metabolism from the degradation mode to the synthesis mode. PP1 removes phosphoryl groups from glycogen
synthase b, converting it into the more active a form. PP1 also removes phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, inhibiting glycogen degradation.

55
Q

Protein phosphatase 1 (PP1) structure

A

Consists of a catalytic subunit and two regulatory subunits. A key regulatory subunit is the G subunit (GL in liver and GM in muscle) that binds glycogen and the catalytic subunit, localizing the enzyme with its substrates. A second regulatory subunit, when phosphorylated, binds to and further inhibits the catalytic subunit

56
Q

Gm function

A

In muscle, phosphorylation of GM leads to dissociation of the catalytic subunit from glycogen and a decrease in the enzyme’s activity

57
Q

Insulin stimulates glycogen synthesis by (2)

A
  1. Activating a signal transduction pathway that results in the
    phosphorylation and inactivation of glycogen synthase kinase. PP1 subsequently dephosphorylates glycogen synthase, generating the active a form of the synthase.
  2. Insulin also facilitates glycogen synthesis by increasing the number of glucose transporters (GLUT4) in the plasma membrane, allowing for increased uptake of glucose and its subsequent conversion into glycogen
58
Q

How does blood glucose affect glycogen?

A

Glycogen degradation in the liver is inhibited, and glycogen

synthesis is stimulated by high blood-glucose levels

59
Q

When does the activity of glycogen synthase begin to increase?

A

The conversion of glycogen phosphorylase a from the R state to the
T state by the binding of glucose results in the activation of PP1 that
is associated with the phosphorylase. PP1 converts glycogen metabolism from a degradation mode to a synthesis mode. The lag between the decrease in glycogen degradation and the increase in synthesis prevents the two pathways from operating simultaneously. It is caused by the fact that there are approximately 10 times more copies of phosphorylase a than phosphatase. Therefore, the activity of glycogen synthase begins to increase only after most of phosphorylase a is converted into b

60
Q

How does glucose affect phosphorylase and synthase?

A

As glucose is added, synthase increases and phosphorylase decreases

61
Q

von Gierke disease

A

The the earliest description of a glycogen-storage disease was in 1929. von Gierke disease became better understood in the 1950s, when it became clear that the enlarged liver is caused by an inability to express glucose 6-phosphatase, leading to abnormally large
amounts of glycogen. Seven other glycogen-storage diseases have been characterized.

62
Q

McArdle disease

A

Type V glycogen storage disease, is caused by an inability to express muscle phosphorylase. It is characterized by painful muscle fatigue as well as burgundy-colored urine following an attempt at vigorous exercise. The coloration is due to rhabdomylosis (rapid breakdown of skeletal muscle), which causes release of myoglobin in the blood and urine.

63
Q

How does skeletal muscle damage occur in McArdle disease?

A

During vigorous exercise, especially in the first few minutes, skeletal
muscle contractions are powered by glycogen mobilization by
glycogen phosphorylase. If skeletal muscle is made to work vigorously without an adequate energy supply, the cells will break down and leak myoglobin into the blood, which will be passed in the urine. The heme group gives globins their red color, and its presence in the urine accounts for the burgundy color

64
Q

In healthy individuals, what happens when lactic acid is produced?

A

In an unaffected individual, intracellular and blood pH fall as lactic
acid is produced during aerobic glycolysis. Because McArdle
patients are unable to mobilize glucose, lactic acid is not produced
and pH does not drop. Interestingly, the pH actually rises in these
individuals

65
Q

Why does blood pH rise in individuals with McArdle disease?

A

In skeletal muscle, an immediate source of ATP is creatine phosphate. In a futile attempt to power exercise, the muscle cells of
affected individuals rapidly synthesize ATP at the expense
of creatine phosphate. However, the guanidinium group of creatine is a strong base and becomes protonated, causing an increase in pH

66
Q

Pompe’s disease

A

Type 2 glycogen storage disease. The defective enzyme is alpha-1,4- glucosidase. All organs are affected. There is a massive increase in amount of glycogen in the affected organs, but structure is normal. Characterized by cardiorespiratory failure that causes death, usually before age 2.

67
Q

Why is pyruvate necessary in healthy individuals?

A

As exercise continues, unaffected individuals switch from aerobic glycolysis to cellular respiration, necessitating an increase in synthesis of a key citric acid cycle intermediate (oxaloacetate) from pyruvate

68
Q

What happens in McArdle’s disease due to a lack of pyruvate?

A

The most common source of pyruvate in skeletal muscle is from
the metabolism of glucose, generated by glycogen mobilization, and
McArdle patients cannot generate the necessary glucose. At rest, however, the skeletal muscles of McArdle patients are able to obtain
most of their energy from fatty acid oxidation rather than from glycogen mobilization.

Biochemistry (13 decks)

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