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Biochemistry II > Gluconeogenesis, glycogenesis, regulation > Flashcards

Gluconeogenesis, glycogenesis, regulation Flashcards

1
Q

Glucose is transported into the cell via 5 isoforms of GLUT transporters.

Describe GLUT 1.

It has similar characteristics to GLUT.. ?

A

GLUT 1, 3

  • high affinity (Km = 1 mM)
  • GLUT1: in brain, erythrocytes
  • GLUT3: in brain

⇒ ensures steady/basal glucose uptake in glucose dependent cells

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2
Q

Glucose is transported into the cell via 5 isoforms of GLUT transporters.

Describe GLUT 2.

A

GLUT 2

  • low affinity (Km = 15 mM)
  • in enterocytes, hepatocytes, pancreatic β-cells (glucose sensor cells)

⇒ glucose uptake proportional to blood glucose concentration

NOTE: allows bidirectional glucose transport

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3
Q

Glucose is transported into the cell via 5 isoforms of GLUT transporters.

Describe GLUT 4.

A

GLUT 4

  • intermediate affinity (Km = 5 mM)
  • insulin-dependent expression
  • in skeletal/heart muscle, adipocytes (= facultative glucose consuming cells)

⇒ adjusts glucose consumption to availability
(↑ [glucose] → ↑ [insulin] → cell takes up glucose)

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4
Q

Glucose is transported into the cell via 5 isoforms of GLUT transporters.

Describe GLUT 5.

A

GLUT 5

  • in intestinal, tubular kidney epithelium

​⇒ glucose absorption and reabsorption

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5
Q

How much glucose can we find in a 70-kg human being?

Where?

A
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6
Q

Which tissues are glucose dependent?

A
  • CNS
  • kidney medulla
  • testis
  • RBCs
  • embryonic tissues
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7
Q

What is gluconeogenesis?

Why is it important?

A

glucose formation from non-carbohydrates precursors (e.g. lactate, glucogenic AAs, glycerol) via conversion to pyruvate or intermediates of TCA cycle

⇒ provides glucose for glucose dependent tissues in case of starvation

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8
Q

Which organs are able to undergo gluconeogenesis?

A

kidney + liver

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9
Q

Which enzymes are required for gluconeogenesis?

A

the 3 irreversible reactions of glycolysis must be bypassed to produce glucose:

  1. pyruvate carboxylase + phosphoenolpyruvate carboxykinase (pyruvate kinase)
  2. fructose 1,6-bisphosphatase 1 (PFK 1)
  3. glucose 6-phosphatase (hexokinase)
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10
Q

Pyruvate carboxylase catalyzes the first step of gluconeogenesis.

Reaction?

Where does it happen?

A

starts gluconeogenesis in mitochondria

pyruvate + CO2 + ATP → ADP + Pi + OXA

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11
Q

What are the cofactors of pyruvate carboxylase?

A

“has MBA”

uses Mg2+, biotin, ATP

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12
Q

How is OXA transported out of the mitochondrium for further gluconeogenesis?

A
  1. in mitochondrium
    OXA + NADH → malate + NAD+
  2. malate aspartate shuttle
  3. in cytosol
    malate + NAD+ → OXA + NADH

→ remaining steps of gluconeogensis also happen in cytosol

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13
Q

How does phosphoenolpyruvate carboxykinase contribute to gluconeogenesis?

What happens with its product?

A

= PEPCK

OXA + GTP → PEP + GDP + CO2

⇒ phosphoenolpyruvate undergoes reversible reactions in glycolysis

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14
Q

How does fructose 1,6-bisphosphatase 1 contribute to gluconeogenesis?

A

= F1,6BPase 1

F1,6BP + H2O → F6P + Pi

reverses reaction of PFK 1

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15
Q

How does glucose 6-phosphatase contribute to gluconeogenesis?

Where can it be found?

A

reverses reaction of hexokinase/glucokinase

G6P + H2O → glucose + Pi

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16
Q

How much energy is required to produce glucose from pyruvate?

A

3 mol ATP/triosphosphate → 6 mol ATP/glucose

  • 1 ATP: pyruvate carboxylase
  • 1 GTP: PEPCK
  • 1 ATP: F1,6BPase 1
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17
Q

Which mechanisms/enzymes are responsible for the regulation of glycolysis?

A
  • GLUT transporters: regulate glucose influx
  • all irreversible steps:
    • HK/GK
    • PFK1: rate-limiting step of glycolysis
    • PK
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18
Q

Where can hexokinase be found?

How is its activity regulated?

A

in extrahepatic tissues

  • inhibited by G6P (product inhibition)
  • induced by insulin
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19
Q

Where can glucokinase be found?

How is it regulated?

A

in liver, pancreatic beta cells, kidney

  • induced by insulin
  • regulated by GKRP
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20
Q

How does GKRP regulate the glucokinase?

Explain.

A

glucokinase regulator protein

competes w/ glucose for GK, inactivates it

  • ↑ [glucose]: GKRP does not bind to GK, GK active in cytosol
  • ↓ [glucose]: GKRP binds to GK, inactivates it + translocates into nucleus

*

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21
Q

How is the activity of GKRP modulated?

A
  • F6P: binds to GKRP, incr. its affinity to GK → inactivation
  • F1P: inhibits GKRP, frees GK → activation

⇒ if we have much F6P (very much glucose), so we don’t want to generate even more energy via glycolysis, rather use the glucose for glycogenesis, but if F1P present (indicating high fructose levels) we still generate energy → nem jo

reason why F1P can cause fatty liver due to exc. ATP production

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22
Q

Which substances regulate the activity of G6Pase?

A
  • repressed by: insulin
  • induced by: glucagon, glucocorticoids

​→ in fight or flight situation, we want glucose in our blood stream

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23
Q

As a summary…

Describe the effects on glucokinase and G6P in the liver after we eat bunch of carbs.

A

GLUT 2 transporters import glucose

  • ↑ [glucose]: GKRP does not associate, GK produces much [G6P] for glycogenesis
  • insulin
    • ​induction of glucokinase
    • repression of G6Pase
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24
Q

As a summary…

Describe the effects on glucokinase and G6P in the liver in periods of starvation.

A

no glucose transport into cell

  • ↓ [glucose]: GKRP binds to GK, inactivating it
  • glucagon → induction of G6Pase

⇒ glucose formed, exported into blood stream

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25
Q

Which substances regulate the activity of PFK 1?

A

allosteric inhibitors:

  • ATP, FAs: much energy in cell
  • citrate

​allosteric activators:

  • AMP
  • F2,6BP, most important regulator of glycolysis
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26
Q

Which mechanism is described by the Pasteur effect?

Importance?

A

increased rate of glycolysis during hypoxia/anoxia to compensate “missing” ATP production by oxidative phosphorylation
→ ↓ [O2] → ↑ [AMP] → activation of PFK 1 (rate-limiting)

important for survival of tissues during hypoxia (e.g. after vascular obstruction)

27
Q

Explain the regulation of glycolysis by F2,6BP.

A
  • inhibits F1,6BPase
  • activates PFK 1

​⇒ ↑ [F1,6BP] = all. activator of pyruvate kinase → glycolysis

28
Q

Which enzyme produces F2,6BP?

Reaction.

A

tandem (= bifunctional) enzyme PFK2/FBPase2
has 2 activities

  • PFK2: F6P → F2,6BP
  • FBPase2: F2,6BP → F6P
29
Q

How is PFK2/FBPase2 regulated in the liver?

A

activities are dependent on de-/phosphorylation
controlled by hormone status in response to blood glucose levels

  • catecholamines/glucagon: ↑ cAMP → PKA → phosphorylation → FBPase2 activity
    ⇒ F6P generated, used for gluconeogenesis
  • insulin ​→ protein phosphatase 1 → dephosphorylation → PFK2 activity
    ⇒ F2,6BP generated, activates glycolysis
30
Q

What are the effects of phosphorylation/dephosphorylation of PFK2/FBPase2 in skeletal and heart muscle?

A
  • in heart: phosphorylation → PFK2 activity
    ⇒ catecholamines incr. rate of glycolysis to cover for E requirements
  • in sk. muscle: no phosphorylation, but catecholamines incr. F2,6BP due to ↑ [glucose]
31
Q

What is the futile cycle?

Why is it useful?

A

in flying mm. of bumblebees: PFK 1 and F1,6BPase active
→ excessive ATP generation, resulting in thermogenesis

BUT: permits very rapid incr. in rate of glycolysis, if necessary for mm. contraction

32
Q

What is special about pyruvate kinase?

Why is it important?

A

2 isoenzymes

  • PK-L in Liver, allosterically and covalently modified in response to hormones (otherwise unregulated production of pyruvate = futile cycle)
  • PK-M in sk. Muscle, not regulated b/c no gluconeogenesis
33
Q

How is the activity of PK-L allosterically regulated?

Effects.

A
  • activated by: F1,6P (feedforward)
    → glycolysis/E generation
  • inhibited by: → gluconeogenesis
    • ATP (product inhibition)
    • Ala
34
Q

What are the effects of de-/phosphorylation of PK-L?

A
  • activated by dephosphorylation: insulin
  • inactivated by phosphorylation: glucagon
35
Q

How is PEPCK regulated?

A

induced by → gluconeogenesis

  • glucocorticoids
  • glucagon
  • retinoids

​repressed by → glycolysis + glycogenesis

  • ​insulin
36
Q

What is the function of glycogen in liver and skeletal mm.?

Describe its structure.

A
  • in liver: maintenance of blood glucose level
  • in skeletal mm.: provides glucose during exercise

glycogen granule in the core, main chain w/ α1,4-glycosidic linkages, branches w/ 1,6-glycosidic linkages

⇒ free, non-reducing ends

37
Q

What must happen to glucose before it can be stored as glycogen?

Enzymes + reactions.

A

conversion of glucose to UDP-glucose

  1. phosphoglucomutase: G6P ⇔ G1P
  2. UDP-glucose pyrophosphorylase:
    G1P + UTP → UDP-glucose + PPi

​β and γ-phosphate of UTP → pyrophosphate

38
Q

Which substance inhibits phosphoglucomutase?

A

DIPF = diisopropylfuorophosphate

→ no conversion of G6P to G1P

39
Q

What happens with the UDP-glucose units during glycogenesis?

A

glycogen synthase binds UDP-glucose to non-reducing ends of either

  • preexisting glycogen chain, or
  • glycogenin

forming α 1,4-glycosidic linkages

40
Q

What is the function of glycogenin?

Where can it be found?

A

protein forms the “primer” of glycogenesis
→ at core of glycogen granule

⇒ amount of glycogenin determines the cellular glycogen content (since primer for glycogen molecule)

41
Q

Which enzyme is responsible for the α 1,6 branches btw glucose units in glycogen?

Explain.

Why is the branching of glycogen important?

A

glycosyl 4,6-transferase = branching enzyme

when main glycogen chain at least consisting of 11 glucose units, part of chain transferred → α 1,6 branch points formed

⇒ incr. solubility, more non-reducing terminal residues incr. rate of metabolism

42
Q

What is the energy balance of glycogenesis for one glycosyl unit?

A

G6P + ATP + glycogen (n) + H20

↓

glycogen (n+1) + ADP + 2Pi

43
Q

What is the underlying mechanism of glycogenolysis?

Reaction.

Why is this mechanism physiologically very advantageous?

A

phosphorylation by glycogen phosphorylase (rather than hydrolysis)
→ even possible under anaerobic conditions (ex: exercise)

glycogen (n) + Pi → G1P + glyogen (n-1)​

44
Q

Which enzyme is responsible for glycogenolysis?

Explain its mechanism.

A

glycogen phosphorylase
2 subunits w/ PLP at catalytic site (prosthetic group)

⇒ acting as acid-base catalyst to cleave α1,4-glycosidic bonds in glycogen
(until 4 glucose residues remaining on either side of α1,6 branch)

45
Q

Which enzyme is responsible for 1,6 glycogenolysis?

Explain its mechanism.

A

debranching enzyme = 2 diff. catalytic sites

  1. glucan transferase: transfers trisaccharide to α 1-4 main chain
  2. α 1,6-glycosidase: hydrolyzes 1,6 linkage → free glucose formed
46
Q

What is von Gierke’s disease?

Differentiate btw its 2 types.

A
  • glycogenosis type Ia: G6Pase defect
  • glycogenosis type Ib: G6P transporter mutation

⇒ G6P accumulates in liver

47
Q

What are the consequences of von Gierke’s disease?

A

⇒ G6P accumulates in liver

  • causes ↑[G1P] → inhibition of glycogenolysis → hepatomegaly
  • no glucose export → hypoglycemia, ketosis, hyperuricemia, hyperlipemia
48
Q

What is McArdle disease?

Clinical features?

A

deficiency of muscle glycogen phosphorylase

  • poor exercise tolerance
  • muscle glycogen abnormally high (2-4%)
  • blood lactate very low after exercise
49
Q

Which enzymes regulate the glycogen metabolism?

When are they active, what do they cause?

A
  • phosphorylase: active at low [glucose] → glycogenolysis
  • glycogen synthase: active at high [glucose] → glycogenesis
50
Q

Differentiate btw the types of phosphorylase in different tissues w/r/t structure and regulation mechanism.

A

isoenzymes in sk. mm, and liver

regulatory mechanisms:

  • allosterically:
    • inactive T state
    • active R state
  • covalently mod.:
    • ​phosphorylated active phosphorylase a
    • dephosphorylated inactive phosphorylase b

⇒ phosphorylase a mainly in R state, b mainly in T state

51
Q

Which main form of phosphorylase can be found in skeletal muscle?

Explain the function of its regulatory substances.

A

phosphorylase b
⇒ regulated by energy state of muscle cell

activation → glycogenolysis

  • allosterically by AMP → R state

inactivation

  • allosterically by ATP, G6P → stabilized T state
52
Q

What is the special function of phosphorylase in the liver and how does it work?

A

glucose sensor function
b/c glucose is only regulator of liver’s glycogen phosphorylase

⇒ high [glucose] causes stabilization of T state

53
Q

Which enzymes are responsible for phosphorylation and dephosphorylation of phosphorylase a to b and vice versa?

A
54
Q

Explain the activating effect of hormones on phosphorylase.

Which hormones elicit this cascade?

A

catecholamines , glucagon (only in liver!!)

  1. binds to receptor → activation of adenylate cyclase: ATP to cAMP → PKA
  2. PKA phosphorylates phosphorylase kinase b to a
  3. phosphorylase kinase a phosphorylates phosphorylase b to a
    → glycogenolysis
55
Q

Describe the structure of phosphorylase kinase.

Why is it important?

A

hexadecamer = 4 α, β, γ, δ subunits
→ δ subunits = calmodulin, can bind Ca2+

if Ca2+ binds, activation independently of phosphorylation by PKA
<em>(esp. important during mm. contraction to provide E supply by glycogenolysis)</em>

56
Q

How is glycogen synthase regulated?

A

allosterically + covalently modified​
BUT: reciprocal regulation to glycogen phosphorylase

  • dephosphorylated active form
  • phosphorylated inactive form

has 9 phosphorylation sites → fine adjustment of activity

57
Q

Which enzymes other than PKA are able to phosphorylate glycogen synthase?

A

NOTE: glycogensynthase kinase 3 esp. important

inactivated by insulin

58
Q

Which substance regulates glycogen synthase allosterically?

Why is it important?

A

G6P
⇒ activates glycogen synthase even if phosphorylated

important when rate of glycogenesis should be increased very rapidly in response to insulin

59
Q

What is the function of protein phosphatase 1?

Describe its structure.

A

protein phosphatase 1 (PP1)
catalytic subunit + regulatory tissue specific subunit (G subunit): association → activation

  • dephosphorylates glycogen synthase → activation ⇒ glycogenesis
  • dephosphorylates phosphorlyase kinase a and phosphorylase a → inactivation ⇒ ↓ glycogenolysis
60
Q

How does insulin activate glycogenesis and inhibit glycogenolysis?

A
  • activates phosphodiesterase → ↓ cAMP → inactivated PKA
  • activates insulin-sensitive PK → phosphorylation of G subunit → associates with catalytic subunit of PP1 → dephosphorylates glycogen synthase/phosphorylase kinase a/phosphorylase a
61
Q

How is PP1 inactivated?

A

in response to cAMP → activates PKA, then 2 mechanisms of inactivation

  • phosphorylates inhibitor so it can bind to PP1
  • phosphorylates catalytic subunit, dissociates from G subunit

in skeletal muscle

62
Q

Which substance can be considered as an allosteric activator of PP1?

A

G6P

63
Q

As a summary…

What is the function of PKA?

Effects?

Activated in response to.. ?

A

activated in response to catecholamines, glucagon
via cAMP levels

  • phosphorylates phosphorylase kinase = active
  • phosphorylates synthase = inactive
  • phosphorylates PP1 = less active
  • phosphorylates inhibitor of PP1 = inactive PP1
  • phosphorylates PFK2/FBPase2 = eff. depends on tissue type

Biochemistry II (16 decks)

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