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Biochem BLOCK 2 > gluconeogensis (GNG) > Flashcards

gluconeogensis (GNG) Flashcards

1
Q

Gluconeogensis

A

metabolic pathway that results in the generation of glucose from non-carbohydrate presursors

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2
Q

purpose of gluconeogensis

A

maintain blood glucose levels and avoid hypoglycemia under conditions of fasting (10-18 hours)

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3
Q

What two tissues can synthesize glucose?

A

liver and kidney cortex

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4
Q

What tissue does GNG primarily take place in?

A

liver

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5
Q

When does GNG happen in kidney cortex?

A

only during prolonged fasting, contributes up to 40% of the total glucose production

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6
Q

subcellular localization

A
  • step 1 in mitochondrial matrix
  • cytosol (all reversible steps of glygolysis)
  • ER (last step [dephos] to produce glucose
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7
Q

substrates for gluconeogensis

A
  • glycerol
  • amino acids (AA)
  • lactate
  • Acetyl CoA
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8
Q

glycerol as substrate in GNG

A

-released during hydrolysis of TAGs in adipocytes and is delivered by the blood to the liver
-adipocytes lack glycerol kinase
- in the liver
glyverol—glycerol-phosphate—–DHAP

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9
Q

amino acids as substrate in GNG

A
  • major source are derived from tissue protein hydrolysis
  • very late in starvation mode, after all fat is gone
  • most AA converted in TCA to intermediates that yield OAA at some point
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10
Q

lactate as substrate in GNG

A
  • converted back into pyruvate in the liver by lactate dehydrogenase
  • released from cells under anaerobic conditions
  • Cori cycle
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11
Q

Cori Cycle

A

glucose converted into lactate under anaerobic glycolysis, excreted to plasma and sent to the liver to be converted back to glucose and released into circulation

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12
Q

Acetyl CoA as substrate in GNG

A
  • CANNOT be converted to pyruvate in humans
  • PDH is irreversible and there is NO enzyme for the reverse reaction
  • FA cannot serve as substrate (only glycerol)
  • FA oxidation provides energy to liver required to perform GNG
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13
Q

how many reversible reactions of GNG are there?

A

7

highly dependent on cxn of products and substrates

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14
Q

how many irreversible reactions of GNG are there?

A

3

overcome by using 4 alternative enzymes

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15
Q

4 alternative enzymes used to overcome the 3 irreversible steps

A 
1. pyruvate---OAA
   Pyruvate carboxylase 
2. OAA---PEP
   PEP carboxykinase
3. F-1,6-bis-P-----F-6-P
   F-1,6 bisphosphatase
4. G-6-P----glucose
   Glucose 6 phosphatase
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16
Q
  1. carboxylation of pyruvate to OAA
A
  • unique to GNG
  • mitochondrial matrix
  • provide OAA for GNG and TCA replenishment
  • enzyme: pyruvate carboxylase, malate dehydrogenase, PEP carboxylase
  • OAA cannot be exported (lack of transporter)
  • converted to malate
  • M exported and converted back to OAA
17
Q

pyruvate carboxylase

A
  • enzyme for first step of GNG
  • requires biotin as a coenzyme
  • allosterically activated by acetyl CoA
18
Q

why can OAA not be exported?

A

lack of transporters , has to be converted to malate

19
Q
  1. decarboxylation of cytosolic OAA
A
  • IRREVERSIBLE
  • driven by GTP hydrolysis
  • pairing carboxylation with de-carboxylation makes GNG energetically possible
  • enzyme: PEP-carboxykinase (PEPCK)
20
Q

What makes GNG energetically possible?

A

decarboxylation of cytosolic OAA

21
Q
  1. dephosphorylation of fructose 1,6-bis-P
A
  • hydrolysis reaction
  • bypasses the irreversible PFK-1 reaction
  • important site for regulation
  • enzyme: fructose 1,6-bisphosphatase
22
Q

fructose 1,6-bisphosphatase

A
  • dephosphorylation of fructose 1,6-bis-P
  • inhibited by AMP and allosterically by fructose 2,6 bis-P
  • activated by high ATP, low AMP
23
Q

regulation by fructose 1,6-bisphosphate

A
  • synthesized by PFK-2
  • inactivates fructose 1,6-bisphosphatase and stops GNG
  • commone regulator allows tight regulation assuring the pathways of glycolysis and gluconeogensis are mutually exclusive
24
Q
  1. dephosphorylation of glucose 6-P
A
  • hydrolysis reaction
  • bypasses the irreversible hexo/glucokinase reaction
  • provides energetically favorable step to produce glucose
  • enzyme: glucose 6-phosphatase
25
Q

glucose 6-phosphatase

A
  • enzyme for dephosphorylation of glucose 6-phosphatase
  • also used during glycogenolysis to yield free glucose
  • glucose can then be transported out of the liver to maintain blood glucose
26
Q

gluconeogenesis summary

A

-endergonic
-anabolic
-per 1 glucose
4 ATP and 2 GTP are used
2 NADH are used

27
Q

regulaltion by glucagon

A
  • inhibits PFK-2, lowers fructose 2,6-BP inhibiting glycolysis and activating GNG
  • inhibits pyruvate kinase, therefore PEP is used for GNG as opposed to glycolysis
  • stimulates transcription of PEPCK, insulin inhibits it
28
Q

regulation by substrate availability

A
  • protein breakdown in other tissues and subsequent amino acid release yields gluconeogenic precursors in the liver, which stimulate GNG
  • ATP and NADH are provided by the oxidation of FA in the liver
29
Q

allosteric activation by ACetyl CoA

A
  • buildup of acetly CoA, signals the diversion of OAA for GNG
  • activates pyruvate carboxylase
  • inhibits PDH, assuring pyruvate is diverted to the production of glucose and away from the TCA cycle
30
Q

allosteric inhibition of AMP

A
  • F1,6BP inhibited by AMP
  • PFK-1 activated by AMP
  • as with regulation of the two enzymes by fructose 2,6-BP, the reciprocal regulation of each of these enzmyes by the same allosteric effector assures the two pathways are mutually exclusive
31
Q

regulation of GNG

A
  1. regulation by glucagon
  2. regulation by substrate availability
  3. allosteric activation by acetyl CoA
  4. allosteric inhibition by AMP
32
Q

What ensures that glycolysis and gluconeogensis are mutually exclusive?

A
  • regulation by fructose 2,6-BP

- allosteric inhibition by AMP

Biochem BLOCK 2 (14 decks)

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