Carbohydrate Metabolism: Gluconeogenesis Flashcards

1
Q

What is glucongeogensis?

A

Synthesis of glucose

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2
Q

Where is gluconeogenesis most active in animals?

A

Most active when glycogen stores in the liver and muscle has been depleted

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3
Q

Which organ is most responsible for gluconeogenesis?

A

It is mostly the liver’s job as it is unselfish and gives it to those in need

The muscle is selfish as it stores its own glucose

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4
Q

What are the 4 major carbon sources for glucose synthesis?

A

Glycerol

Amino acids

Lactate

CO2 fixation (in plants)

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5
Q

How is glycerol a major carbon source for glucose synthesis?

A

Triglycerides (fats) are converted into glycerol, which can be converted to DHAP (Dihydroxyacetone phosphate)

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6
Q

How are amino acids a major carbon source for glucose synthesis?

A

Nutrient limitation increases the conversion of amino acids into pyruvate or citrate cycle metabolites

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7
Q

How is lactate a major carbon source for glucose synthesis?

A

Anaerobic respiration increases the pool of lactate, which can be converted into pyruvate for entry into the gluconeogenic pathway

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8
Q

How is CO2 fixation (in plants) a major carbon source for glucose synthesis?

A

Plants use gluconeogenesis to synthesize glucose from triose phosphates generated from CO2 fixation, which is used to produce sucrose and starch for energy storage

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9
Q

Compare and contrast between glycolysis and gluconeogenesis.

A

Glycolysis is the breakdown of glucose while gluconeogenesis is the synthesis of glucose

They are opposing pathways - end product of one is the starting point of the other

They share 7 enzymes (those that catalyze reversible reactions)
- The direction of the reversible reactions is simply a response to the relative concentrations of metabolites

Main determinants of the flux through either pathway are the IRREVERSIBLE reactions

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10
Q

Name 4 gluconeogenic enzymes that bypass 3 exergonic reactions in glycolysis.

A

Pyruvate carboxylase and Phosphoenolpyruvate (PEP) carboxykinase in gluconeogenesis bypass Pyruvate kinase in glycolysis

Fructose-1,6-bisphosphate-1 in gluconeogenesis bypass Phosphofructokinase-1 in glycolysis

Glucose-6-phosphate in gluconeogenesis bypass Hexokinase in glycolysis

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11
Q

Describe the reaction of Pyruvate to Phosphoenolpyruvate.

A

Requires two energy-consuming steps

1st step: pyruvate carboxylase converts pyruvate to OAA (oxaloacetate)

  • Carboxylation using a biotin cofactor
  • Requires transport of pyruvate into the mitochondria

2nd step: PEP carboxykinase converts OAA to PEP

  • Phosphorylation and decarboxylation
  • Occurs in mitochondria or cytosol depending on aerobic vs. anaerobic conditions
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12
Q

Describe the synthesis of oxaloacetate.

A

Biotin = an important cofactor for pyruvate carboxylase

Covalently linked to the e amino acid group on Lys in the active site

Biotinylated Lys functions as a swinging arm in the reaction to carry a carboxyl group from one region of the active site to another

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13
Q

What is Biotin?

A

CO2 Carrier; long biotinyl-Lys tether moves CO2 from site 1 to site 2

A vitamin required in the human diet; abundant in many foods; also synthesized by intestinal bacteria

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14
Q

Is biotin deficiency rare?

A

Yes its rare, but can be caused by a diet rich in raw eggs

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15
Q

What is the relation between eggs and biotin?

A

Eggs have a protein called avidin, which binds biotin and prevents its absorption (which will also affect the synthesis of oxaloacetate)

In cooked eggs, avidin is denatured and inactivated

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16
Q

Describe the steps of oxaloacetate to phosphoenolpyruvate.

A

Decarboxylation leads to rearrangement of electrons

Facilities attack of the carbonyl oxygen of the OAA on the y phosphate of GTP

In humans, the reaction can either happen in the mitochondrial matrix or cytosol depending on whether we have aerobic or anaerobic metabolism

17
Q

In aerobic metabolism, how is OAA converted to PEP?

A

OAA –> Malate in mitochondrial matrix

Malate transported to cytosol

Malate brings OAA in the cytosol

  • produces NADPH in the cytosol
  • needed for GAPDH (as if there is not enough NADPH, this reaction of 1,3BPG to G3P will not occur)

OAA –> PEP in the cytosol

PEP –> 1,3BPG

1,3BPG –> G3P by GAPDH (enough NADPH is needed) (GAPDH = glyceraldehyde-3-P dehydrogenase)

G3P –> gluconeogenesis

18
Q

In aerobic metabolism, how is OAA converted to PEP?

A

During vigorous exercise, lactate produced in muscle cells is transported to the liver

Lactate –> Pyruvate by lactate dehydrogenase

Under these conditions cytosolic NADH levels are maintained by the lactate dehydrogenase reaction

Mitochondrial PEPCK converts OAA to PEP (PEPCK = phosphoenolpyruvate carboxykinase)

PEP is exported out to the cytosol (PEP –> G3P by GAPDH)

19
Q

What bypasses the other two irreversible glycolytic reactions?

A

F1,6-BP + H2O –> F6-P + Pi
- by Fructose-1,6-bisphosphate-1
- coordinately/oppositely regulated with PFK-1 (glycolysis)

G6P + H2O –> Glucose + Pi

  • by glucose 6-phosphatase
  • coordinately/oppositely regulated by hexokinase (glycolysis)
20
Q

Where is glucose-6-phosphatase localized?

A

Glucose-6-phosphatase is localized to the lumen of the endoplasmic reticulum

Found in hepatocytes, renal cells and epithelial cells of small intestine

NOT found in other tissues

21
Q

How can glucose leave to the extracellular space?

A

By glucose transporter 2 (GLUT2)

22
Q

What are the metabolic control points of glycolysis?

A

Reaction of Fructose-6-P –> Fructose-1,6-BP:
PFK-1
- positive regulators = Fructose-2,6-BP and AMP
- negative regulators = ATP and citrate

Reaction of 2 PEP –> Pyruvate
Pyruvate kinase
- positive regulator = Fructose-2,6-BP
- negative regulators = ATP, Alanine

23
Q

What are the metabolic control points of gluconeogenesis?

A

Pyruvate –> OAA
Pyruvate carboxylase
- positive regulator = Acetyl-CoA
- negative regulator = ADP

OAA –> PEP
PEPCK
- negative regulator = ADP

Fructose-1,6-BP –> Fructose-6-P
FBPase-1
- positive regulator = citrate
- negative regulator = Fructose-2,6-BP and AMP (not enough AMP, means you can’t do gluconeogenesis, sign just means the energy change)

24
Q

What is the different regulation of PFK-1 and FBPase-1?

A

PFK-1 and FBPase-1 are RECIPROCALLY REGULATED in response to energy needs of the cell

By:
AMP (+ glycolysis, - gluconeogenesis)
Fructose-2,6-BP (- glycolysis, + gluconeogenesis)
Citrate (+ glycolysis, - gluconeogenesis)

25
Q

How is Fructose 2,6 bisphosphate regulation between PFK-1 and FBPase-1?

A

Activator of PFK-1

Negative regulator of FBPase-1

26
Q

What is the main allosteric regulator?

A

Fructose-2,6-bisphosphate

27
Q

What is PFK2 and FBPase-2?

A

PFK2 = Phosphofructokinase-2 (NOT PFK-1)
- activated by insulin signaling

FBPase-2 = Fructose 2,6 bisphosphatase (NOT FBPase-1)
- activated by glucagon signaling

28
Q

If there is plenty of sugar, what pathway do you choose?

A

Glycolysis

29
Q

What is the dual-function enzyme called?

A

Phosphofructokinase-2/fructose-2,6-bisphosphatase

Single protein regulated if there is insulin or glucagon present.

N terminal region = PFK-2
C terminal region = FBPase-2

30
Q

What is the hormonal regulation of glycolysis?

A

Insulin signaling stimulates flux through the glycolytic pathway by increasing levels of fructose-2,6-BP through dephosphorylation and activation of the PFK-2 catalytic activity.

31
Q

What is the hormonal regulation of gluconeogenesis?

A

Glucagon signaling stimulates flux through the gluconeogenic pathway by decreasing fructose-2,6-BP levels through phosphorylation and activation of the FBPase-2 catalytic activity

32
Q

What is the Cori Cycle?

A

Discovered by Carl and Gerty Cori in 1929

Conversion of lactate produced by anaerobic glycolysis in the muscle cells to glucose through gluconeogenesis in liver cells

Costs net 4 ATP

33
Q

What does it mean when you get sore muscles?

A

There is excess lactate in which the sore muscles are due to lower pH