Overview of catabolic pathways
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Overview of catabolic pathways. Catabolism of glucose via glycolysis and the citric acid cycle . NADH. NADH, FADH 2. Converts: 1 glucose 2 pyruvate. Net reaction of glycolysis. +. Two molecules of ATP are produced Two molecules of NAD + are reduced to NADH.

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Net reaction of glycolysis

Converts: cycle 1 glucose2 pyruvate

Net reaction of glycolysis

+

  • Two molecules of ATP are produced

  • Two molecules of NAD+ are reduced to NADH

Glucose + 2 ADP + 2 NAD+ + 2 Pi

2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O


Glycolysis can be divided into two stages
Glycolysis can be divided into two stages cycle

  • Hexosestage: 2 ATP are consumed per glucose

  • Triosestage: 4 ATP are produced per glucose

  • Net: 2 ATP produced per glucose

x2


Fig 11 2
Fig 11.2 cycle

Transfer of a phosphorylgroup from ATP to glucose

enzyme: hexokinase

1

Isomerization of glucose 6-phosphateto fructose 6-phosphate

enzyme: glucose 6-phosphate isomerase

2


Transfer of a second cycle phosphoryl group from ATP to fructose 6-phosphate

enzyme: phosphofructokinase-1

3

Carbon 3 – Carbon 4bond cleavage, yielding twotriose phosphates

enzyme: aldolase

4


Enzyme 1 hexokinase
Enzyme 1. Hexokinase cycle

  • Transfers the g-phosphoryl of ATP to glucose C-6 oxygen to generate glucose 6-phosphate

  • Mechanism: attack of C-6 hydroxyl oxygen of glucose on the g-phosphorous of MgATP2- displacing MgADP-

Fig 11.3


2 glucose 6 phosphate isomerase
2. Glucose 6-Phosphate Isomerase cycle

  • Converts glucose 6-phosphate (an aldose) to fructose 6-phosphate (a ketose)

  • Enzyme converts glucose 6-phosphate to open chain form in the active site

Fig 11.4


3 phosphofructokinase 1 pfk 1
3. Phosphofructokinase-1 (PFK-1) cycle

  • Catalyzes transfer of a phosphoryl group from ATP to the C-1 hydroxyl group of fructose 6-phosphate to form fructose 1,6-bisphosphate (F1,6BP)

  • PFK-1 is metabolically irreversible and a critical regulatorypoint for glycolysis in most cells (PFK-1 is the first committed step of glycolysis)


4 aldolase
4. Aldolase cycle

  • Aldolase cleaves the hexose fructose 1,6-bisphosphate into two triose phosphates: glyceraldehyde 3-phosphate and dihydroxyacetone phosphate


5 triose phosphate isomerase
5. Triose Phosphate Isomerase cycle

  • Conversion of dihydroxyacetone phosphate into glyceraldehyde 3-phosphate



6 glyceraldehyde 3 phosphate dehydrogenase gapdh
6. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) stage

  • Conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate (1,3BPG)

  • Molecule of NAD+ is reduced to NADH


Box 11 2 arsenate aso 4 3 poisoning
Box 11.2 Arsenate (AsO stage43-) poisoning

  • Arsenate can replace Pi as a substrate for glyceraldehyde 3-phosphate dehydrogenase

  • Arseno analog which forms is unstable


7 phosphoglycerate kinase
7. Phosphoglycerate Kinase stage

  • Uses uses the high-energy phosphate of 1,3-bisphosphoglycerate to form ATP from ADP

  • Transfer of phosphoryl group from the energy-rich 1,3-bisphosphoglycerate to ADP yields ATP and 3-phosphoglycerate


8 phosphoglycerate mutase
8. Phosphoglycerate Mutase stage

  • Catalyzes transfer of a phosphoryl group from one part of a substrate molecule to another

  • Reaction occurs without input of ATP energy


9 enolase 2 phosphoglycerate to phosphoenolpyruvate pep
9. Enolase: 2-phosphoglycerate to phosphoenolpyruvate (PEP)

  • Elimination of water (dehydration) yields PEP

  • PEP has a veryhigh phosphoryl group transfer potential because it exists in its unstable enol form


10 pyruvate kinase
10. Pyruvate Kinase (PEP)

  • Metabolically irreversible reaction


Fates of pyruvate
Fates of pyruvate (PEP)

  • For centuries, bakeries and breweries have exploited the conversion of glucose to ethanol and CO2 by glycolysis in yeast


Metabolism of pyruvate
Metabolism of Pyruvate (PEP)

1. Aerobicconditions: pyruvate is oxidized to acetyl CoA, which enters the citric acid cycle for further oxidation

2. Anaerobicconditions (microorganisms): pyruvate is converted to ethanol

3. Anaerobicconditions (muscles, redbloodcells): pyruvate is converted to lactate


Fig 11 10
Fig 11.10 (PEP)

  • Fates of pyruvate


Fig 11 11
Fig 11.11 (PEP)

  • Two enzymes required:

  • (1) Pyruvate decarboxylase

  • (2) Alcohol dehydrogenase

  • Anaerobic conversion of pyruvate to ethanol (yeast - anaerobic)


Reduction of pyruvate to lactate muscles anaerobic
Reduction of Pyruvate to Lactate (PEP)(muscles - anaerobic)

  • Muscles lack pyruvate dehydrogenase and cannot produce ethanol from pyruvate

  • Muscle lactate dehydrogenase converts pyruvate to lactate

  • This reaction regenerates NAD+ for use by glyceraldehyde 3-phosphate dehydrogenase in glycolysis

  • Lactate formed in skeletal muscles during exercise is transported to the liver

  • Liver lactate dehydrogenase can reconvert lactate to pyruvate

  • Lactic acidosis can result from insufficient oxygen (an increase in lactic acid and decrease in blood pH)


Reduction of pyruvate to lactate

Glucose + 2 P (PEP)i2- + 2 ADP3-

2 Lactate- + 2 ATP4- + 2 H2O

Reduction of pyruvate to lactate


Metabolically irreversible steps of glycolysis
Metabolically Irreversible Steps of Glycolysis (PEP)

  • Enzymes not reversible: Reaction 1 - hexokinase Reaction 3 - phosphofructokinase Reaction 10 - pyruvate kinase

  • These steps are metabolicallyirreversible, and these enzymes are regulated

  • All other steps of glycolysis are near equilibrium in cells and not regulated


Regulation of glycolysis
Regulation of Glycolysis (PEP)

  • 1. When ATP is needed, glycolysis is activated

  • Inhibition of phosphofructokinase-1 is relieved.

  • Pyruvate kinase is activated.

  • 2. When ATP levels are sufficient, glycolysis activity decreases

  • Phosphofructokinase-1 is inhibited.

  • Hexokinase is inhibited.


Fig 11 13

Glucose transport (PEP)into the cell

Fig 11.13


Fig 11 14 regulation of glucose transport
Fig 11.14 Regulation of glucose transport (PEP)

  • Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulatedbyinsulin


Regulation of hexokinase
Regulation of Hexokinase (PEP)

  • Hexokinase reaction is metabolically irreversible

  • Glucose 6-phosphate (product) levels increase when glycolysis is inhibited at sites further along in the pathway

  • Glucose 6-phosphate inhibits hexokinase.


Regulation of phosphofructokinase 1 pfk 1
Regulation of Phosphofructokinase-1 (PFK-1) (PEP)

  • ATP is a substrate and an allostericinhibitor of PFK-1

  • High concentrations of ADP and AMP allosterically activate PFK-1 by relieving the ATP inhibition.

  • Elevated levels of citrate (indicate ample substrates for citric acid cycle) also inhibit Phospofructokinase-1


Regulation of pfk 1 by fructose 2 6 bis phosphate f2 6bp
Regulation of PFK-1 by Fructose 2,6- (PEP)bisphosphate (F2,6BP)

  • Fructose 2,6-bisphosphate is formed from Fructose 6-phosphate by the enzyme phosphofructokinase-2 (PFK-2)

  • Fig 11.17 Fructose 2,6-bisphosphate


Formation and hydrolysis of fructose 2 6 bisphosphate
Formation and hydrolysis of (PEP)Fructose 2,6-bisphosphate

Chapter 11


Fig 11 18
Fig. 11.18 (PEP)

  • Effect of glucagon on liver glycolysis

Chapter 11


Regulation of pyruvate kinase pk
Regulation of Pyruvate Kinase (PK) (PEP)

  • Pyruvate Kinase is allosterically activated by Fructose 1,6-bisphosphate, and inhibited by ATP

  • The hormone glucagon stimulates protein kinase A, which phosphorylates Pyruvate Kinase, converting it to a lessactive form.

Chapter 11


Other sugars can enter glycolysis
Other Sugars Can Enter Glycolysis (PEP)

  • Glucose is the mainmetabolicfuel in most organisms

  • Other sugars convert to glycolytic intermediates

  • Fructose and sucrose (contains fructose) are major sweeteners in many foods and beverages

  • Galactose from milk lactose (a disaccharide)

  • Mannose from dietary polysaccharides, glycoproteins

Chapter 11



Galactose is converted to glucose 1 phosphate
Galactose is Converted to (PEP)Glucose 1-Phosphate

Fig 11.22


Mannose is converted to fructose 6 phosphate
Mannose is Converted to (PEP)Fructose 6-Phosphate


Formation of 2 3 bis phosphoglycerate in red blood cells
Formation of 2,3- (PEP)Bisphosphoglycerate in Red Blood Cells

  • 2,3-Bisphosphoglycerate (2,3BPG) allosterically regulates hemoglobin oxygenation (red blood cells)

  • Erythrocytes contain bisphosphoglycerate mutase which forms 2,3BPG from 1,3BPG

  • In red blood cells about 20% of the glycolytic flux is diverted for the production of the important oxygen regulator 2,3BPG

Chapter 11


Fig 11 24
Fig 11.24 (PEP)

  • Formation of 2,3BPG in red blood cells


Feedback inhibition
Feedback inhibition (PEP)

  • Product of a pathway controls the rate of its own synthesis by inhibiting an enzyme catalyzing an early step

Feed-forward activation

  • Metabolite early in the pathway activates an enzyme further down the pathway

Chapter 11


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