Updated: 12/5/2020

Glycolysis

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Topic
Overview
  • Function 
    • generation of ATP from glucose via substrate-level phosphorylation (as opposed to oxidative phosphorylation) 
      • used by all cells
        • with O2
          • pyruvate enters citric acid cycle (after being created in glycolysis)
          • NAD+ regenerated via oxidative phosphorylation
        • without O2
          • pyruvate cannot enter citric acid cycle after glycolysis
          • NAD+ must be regenerated via conversion of pyruvate to lactate
            • catalyzed by lactate dehydrogenase
      • only source of energy for RBCs
    • generation of intermediates for other pathways
      • 1,3-BPG
        • intermediate of glycolysis
        • can be converted to 2,3-DPG
          • modifies the hemoglobin-O2 binding curve
            • binds HbA and ↓ binding affinity of O2
            • a compensatory mechanism for ↓pO2
  • Pathway
    • in cytoplasm
    • irreversible
    • net reaction
      • glucose + 2Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2H+ + 2 H2O
  • Important enzymes
    • hexokinase - converts glucose into glucose-6-phosphate allowing "trapping" inside cell 
      • distribution
        • widely present in most body tissues 
          • allows trapping of glucose at all blood glucose levels
      • kinetics 
        • high affinity → low Km
        • low capacity → low Vmax
      • regulation
        • feedback inhibited by glucose-6-phosphate
    • glucokinase (hexokinase IV) 
      • distribution
        • liver
        • β cells of pancreas
          • uses as a means to measure blood glucose and release insulin accordingly
          • mutated in the monogenenic, autosomal dominant form of diabetes called Maturity Onset Diabetes of the Young type 2 (MODY2)
      • kinetics
        • low affinity → high Km
        • high capacity → high Vmax
      • regulation
        • induced by insulin (to store glucose in liver after a meal)
        • no direct feedback inhibition
    • phosphofructokinase-1  
      • rate-limiting step
      • inhibited by ATP, citrate
      • stimulated by AMP, fructose-2,6-bisphosphate
        • fructose 2,6-bisphosphate synthesized by phosphofructokinase-2
    • pyruvate kinase 
      • catalyzes substrate-level phosphorylation
      • inhibited by ATP, alanine
      • activated by fructose-1,6-bisphosphate
  • Hormonal regulation 
    • fasting state
      • ↑ glucagon → ↑ cAMP → ↑ protein kinase A → ↑ FBPase-2, ↓ PFK-2
    • fed state
      • ↑ insulin → ↓ cAMP → ↓ protein kinase A → ↓ FBPase-2, ↑ PFK-2
Disorders of Glycolysis
  • Pyruvate kinase deficiency 
    • AR (most commonly)
    • pathophysiology
      • ↓ ATP generation
        • inability to maintain Na+/K+ ATPase leads to
          • RBC swelling
          • RBC lysis
      • back up of glycolysis
        • ↑ 2,3-BPG and other glycolytic intermediates
    • presentation 
      • chronic hemolysis
      • ↓ O2 affinity for HbA
        • due to ↑ 2,3-BPG
      • no Heinz bodies
        • unlike glucose 6-phosphate dehydrogenase deficiency

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Questions (7)
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(M1.BC.15.74) Maturity Onset Diabetes of the Young (MODY) type 2 is a consequence of a defective pancreatic enzyme, which normally acts as a glucose sensor, resulting in a mild hyperglycemia. The hyperglycemia is especially exacerbated during pregnancy. Which of the following pathways is controlled by this enzyme?

QID: 106604
1

Glucose --> glucose-6-phosphate

63%

(152/242)

2

Glucose-6-phosphate --> fructose-6-phosphate

12%

(29/242)

3

Fructose-6-phosphate --> fructose-1,6-biphosphate

15%

(37/242)

4

Glyceraldehyde-3-phosphate --> 1,3-bisphosphoglycerate

3%

(8/242)

5

Phosphoenolpyruvate --> pyruvate

5%

(11/242)

M 1 D

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(M1.BC.14.79) A mother brings her newborn baby to the pediatrician after noting that his skin looks yellow. The patient's lactate dehydrogenase is elevated and haptoglobin is decreased. A smear of the child's blood is shown below. The patient is ultimately found to have decreased ability to process phosphoenolpyruvate to pyruvate. Which of the following metabolic changes is most likely to occur in this patient?

QID: 106905
FIGURES:
1

Left shift of the oxyhemoglobin curve

33%

(15/45)

2

Right shift of the oxyhemoglobin curve

51%

(23/45)

3

Broadening of the oxyhemoglobin curve

7%

(3/45)

4

Narrowing of the oxyhemoglobin curve

4%

(2/45)

5

Increased ATP availability

0%

(0/45)

M 1 D

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EXPERT COMMENTS (24)
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