Glycolysis and Pyruvate Dehydrogenase

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What is Glycolysis:

• All cells carry out glycolysis.

• Only energy producing pathway in RBCs.

• Glucose, galactose, and fructose can be used.

• Steps: transport across membrane to inside the cell, the phosphorylation by kinase enzymes within the cell.

Carbohydrate Metabolism:

• Most carbohydrates we eat are complex; these have to be broken down.

• In the mouth, salivary amylase hydrolyzes starch polymers to dextrins.

• Disaccharides in intestinal brush border complete the digestion process.

• Maltase cleaves maltose to 2 glucoses.

• Isomaltase cleaves isomaltose to 2 glucoses.

• Lactase cleaves lactose to glucose and galactose.

• Sucrase cleaves sucrose to glucose and fructose.

Glucose Transport:

• Glucose entry into cells is concentration driven and independent of Na.

• Sodium/glucose transporter uptakes glucose from mucosal cells.

Glucose Transport Proteins:

GLUT1 and GLUT3:

• Most tissues including brain, nerves, and RBCs; provides glucose in hypoglycemia.

GLUT2:

• Hepatocytes, pancreatic beta-cells; activated after a meal; stores excess glucose.

GLUT4:

• Adipose tissue and muscle; rate of glucose transport increased by insulin; stimulated during exercise.

Metabolism Using Glycolysis:

• Converts glucose to two pyruvates.

• Two susbtrate-level phosphorylations, and one oxidation reaction.

• Aerobic if cell has mitochondria; anaerobic if there is no mitochondria or there is no O2.

Glycolysis Rate Limiting Step:

• Carried out by phosphofructokinases:

• F6P phosphorylated to F-1,6-Bisphosphate.

Phosphofructokinase-1:

• Rate limiting enzyme of glycolysis.

Phosphofructokinase-1:

• Inhibited by ATP, citrate; activated by AMP.

Phosphofructokinase-2:

• Activated by insulin; inhibited by glucagon.

Arsenate:

• Prevents conversion of glyceraldehyde 3-P to 1,3-bisphosphoglycerate.

Glucokinase Gene Mutations:

• Inability of pancreatic beta-cells to absorb glucose via GLUT2 receptors.

Glysolysis Intermediates:

DHAP:

• Used in the liver and adipose for triglyceride synthesis.

PEP:

• Used to generate ATP by substrate-level phosphorylation.

ATP Production and Electron Shuttles:

• Anaerobic glycolysis yields 2 ATP/glucose.

Aerobic Glycolysis Yields:

• Malate shuttle: electrons passed to mitochondrial NADH, and then to ETC; 8 ATP/glucose.

• Glycerol phosphate shuttle: electrons passed to mitochondrial FADH2; 6 ATP/glucose.

Glycolysis in RBC:

• 2 ATP/glucose.

• In RBCs, bisphosphoglycerate mutase produces 2,3-BPG from 1,3-BPG in glycolysis.

• 2,3-BPG binds beta-chains in HbA and decreases affinity for oxygen.

• Rightward shift; unloading of oxygen in tissues.

Pyruvate Kinase Deficiency:

• G6PD; hemolytic anemia.

• Increased 2,3-BPG causes lower O2 affinity for HbA.

• Absence of Heinz bodies.

Galactose Metabolism:

• Milk is an important source of galactose.

• Lactase deficiency: cramps, bloating, diarrhea.

• Galactokinase deficiency: cataracts.

• Galactose 1-P uridyl transferase: deficiency causes galactosemia; cataracts, vomiting, diarrhea, lethargy, mental retardation, liver damage.

• Galactose is converted to galactitol by aldose reductase; galactitol trapped in lens causes swelling and catracts.

• Administer galactose to increase glucose during hypoglycemia.

• Galactosemia: defective galactokinase gene or galactose 1-P uridyltransferase gene.

Fructose Metabolism:

• Found in honey, fruit, and part of table sugar.

• Fructokinase deficiency is asymptomatic.

• Aldolase B (F 1-P aldolase) deficiency: lethargy, vomiting, liver damage, hyperbilirubinemia, hypoglycemia, hyperuricemia, renal proximal tube defect.

Hereditary Fructose Intolerance:

• Accumulation of fructose 1-phosphate in hepatocytes.

Pyruvate Dehydrogenase:

• Converted to acetyl-CoA; enters into CAC to produce ATP, or fatty acid synthesis.

• Pyruvate dehydrogenase inhibited by acetyl-CoA.

Thiamine Deficiency:

• Aerobic tissues like brain and cardiac muscle fail, causing Wernicke-Korsakoff Syndrome.

Additional Notes:

• Cori cycle: transfers lactic acid from muscle to liver.

• Pyruvate kinase deficiency: nonspherocytic hemolytic anemia due to low cellular ATP levels.

• First step in gluconeogenesis: pyruvate converted to oxaloacetate.

• Anerobic conditions: NAD+ regenerated to NADH by lactate dehydrogenase.

• Niacin: NAD component involved in glycolysis and CAC.

• Major regulatory glycolytic pathway: F6P to F 1,6 BP.

• Iodoacetate inhibits: glyceraldehyde-3-phosphate dehydrogenase.

Additional Readings:

Basic Biochemistry

1. Nucleic Acid Structure and Organization
2. DNA Replication and Repair
3. Transcription and RNA Processing
4. Genetic Code, Mutations, and Translation
5. Genetic Regulation
6. Recombinant DNA
7. Amino Acids, Proteins, Enzymes
8. Hormones
9. Vitamins
10. Energy Metabolism
11. Glycolysis and Pyruvate Dehydrogenase
12. Citric Acid Cycle and Oxidative Phosphorylation
13. Glycogen, Gluconeogenesis, and Hexose Monophosphate Shunt
14. Lipid Synthesis and Storage
15. Lipid Mobilization and Catabolism
16. Amino Acid Metabolism Disorders
17. Purine and Pyrimidine Metabolism
18. Electron Transport
19. Citric Acid Cycle and Glyoxylate Cycle
20. Glycolysis
21. Pyruvate Metabolism
22. Mitochondrial ATP formation
23. Gluconeogenesis
24. Glycogen Metabolism
25. Nitrogen Fixation (Metabolism) reactions, and Heme Metabolism
26. Amino Acid Metabolism
27. What is Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)?

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