1. Introduction of Glucose Metabolism Lecture-2 Glycolysis

2. Glycolysis Glycolysis is the breakdown of glucose to: 1- Provide energyin the form of ATP (main function) 2- Provide intermediatesfor other metabolic pathways. It occurs in cytosolsof all tissues All sugars can be converted to glucose & thus can be metabolized by glycolysis.

3. End products of glycolysis 1- In cells with mitochondria & an adequate supply of oxygen (Aerobic glycolysis) - Pyruvate: enters the mitochondria & is converted into acetyl CoA. Acetyl CoA enters citric acid cycle (Krebs cycle) to yield energy in the form of ATP - NADH: utilizes mitochondria & oxygen to yield energy 2- In cells with no mitochondria or adequate oxygen (or Both) (Anaerobic glycolysis) Lactate: formed from pyruvate (by utilizing NADH)

4. Overall reactions of glycolysis

5. Glycolysis Glucose (6C) 2 ATP 4 ADP 2 ADP 4 ATP 2 NAD 2 NADH+ H+ 2 Pyruvate (3C)

6. Glycolysis Glucokinase or hexokinase

7. Hexokinase & glucokinase

8. Glycolysis

9. Glycolysis

11. End products of glycolysis AEROBIC GLYCOLYSIS Mitochondria & Oxygen NADH is an end product of aerobic glycolysis ANAEROBIC GLYCOLYSIS No mitochondria No Oxygen Or Both Pyruvate is the end product of aerobic glycolysis Lactate is the end product of anaerobic glycolysis

12. Key enzymes in glycolysis 1-Hexokinase & Glucokinase Glucose Glucose6-phosphate 2-Phosphofructokinase (PFK) Fructose 6-phosphate Fructose 1,6 bisphosphate 3-Pyruvate Kinase (PK) Phosphoenel pyruvate Pyruvate

13. Key enzymes in glycolysis Steps catalyzed By key enzymes ONE WAY REACTIONS 1 2 3

14. Energy yield from glycolysis 1- Anerobic glycolysis 2 molecule of ATP for each one molecule of glucose converted to 2 molecules of lactate It is a valuable source of energy under the following conditions 1- Oxygen supply is limited as in 2- Tissues with no mitochondria skeletal muscles during intensive exercise Kidney medulla RBCs Leukocytes Lens & cornea cells Testes 2-Aerobic glycolysis 2 moles of ATP for each one mol of glucose converted to 2 moles of pyruvate 2 molecules of NADH for each molecule of glucose 2 X 3 ATPs for each NADH entering electric transport chain (ETC) in mitochondria.

15. Energy yield from glycolysis In anaerobic glycolysis: 2 ATP for one glucose molecule In aerobic glycolysis Glycolysis: 2 ATP 2 NADH: 2 X 3 = 6 ATP NADH Pyruvate Acetyl CoA 2 Pyruvate produce 2 Acetyl CoA (& 2 NADH): 2 X 3 = 6 ATP 2 AcetlCoA in citric acid cycle: 2 X 12 = 24 ATP

16. Energy yield of aerobic glycolysis Energy yield of anaerobic glycolysis GLUCOSE Net = 38 ATP / glucose molecule Net = 2 ATP/ glucose molecule 2NAD+ 2 ATP 2 NADH = 2 X 3 = 6 ATP No Oxygen No Mitochondria OR BOTH Oxygen & Mitochondria 2 Lactate 2 PYRUVATE 2NAD+ 2 NADH = 2 X 3 = 6 ATP 2 ACETYL CoA CITRIC ACID CYCLE = 2 X 12 = 24 ATP

17. ENERGY PRODUCTIONOxidative phosphorylation & Substrate-level phosphorylation Oxidative phosphorylation:  The formation of high-energy phosphate bonds by phosphorylation of ADP to ATP coupled to the the electron transport chain (ETC) that occurs in the mitochondria. Substrate-levelphosphorylation:  The formation of high-energy phosphate bonds by phosphorylation of ADP to ATP (or GDP to GTP) It is coupled to cleavage of a high-energy metabolic intermediate (substrate). It may occur in cytosol or mitochondria Example: in glycolysis ATPs are produced

18. Regulation of key enzyme of glycolysis The regulation of the activity of key enzyme is conducted through: 1- General: (occurs in all types of enzymes in the body) increasing substrate concentration will lead to increase activity of the enzyme 2-Special regulatory mechanisms: i- Allosteric effectors ii- Covalent modification iii. Induction/Repression of enzyme synthesis( long –term regulation)

19. Example of Covalent Modification (short-term regulation)

20. Long-term Regulation of glycolysisInduction & Respressionof enzymes synthesis Insulin: Induction Glucagon: Repression

21. Genetic defects of glycolytic enzymes Pyruvate kinase deficiency Pyruvatekinase (PK) deficiency leads to a reduced rate of glycolysis with decreased ATP production. PK deficiency effect is restricted RBCs. As RBCs has no mitochondria & so get ATP only from glycolysis. RBCs needs ATP mainly for maintaining the bio- concave flexible shape of the cell. PK deficiency leads to severe deficiency of ATP for RBCs. So, RBCs fail to maintain bi-concave shape ending in liability to be lysed (hemolysis). Excessive lysis of RBCs leads to chronic hemolytic anemia.