Glycolysis

Introduction of Glucose Metabolism Lecture-2

Glycolysis

Glycolysis is the breakdown of glucose to: 1- Provide energy in the form of ATP (main function)2- Provide intermediates for other metabolic pathways.

It occurs in cytosols of all tissues

All sugars can be converted to glucose & thus can be metabolized by glycolysis.

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)

Overall reactions of glycolysis

Glycolysis

Glucose (6C)

2 Pyruvate (3C)

2 ATP

2 ADP4 ADP

4 ATP

2 NAD

2 NADH+ H+

Glycolysis

Glucokinase or hexokinase

Hexokinase & glucokinase

HEXOKINASE

GLUCOKINASE

LOCALIZATION Most tissues Hepatocytes & Pancreas

Specificity Broad specificity for all hexoses

Same

KineticsKm

Low Km

High Affinity

Permits efficient phosph. of glucose even when tissue concentration of glucose is low

High Km

Low Affinity

Requires high concentration of glucose for 1/2 saturation

SoIt permits metabolism of glucose when I.C. concentration of glucose in liver cells are

increased

Vmax

Low Vmax

Cannot trap glucose more than cell need

High Vmax

Allow liver to remove flux of glucose from blood

(after absorption)To

Reduce hyperglycemia after diet & absorption.

Effect of insulin(regulation by insulin)

Synthesis not affected by insulin Synthesis is increased by insulin

Glycolysis

Glycolysis

Pyruvate is the end product

of aerobic glycolysis

Lactate is the end product

of anaerobic glycolysis

End products of glycolysis

NADH is an end product

of aerobic glycolysis

AEROBIC GLYCOLYSISMitochondria & Oxygen

ANAEROBIC GLYCOLYSISNo mitochondria

No Oxygen Or Both

Key enzymes in glycolysis

 1- Hexokinase & Glucokinase Glucose Glucose 6-phosphate 2- Phosphofructokinase (PFK) Fructose 6-phosphate Fructose 1,6 bisphosphate 3- Pyruvate Kinase (PK) Phosphoenel pyruvate Pyruvate

Steps catalyzed By

key enzymesONE WAY REACTIONS

12

3

Key enzymes in glycolysis

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. 

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 NADHPyruvate Acetyl CoA

2 Pyruvate produce 2 Acetyl CoA (& 2 NADH): 2 X 3 = 6 ATP

2 Acetl CoA in citric acid cycle: 2 X 12 = 24 ATP

Energy yield of aerobic glycolysis

2 Lactate

Oxygen&

Mitochondria

No OxygenNo Mitochondria

OR BOTH

GLUCOSE

2 PYRUVATE

2NAD+

2 NADH

= 2 X 3 = 6 ATP

2 ACETYL CoA

CITRIC ACID CYCLE = 2 X 12 = 24 ATP

2NAD+ 2

NADH = 2 X 3 = 6 ATP

Energy yield of anaerobic glycolysis

2 ATP

Net = 2 ATP/ glucose moleculeNet = 38 ATP / glucose molecule

Oxidative phosphorylation:  The formation of high-energy phosphate bonds by phosphorylation of ADP to ATPcoupled to the the electron transport chain (ETC) that occurs in the mitochondria.

Substrate-level phosphorylation:  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 mitochondriaExample: in glycolysis ATPs are produced

ENERGY PRODUCTIONOxidative phosphorylation & Substrate-level

phosphorylation

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)

Example of Covalent Modification (short-term regulation)

Long-term Regulation of glycolysis

Induction & Respressionof enzymes synthesis

Insulin: Induction

Glucagon: Repression

Genetic defects of glycolytic enzymes

Pyruvate kinase deficiency

Pyruvate kinase (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.