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Glycolysis

Objective

• At the end of this lecture, student will be able to

– Explain reaction involved in glycolysis

– Describe energetics of glycolysis

– Discuss the disorders associated with glycolysis

Glycolysis

• Universal pathway in the living cells

• Elucidated in 1940 by Embden-Meyerhof and referred to as Embden- Meyerhof pathway (E.M, pathway)

• Defined as the sequence of reactions converting glucose to pyruvate or lactate, with the production of ATP

• Chemical formula: C6H12O6

Salient features

• Takes place in all cells of the body & enzymes of this pathway are present in the cytosol of the cell

• Occurs in the absence of oxygen (anaerobic) or in the presence of oxygen (aerobic)

• Lactate is the end product under anaerobic condition & in aerobic condition pyruvate, which is then oxidized to CO2 & H2O

• Major pathway for ATP synthesis in tissues lacking mitochondria e.g. erythrocytes, cornea, lens etc.

• Very essential for brain which is dependent on glucose for energy

• Central metabolic pathway with many of its intermediates providing branch point to other pathways. Thus, the intermediates are useful for the synthesis of amino acids and fat

Reactions of glycolysis: The pathway can be divided into 3 phases

1. Energy investment phase or priming stage

2. Splitting phase

3. Energy generation phase.

1. Energy investment phase

• Glucose is phosphorylated to G-6-P by hexokinase or glucokinase

• This is an irreversible reaction, dependent on ATP and Mg2+

• G-6-P is impermeable to the cell membrane, thus, G-6-P undergoes isomerization to give F-6-P in the presence of phosphohexose isomerase and Mg2+

• F-6-P is phosphorylated to fructose 1, 6 bisphosphate by phosphofructokinase

• This is an irreversible and a regulatory step in glycolysis

2. Splitting phase

• 6 C fructose 1, 6-bisphosphates split to two 3C compounds glyceraldehyde-3-P & di hydroxyacetone phosphate by the aldolase

• Enzyme phosphotriose isomerase catalyses the reversible interconversion of glyceraldehyde-3-P & dihydroxyacetone phosphate. Thus, 2 molecules of glyceraldehyde- 3-phosphate are obtained from one molecule of glucose

3. Energy generation phase

• Glyceraldehyde-3-phosphate dehydrogenase converts glyceraldehyde-3- P to 1,3-bisphosphoglycerate

• This step is important as it is involved in the formation of NADH + H+ & high energy compound 1,3-bisphosphoglycerate

• NADH passes through the ETC & 6 ATP are synthesized by oxidative phosphorylation

• Enzyme phosphoglycerate kinase acts on 1,3-bisphosphoglycerate resulting in the synthesis of ATP and formation of 3-phosphoglycerate. This is a good example of substrate Ievel phosphorylation and reaction is reversible

• 3-Phosphoglycerate is converted to 2- phosphoglycerate by phosphoglycerate mutase. This is an isomerization reaction

• High energy compound phosphoenol pyruvate is generated from 2-phosphoglycerate by enolase, requires Mg2+ or Mn2+

• Enzyme pyruvate kinase catalyses the transfer of high energy phosphate from phosphoenol pyruvate to ADP, leads to form of ATP and pyruvate. This step also is a substrate level phosphorylation & reaction is irreversible

• Glycolysis under aerobic condition produce pyruvate and under anaerobic condition produce lactate

• Conversion of pyruvate to lactate is by lactate dehydrogenase and NADH

Lactic acidosis

• Normal plasma concentration lactic acid is 4-15 mg/dl

• Elevation of lactic acid in the circulation may occur due to its increased production or decreased utilization of lactic acid

• Mild forms are associated with strenuous exercise, shock, respiratory diseases, cancers/low pyruvate dehydrogenase activity

• Severe forms are observed due to impairment/collapse of circulatory system which is often encountered in MI, pulmonary embolism, uncontrolled hemorrhage and severe shock, which may even lead to death

Energetics: Production of ATP

• Under anaerobic conditions, 2 ATP are synthesized while, under aerobic conditions, 8 or 6 ATP are synthesized depending on the shuttle pathway that operates.