Glycolysis is the pathway that converts glucose to pyruvate, generating a small amount of ATP. The liver plays a key role in monitoring and stabilizing blood glucose levels. Glycolysis occurs through three phases: 1) energy investment where glucose is phosphorylated, 2) splitting of a six-carbon molecule into two three-carbon molecules, and 3) energy generation where ATP is produced from the breakdown of the three-carbon molecules. The pathway generates 2 ATP per glucose under anaerobic conditions and up to 8 ATP per glucose under aerobic conditions using shuttle pathways to further oxidize NADH in the mitochondria.
2. Glycolysis(Embden-Meyerhof pathway)
• The monosaccharide glucose is the central molecule in carbohydrate metabolism
since all the major pathways of carbohydrate metabolism are connected with it.
• The fasting blood glucose level in normal individuals is 70-100 mg/dl (+.5-5.5
mmol/l) and it is very efficiently maintained at this level.
• Liver plays a key role in monitoring and stabilizing blood glucose levels. Thus liver
may be appropriately considered as glucostat monitor.
3. Major pathways of carbohydrate metabolism
• Glycolysis is defined as “The oxidation of glucose to pyruvate and lactate.”
• Citric acid cycle (Krebs cycle or tricarboxylic acid cycle) : The oxidation of
acetyl CoA to CO2. Krebs cycle is the final common oxidative pathway for
carbohydrates, fats or amino acids, through acetyl CoA.
4. • Gluconeogenesis : The synthesis of glucose from non-carbohydrate precursors (e.g. amino
acids, glycerol etc.)
• Glycogenesis : The formation of glycogen from glucose.
• Glycogenolysis : The breakdown of glycogen to glucose.
• Hexose monophosphate shunt (pentose phosphate pathway or direct oxidative pathway) :
This pathway is an alternative to glycolysis.
5. Glycolysis
• Glycolysis is derived from the Creek words (glycose-sweet or sugar; lysis-dissolution).
• “Glycolysis is defined as the sequence of reactions converting glucose (or
glycogen) to pyruvate or lactate, with the production of ATP.”
• Glycolysis occurs in the absence of oxygen (anaerobic) or in the presence of oxygen
(aerobic). Lactate is the end product under anaerobic condition. In the aerobic condition,
pyruvate is formed, which is then oxidized to CO2 and H2O.
6. • Glycolysis is a major pathway for ATP synthesis in tissues lacking mitochondria,
e.g. erythrocytes, cornea, lens etc.
• Glycolysis is very essential for brain which is dependent on glucose for energy.
7. Reactions of glycolysis
A. Energy investment phase or priming stage
B. Splitting phase
C. Energy generation phase.
8. A. Energy investment phase
• Glucose is phosphorylated to glucose 6-phosphate by hexokinase or glucokinase.
• This is an irreversible reaction, dependent on ATP and Mg2+. The enzyme hexokinase is
present in almost all the tissues.
• Glucose 6-phosphate undergoes isomerization to give fructose 6-phosphate in the presence
of the enzyme phosphohexose isomerase and Mg2*.
• Fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate by
phosphofructokinase (PFK). This is an irreversible and a regulatory step in glycolysis.
9. B. Splitting phase
• The six carbon fructose 1,6- bisphosphate is split (hence the name glycolysis) to two
three-carbon compounds, glyceraldehyde 3-phosphate and di hydroxy acetone
phosphate by the enzyme aldolase (fructose 1,6- bisphosphate aldolase).
• The enzyme phosphotriose isomerase catalyses the reversible interconversion of
glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Thus, two molecules
of glyceraldehyde 3-phosphate are obtained from one molecule of glucose.
10. C. Energy generation phase
• Glyceraldehyde 3-phosphate dehydrogenase converts glyceraldehyde 3-phosphate to 1,3-
bisphosphoglycerat.
• The enzyme phosphoglycerate kinase acts on 1,3-bisphosphoglycerate resulting in the
synthesis of ATP and formation of 3-phosphoglycerate. This step is a good example of
substrate Ievel phosphorylation, since ATP is synthesized from the substrate without the
involvement of electron transport chain. Phosphoglycerate kinase reaction is reversible, a
rare example among the kinase reactions.
11. • 3-Phosphoglycerate is converted to 2-phosphoglycerate by phosphoglycerate mutase.
This is an isomerization reaction.
• The high energy compound phosphoenol pyruvate is generated from 2-phosphoglycerate
by the enzyme enolase. This enzyme requires Mg2* or Mn2* and is inhihited by fluoride.
For blood glucose estimation in the laboratory, fluoride is added to the blood to prevent
glycolysis by the cells.
12.
13. • The enzyme pyruvate kinase catalyzes the transfer of high energy phosphate
from phosphoenol Pyruvate to ADR leading to the formation of ATP. This step
also is a substrate level phosphorylation. (Pyruvate kinase t requires K+ and
either Mg2+ or Mn2*.) This reaction is irreversible.
14. Production of ATP in glycolysis
• The details of ATP generation in glycolysis (from glucose) are given in Table 13.1
.Under anaerobic conditions, 2 ATP are synthesized while, under aerobic
conditions, 8 or 6 ATP are synthesized-depending on the shuttle pathway that
operates
16. Glycolysis and shuttle pathways
• In the presence of mitochondria and oxygen, the NADH produced in glycolysis can
participate in the shuttle pathways (Refer Chapter 1l) lor the synthesis of ATP. lf the
cytosolic NADH uses malate-aspartate shuttle, 3 ATP are generated from each
molecule of NADH. This is in contrast to glycerol phosphate shuttle that produces
only 2 ATP.
