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Salient features of Glycolysis
- It is carried out in the cytosol of cells,
- It is unique, in that it can function either aerobically or anaerobically, depending on the availability of oxygen and the electron transport chain.
- Erythrocytes and the cells which lack mitochondria, are completely reliant on glucose as their metabolic fuel, and metabolize it by anaerobic glycolysis.
- However, to oxidize glucose beyond pyruvate (the end product of glycolysis) requires both oxygen and mitochondrial enzyme systems such as the pyruvate dehydrogenase complex, the citric acid cycle, and the respiratory chain.
- Living things first appeared in an environment lacking O2, and glycolysis was an early and important pathway for extracting energy from nutrient molecules.
- It played a central role in anaerobic metabolic processes during the first 2 billion years of biological evolution on earth.
- Modern organisms still employ glycolysis to provide precursor molecules for aerobic catabolic pathways (such as the tricarboxylic acid cycle) and as a short-term energy source when oxygen is limiting.
- The other hexoses, trioses and glycerol can also be oxidized through this pathway.
Overview of Glycolysis
Glycolysis consists of two phases. In the first phase, through a series of five reactions, glucose is broken down to two molecules of glyceraldehyde-3-phosphate. Phase 1 consumes two molecules of ATP. It is also called ,’Energy investment phase”.
In the second phase, five subsequent reactions convert these two molecules of glyceraldehyde-3-phosphate into two molecules of pyruvate (Figure-1). The later stages of glycolysis result in the production of 2 molecules of ATP (in the absence of O2) and 8 ATP molecules (in the presence of O2) per molecule of glucose oxidized. Phase 2 is also called ” Pay back phase or phase of energy generation “(Figure-2) .
Figure-1- Phase-1 of Glycolysis involves two phosphorylation reactions to form Hexose bisphosphate ( Fructose-1,6 bisphosphate) that undergoes lysis to form two phosphorylated trioses which are subsequently converted to two pyruvate molecules by phase 2 reactions.
Figure-2- Phase -1 involves consumption of two ATP molecules to energize the substrate for easy cleavage. The ATP debt is paid back in the 2 nd phase by net generation of two ATP molecules under anaerobic and 8ATP molecules per glucose under aerobic conditions. Each NADH upon oxidation in electron transport chain yields 3 ATP molecules.
Reactions of glycolysis
Most of the details of this pathway (the first metabolic pathway to be elucidated) were worked out in the first half of the 20th century by the German biochemists Otto Warburg, G. Embden, and O. Meyerhof. In fact, the sequence of reactions in is often referred to as the Embden-Meyerhof pathway.
Figure-3- Out of the 10 reactions, 3 reactions are irreversible and the seven reversible reactions are of advantage in glucose production in the pathway of gluconeogenesis.
Details of reactions
Phase-1 of Glycolysis
One way to synthesize ATP using the metabolic free energy contained in the glucose molecule would be to convert glucose into one (or more) of the high-energy phosphates that have standard-state free energies of hydrolysis more negative than that of ATP. In fact, in the first stage of glycolysis, glucose is converted into two molecules of glyceraldehyde-3-phosphate. Energy released from this high-energy molecule in the second phase of glycolysis is then used to synthesize ATP (Figure-2) .
Reaction 1: Phosphorylation of Glucose by Hexokinase or Glucokinase —The First Priming Reaction
Glucose enters glycolysis by phosphorylation to glucose 6-phosphate, catalyzed by hexokinase, using ATP as the phosphate donor. Under physiologic conditions, the phosphorylation of glucose to glucose 6-phosphate can be regarded as irreversible. (Reaction -1).
The formation of such a phosphoester is thermodynamically unfavorable and requires energy input to operate in the forward direction .The energy comes from ATP, a requirement that at first seems counterproductive. Glycolysis is designed to make ATP, not consume it. However, the hexokinase, glucokinase reaction is one of two priming reactions in the cycle.
The incorporation of a phosphate into glucose in this energetically favorable reaction is important for several reasons-
1) First, phosphorylation keeps the substrate in the cell.Glucose is a neutral molecule and could diffuse across the cell membrane, but phosphorylation confers a negative charge on glucose, and the plasma membrane is essentially impermeable to glucose-6-phosphate (Figure-4).
2) Moreover, rapid conversion of glucose to glucose-6-phosphate keeps the intracellular concentration of glucose low, favoring diffusion of glucose into the cell.
3) In addition the addition of the phosphoryl group begins to destabilize glucose, thus facilitating its further metabolism.
4) Furthermore, because regulatory control can be imposed only on reactions not at equilibrium, the favorable thermodynamics of this first reaction makes it an important site for regulation.
Figure-4- Glucose is trapped inside the cell by phosphorylation to from Glucose-6-phosphate.
In tissues other than the liver (and pancreatic beta-islet cells), the availability of glucose for glycolysis (or glycogen synthesis in muscle and lipogenesis in adipose tissue) is controlled by transport into the cell, which in turn is regulated by insulin. Hexokinase has a high affinity (low Km) for glucose, and in the liver it is saturated under normal conditions, and so acts at a constant rate to provide glucose 6-phosphate to meet the cell’s need. Liver cells also contain an isoenzyme of hexokinase, Glucokinase, which has a Km very much higher than the normal intracellular concentration of glucose. The function of glucokinase in the liver is to remove glucose from the blood following a meal, providing glucose 6-phosphate in excess of requirements for glycolysis, which is used for glycogen synthesis and lipogenesis.
The important differences between hexokinase and glucokinase can be summarized as follows-
|1)||Tissue distribution||Most tissues||Liver and β cells of Pancreas|
|2)||Km||Low (0.05 mM)||High (10 mM)|
|4)||Product inhibition||Inhibited by G6P||Not inhibited by G6P|
|6)||Function/Biological significance||Maintains intracellular glucose concentration||Maintains blood glucose concentration|
|7)||Clinical Significance||Deficiency causes hemolytic anemia||Decreased activity is observed in diabetes mellitus|
Significance of Glucose-6-phosphate
Glucose 6-phosphate is an important compound at the junction of several metabolic pathways: glycolysis, gluconeogenesis, the pentose phosphate pathway, uronic acid pathway, glycogenesis, and glycogenolysis. It can enter any of the pathways depending upon the cellular requirement.
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