Glycolysis


INTRODUCTION:
Glycolysis comes from the Greek words: Glycose=sugar or sweet and Lysis=splitting or dissolution. It is a pathway in all of the cells of the body. The entire pathway has been elucidated in the year 1940. This pathway can be called an Embden-Meyerhof pathway (E.M. pathway) in honour of the 2 biochemists who made a significant contribution to the process of Glycolysis.




 DEFINITION:

The process of Glycolysis can be defined as the Order of reactions Converting glucose (or Glycogen) to lactate or pyruvate together with ATP production.

PURPOSE:
Transfer of glucose to pyruvate.  Pyruvate is further Processed for the production of ATP. (ATP- Adenosine Tri- Phosphate; it is the energy currency of the cell. Splitting of a single molecule of ATP provides the energy of 7.3 calories. This energy is utilized by the cell for a variety of functions).

 SITE:

The phenomenon of Glycolysis takes place in the “cytoplasm." of the cell.
Glycolysis-in-the-cytoplasm

TYPES:


a. Aerobic Glycolysis
The process of Aerobic Glycolysis takes place in the presence of oxygen.
The end product of Aerobic Glycolysis is Pyruvate.
Energy generated - 8 ATPs.

b. Anaerobic Glycolysis
The phenomenon of Anaerobic Glycolysis takes place in the absence of oxygen.
The end product of Anaerobic Glycolysis is Lactate.
Energy generated - two ATPs.

FEATURES:
1. It happens in the presence of oxygen, as well as in lack of oxygen. 
2. It is a significant pathway for ATP synthesis in both type of cells, containing Mitochondria and cells lacking Mitochondria. (Such as RBC, Cornea, Lens.)
3. The brain utilizes almost two-thirds of the whole blood glucose. Glycolysis plays a significant role in energy generation for the brain cells.
4. Intermediates of Glycolysis can be utilized by the cell for synthesizing amino Acid along with Fat.

GLYCOLYSIS PATHWAY:

The pathway (sequence of reactions) are split into 3 different stages:

Stage 1: Energy Investment stage.

Stage 2: Splitting stage.

Stage 3: Energy Generation stage.

These three stages collectively constitute 10 reactions.

AN OVERALL PICTURE OF GLYCOLYSIS:

GLUCOSE
1HEXOKINASE OR GLUCOKINASE
GLUCOSE 6-PHOSPHATE

2 PHOSPHOHEXOSE ISOMERASE
FRUCTOSE 6-PHOSPHATE

3 PHOSPHOFRUCTOKINASE
FRUCTOSE 1, 6-BISPHOSPHATE

4 ALDOLASE

DHAP ↔ GLYCERALDEHYDE 3-PHOSPHATE
 PHOSPHOTRIOSE ISOMERASE

6 GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE
1, 3 -BISPHOSPHOGLYCERATE

7 PHOSPHOGLYCERATE KINASE
3-PHOSPHOGLYCERATE

8 PHOSPHOGLYCERATE MUTASE
2-PHOSPHOGLYCERATE

9 ENOLASE
PHOSPHOENOL PYRUVATE

10 PYRUVATE KINASE
PYRUVATE


DHAP (Dihydroxy Acetone Phosphate)



Reactions 1, 2, 3, 4 comprise energy Investment Phase.
Reaction 5 comprise Splitting Phase.
Reaction 6, 7, 8, 9, 10 comprise Energy production phase.
(The  enzymes catalyzing the various reactions are mentioned on
the arrows).

REACTIONS IN DETAIL:

1.  PHOSPHORYLATION: Glucose is phosphorylated to glucose 6-phosphate by the action of hexokinase or glucokinase (both are Iso-Enzymes). This is an irreversible reaction. ATP and Magnesium ion are required for the reaction to proceed.
2. ISOMERIZATION: Glucose 6-phosphate is isomerized to fructose 6-phosphate by the action of the enzyme phosphohexose isomerase and in the presence of Magnesium ion.
3.  PHOSPHORYLATION: Fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate with the help of phosphofructokinase enzyme. This reaction is an irreversible and regulatory step of glycolysis.
4. CLEAVAGE: The six carbon-containing fructose 1, 6- bisphosphate is divided into glyceraldehyde 3- phosphate and dihydroxyacetone phosphate (DHAP). Both of these are 3 carbon compounds. Aldolase catalyzes the reaction.
5. ISOMERIZATION: DHAP is isomerized to Glyceraldehyde 3-phosphate by the action of enzyme Phosphotriose Isomerase. So, currently, there are two molecules of glyceraldehyde 3-phosphate available.
6. OXIDATION: Glyceraldehyde 3-phosphate is oxidized to 1,3 bisphosphoglycerate with the help of enzyme glyceraldehyde 3-phosphate dehydrogenase (G-3-P dehydrogenase). Here 1 molecule of NADH is produced from 1 molecule of NAD+. This NADH also participates in Electron Transport Chain to synthesize ATP.
7. DEPHOSPHORYLATION: 1,3 Bisphosphoglycerate is switched to 3-phosphoglycerate by catalyzing action of the enzyme phosphoglycerate kinase. Here 1 molecule of phosphate from the substrate is released. This phosphate is consumed by a molecule of ADP to synthesize 1 molecule of ATP. This is SUBSTRATE LEVEL PHOSPHORYLATION. This is an uncommon example of a reversible kinase reaction. Magnesium ion is also needed in this reaction.
8. ISOMERIZATION: 3-phosphoglycerate is transformed into 2-phosphoglycerate by the action of enzyme phosphoglycerate mutase. This is an isomerization reaction.
9. DEHYDRATION: 2-phosphoglycerate is converted into Phosphoenol Pyruvate by the elimination of a single molecule of Water by the activity of the enzyme Enolase. For this reaction, Magnesium ion or Manganese ion is required. Phosphoenol Pyruvate is a high energy compound.
10.  DEPHOSPHORYLATION: Phosphoenol Pyruvate is converted into Pyruvate by the elimination of one molecule of Phosphate(Pi) that is consumed by a single molecule of ADP to make 1 molecule of ATP. This is also a SUBSTRATE LEVEL PHOSPHORYLATION. Pyruvate Kinase is the enzyme involved. The enzymes require Potassium ion and Magnesium ion or Manganese ion. The reaction is irreversible.

ENERGETICS OF GLYCOLYSIS:
Aerobic Glycolysis
1. 1 molecule of NADH participates in ETC (Electron Transport Chain) to produce 3 ATPs. There are two NADH synthesize from two molecules of Glyceraldehyde 3-phosphate so liberating 6 ATPs.
2. 1 molecule of ATP is made by Substrate Level Phosphorylation in reaction 7. Total 2 ATPs are synthesized because there are two Glyceraldehyde 3-Phosphate molecules.
3. In reaction 10, again there's a Substrate Level Phosphorylation from Phosphoenol Pyruvate. Since there are two Phosphoenol Pyruvate molecules generated from two molecules of Glyceraldehyde 3- Phosphate, two ATPs are produced.
4. In Energy investment phase, two ATPs are utilized. one ATP in reaction 1 and one ATP in reaction   3.
Thus, the total ATP molecules Synthesis in glycolysis is 8 ATPs.
(2NADH = 6 ATPs
Reaction 7 = 2 ATPs
Reaction 10 = 2ATPs
Net = 10 ATPs
ATP employed = 2 ATP (in energy investment phase)
Net Production= 10-2=8 ATPs).

ANAEROBIC GLYCOLYSIS:
Here pyruvate is converted to lactate by lactate dehydrogenase. 1 NADH is converted to NAD. That usually means the NADH generated in reaction 6 isn't utilized for ATP production. Hence here just 2 ATPs are produced.
(2 NADH =0 ATP
Reaction 7=2 ATPs
Reaction 10=2ATPs
ATP utilized = 2 ATPs (in energy investment phase)
Net Generation =4-2=2ATPs).

FATE OF PYRUVATE:
The Pyruvate generated as the end product of glycolysis undergoes oxidative decarboxylation and therefore forms Acetyl Co-A that's utilized in Citric Acid Cycle to synthesize ATP.

INHIBITORS OF GLYCOLYSIS:
1. Iodoacetate and Arsenate inhibit the enzyme Glyceraldehyde 3-Phosphate Dehydrogenase of reaction 6 of glycolysis.
2. Fluoride inhibits Enolase of reaction 9 of glycolysis.

GLYCOLYSIS RELATED DETAILS:
1. Lactic Acidosis: Accumulation of lactic acid is observed in its own excessive production as a result of anaerobic glycolysis, example: in skeletal muscle during strenuous exercise. Its low elimination may also cause lactic acidosis. In Lactic Acidosis ATP generation is decreased. The reason is the absence of Oxygen supply. It could lead to pain in muscles during severe exercise. Normal plasma lactic acid concentration- 4-15 mg/dl.
2. Oxygen Debt: It is the additional quantity of Oxygen necessary to recover from anaerobic glycolysis.
3. Cancer and Glycolysis: In cancer, there's excess regeneration of cells. The surplus number of cells demonstrate increased uptake of glucose and consequently, glycolysis. As the tumour grows in size, there's increased need for Oxygen by the tumour, and also the blood vessels are not able to supply. Therefore, Hypoxic conditions become established in the tumour. So, anaerobic glycolysis raises.
Later the tumour cells become accustomed to hypoxia by the participation of the transcription factor called Hypoxia-Inducible Transcription Factor (HIF). HIF raises the production of glycolytic enzymes and glucose transporters.
However, the tumours can't endure for long under these hypoxic conditions. So, a process of therapy of cancer is to decrease the vascularization to the tumour so that hypoxia prevails and the cancers could be removed.
4. Pasteur Effect: The inhibition of Glycolysis by Oxygen (aerobic condition) is called the Pasteur effect. It is because of the inhibition of the enzyme Phosphofructokinase of reaction number 3 by the impact of ATP generated in the presence of Oxygen via Glycolysis.
5. Crabtree Effect: The process of inhibition of oxygen uptake by the addition of glucose to the cells having high aerobic glycolysis. It is because when glucose is inserted into a tissue having high aerobic glycolysis more glycolysis occurs, resulting in the generation of more ATP. So the requirement of Oxygen for generating ATP through the Citric Acid Cycle is decreased, and thus, Oxygen consumption is diminished.

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Cheers,
Saqi


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