Glycolysis

The glycolysis (grc γλῠκὖς glykýs “sweetened” and grc λύσις lýsis “dissolution”) or way of Embden-Meyerhof-Parnas is held in the Hyaloplasme (or cytosol) of the cell. As its name indicates it requires Glucose. This first stage produces Pyruvate which either will be consumed thereafter by the Cycle of Krebs (after passage in a Mitochondrie) in aerobiosis, or by Fermentation in anaérobiose, where it will become lactate (or lactic acid).

Glycolysis is a mechanism of regeneration of the ATP which is held in Anaérobie (absence of oxygen). During this process, one assists with:

• of the reactions of oxydoreduction during which an acceptor of electrons (Coenzyme NAD) is reduced:

NAD⁺ + 2:00 ⁺ + 2e⁻ → (NADH, H⁺)

• of the syntheses of ATP by phosphorylation of the ADP (formation of 4 molecules of ATP, but consumption of 2, is on the whole formation of 2 molecules of ATP: 2 ADP + 2 P_i → 2 ATP + 2:00 ₂O). The P_i symbol represents phosphate here H₃PO₄ hydrogen still called inorganic phosphate.

Glycolysis resulting in the reduction of coenzymes, it is thus accompanied by the oxidation of organic molecules. One can say that it corresponds to oxidation glucose in Pyruvate:

C₆H₁₂O₆ + 2 NAD⁺ → 2 CH ₃-CO-COOH + 2 (NADH, H⁺)

coupled to

2 ADP + 2 P_i → 2 ATP + 2:00 ₂O

that is to say on the whole

glucose + 2 ADP + 2 P_i + 2 NAD⁺ → 2 pyruvate + 2 ATP + 2 (NADH, H⁺) + 2:00 ₂O

(in the reaction above, the term “pyruvate” CH₃-CO-COO^- indicates in any rigor its Acide combined the pyruvic acid CH₃-CO-COOH)

Stages of glycolysis

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Activation of hexoses

Synthesis of glucose-6-phosphate

• This reaction is irreversible. It is catalyzed by a Kinase, is a Hexokinase, nonspecific of the Glucose which is generally in the muscle, that is to say a Glucokinase, specific Glucose. It will be announced that these two enzymes have a $K\_m$ different with for value respective 0,1mM and 10mM by knowing that the km and proportionally reversible with affinity from the enzyme. These two enzymes are Mg²⁺ dependant. One locates the Glucokinase in the liver and the pancreatic cells. Indeed, the latter is adapted perfectly to the function of storage of the liver (it functions mainly at the time of important surges of glucose, after a meal for example, and thus contributes to the regulation of the glycemia). A dysfunction of this enzyme is thus responsible for certain types of diabetes (diabetes MODY which, for 50% of the cases, are due to a change of the glucokinase ).

• (In the images below, the symbol P in a black circle represents a grouping - O-PO₃^2-). The phosphorylation of glucose is not specific glycolysis. This stage is also used as starting point in the Voie of pentoses phosphates or for the glycogènogénèse.

Note: all the reactions which have a variation of important free energy are irrevesibles, and as this phosphorylation is very favoured énergétiquement, the reaction is irrevesible. This is why this enzyme is very controlled in order to avoid the racing of the system, following the example two other irreversible stages of glycolysis. (Phosphofructokinase, Pyruvate kinase) It is in particular inhibited by its characteristic produced, the Glucose-6-phosphate (negative Rétrocontrôle), and its genic expression is induced by insulin.

Isomerization of glucose-6-phosphate

It is about a Isomérisation, reversible reaction catalyzed by a phosphohexose Isomérase giving, starting from Glucose-6-phosphate Fructose-6-phosphate.

Fructose-1,6-biphosphate synthesis

This reaction, catalyzed by a phosphofructo Kinase (PFK) is irreversible and Mg²⁺ dependant. This enzyme catalyzes the first stage which is specific glycolysis. It is very strongly controlled in a allosteric way by ATP_libre (ATP_libre is the form of the ATP not complexed with magnesium), which is the finished product " utile" glycolysis. The more important the concentration in ATP_libre is, plus this reaction is slow and, conversely, plus the concentration in ATP_libre is weak, plus the enzyme is active. It is about a system Cybernétique of Autocontrôle of glycolysis. Several mathematical models of glycolysis were developed and show that this stage is most important of those which control the flow of glycolysis. Inhibition by the ATP is reversible by the AMP, which makes it possible to keep a constant report/ratio ATP/AMP.

But it is especially controlled by the Fructose-2,6-biphosphate (F26BP): Indeed, the production of F26BP starting from the F6P has for only function to highlight a saturation of the way in F6P (" too much plein"), because the F26BP does not have to become metabolic. By allostery, the F26BP thus activates the phosphofructokinase in order to stimulate the consumption of F6P and thus to prevent its own training.

Formation of the trioses phosphates

Formation of D Glycéraldéhyde-3-phosphate (GAP or G3P) and of the dihydroxyacétonephosphate (DHAP)

This reaction reversible and is catalyzed by an aldolase (group of the Lyase S). (The dihydroxyacétonephosphate is the molecule of bottom). It is possible to pass, in a reversible way, D Glycéraldéhyde-3-phosphate (GAP) with dihydroxyacétonephosphate (DHAP) thanks to the triosephosphateisomérase. It is the opposite reaction of aldolic condensation.

Isomerization of the triosephosphates

This reaction reversible (is catalyzed by a triosephosphate Isomérase) but the following reaction consuming of D-glycéraldéhyde-3-phosphate, balance is moved in the direction of the synthesis of this last. (In the following images, the symbol P encircled represents a grouping - PO₃^2-).

Recuperation of the energy

Synthesis of the 1,3-diphosphoglycérate

This reaction of oxydoreduction, reversible and catalyzed by a D-glycéraldéhyde-3-phosphate déshydrogénase (Oxydo-réductase), led to the formation of a compound rich in energy because comprising a connection acylthioester. This stage constitutes the beginning of the second left glycolysis. The energy contained in the connections rich in energy will be used for the synthesis of the ATP. The coenzymes are reduced (profit of electrons).

In the érythrocyte, a reaction catalyzed by a mutase produces 2,3-diphosphoglycérate starting from the 1,3-diphosphoglycérate, an important effector allosteric of the Hémoglobine (regulation of its affinity for oxygen). The 2,3-diphosphoglycérate is then converted into 3-phosphoglycérate sans production of a molecule of ATP (salting out of an inorganic phosphate) by the 2,3-diphosphoglycérate phosphatase, which follows the way of glycolysis.

Synthesis of 3-phosphoglycérate and recovery of ATP

It there has synthesis of ATP (recuperation of energy), this reaction, reversible, is catalyzed by a phosphoglycératekinase (Transférase).

Synthesis of the 2-phosphoglycérate

This reaction, reversible, is catalyzed by a phosphoglycératemutase (group of the Transférase S).

Synthesis of the phosphoénolpyruvate

This reaction, catalyzed by a énolase (group of the Lyase S), reversible, led to the formation of a compound rich in energy (function énolphosphate), phosphoénolpyruvate (PEP) with ΔG° = 51 kJ.mol^-1.

Synthesis of Pyruvate and recovery of ATP

The grouping phosphates and its connection rich in energy allow by coupling the synthesis of a molecule of ATP. This reaction, Mg²⁺ dependant and irreversible, is catalyzed by a pyruvate Kinase.

Assessment of glycolysis

One uses:

• 1 mole of glucose
• 2 oxidized moles of coenzymes
• 2 moles of ADP
• 2 moles of P_i (inorganic phosphate)

To produce:

• 2 moles of pyruvate
• 2 reduced moles of coenzymes
• 2 moles of ATP
• 2 moles of water

one also gains 4 protons (H⁺): 2 when 2NAD⁺ GIVES 2NADH + 2:00 ⁺, 1 when glucose becomes glucose-6-phosphate and 1 when fructose-6-phosphate becomes fructose-1,6-diphosphate.

One finally produced 2 moles of ATP to lyse 1 mole of glucose. This assessment is weak.

Regulation of glycolysis

Glycolysis is mainly controlled on the level of 2 key enzymes which are PFK-1 and the Pyruvate kinase.

Regulation of the PFK-1

PFK-1 is controlled in a allosteric way :

• ATP and the Citrate act like inhibiteurs
  

• AMP and the F 2,6 di-P act like activators.

The concentration out of F 2,6 di-P is thus paramount on glycolysis. It is controlled by the phosphofructokinase-2 from which the activity will be different depending on its phosphorylation state:

• By the action of the Glucagon (hyperglysemic hormone), it will be phosphorylée and will catalyze the reaction F 2,6 di-P + H₂O - > F6P + pi. Thus the concentration of F 2,6 di-P will decrease and glycolysis will be ralentie.
  

• By the action of the Insuline (hormone hypoglycémiante) it will be déphosphorylée and will catalyze the reaction F6P + ATP - > F 2,6 di-P + ADP. Thus the concentration of F 2,6 di-P will increase and glycolysis will be accelerated.

Regulation of the pyruvate kinase

The pyruvate kinase is controlled allostériquement and this in way ubiquitaire:

• the AMP and the F 1,6 di-P are activateurs
  

• the ATP, the Acétyl-CoA and the Alanine is inhibiters.

On the level of the liver, it is also controlled in a covalent way (by the action of Hormones)

• glucagon goes phosphoryler this enzyme for the inhiber
  

• insulin will carry out the action reverses to activate it.

Reoxidation of the coenzymes

It is important to understand that glycolysis ceases when the coenzymes are not réoxydés in the NAD⁺ form. Without these coenzymes, the stage catalyzed by the enzyme D-glycéraldéhyde-3-phosphate déshydrogénase cannot occur, causing the stop of glycolysis. It is thus crucial to regenerate these coenzymes.

There exist two principal metabolic ways for that: one does not require a Dioxygène, and is called Fermentation. There are several kinds: lactic fermentation (which occurs in the Muscle not oxygenated), butyric fermentation , alcoholic… the other way of reoxidation of the coenzymes requires the dioxygene, which plays the part of acceptor of final electron, east is called Respiration, some speak about cellular breathing to differentiate it from the pulmonary Ventilation, although the contexts of use do not lend to confusion. It takes place on the level of the respiratory Chaîne of the Mitochondries (phosphorylation oxydente. The energy assessment of the glycolysis followed by breathing (32 ATP) is approximately 20 times higher than that of the glycolysis followed by fermentation (2 ATP for lactic fermentation).

See too

Other ways of degradation of glucose:

• the Voie of pentoses phosphates
• the way of Entner-Doudoroff
• Pyruvate
• the way reverses glycolysis, the Néoglucogenèse

External bonds

• the chemical logic of glycolysis (English)

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