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Glycolysis - Our In House Red Bull

“Eating and reading are two pleasures that combine admirably.”
                                                                                          -C.S. Lewis

And with that quote, let’s proceed to read about what happens to the food we eat through the pathway of glycolysis.

Glycolysis- the splitting of glucose - is the main metabolic pathway for carbohydrates (Not just glucose- fructose, galactose as well).

Glycolysis takes place in the cytosol, which is why all the enzymes required for glycolysis are found here. How does glucose get into the cell? By our friendly neighbourhood insulin, of course. Insulin is the hormone that regulates the entry of glucose into cells. (Here, we are excluding the hepatocyte and pancreatic beta islet cell). We can summarise the pathway like this:

Glucose + 2Pi + 2ADP + 2 NAD+ à 2 pyruvate + 2 ATP + 2 NADH + 2H+ + 2 H2O

There are two major reactions where ATP is formed, which we will discuss in subsequent paragraphs.

The first step in glycolysis is the formation of glucose-6-phosphate, catabolized by the enzyme hexokinase. Remember, at this point we are concerned with glycolysis in cells apart from hepatocytes and pancreatic islet cells. Hexokinase has a very high affinity for glucose and is present in the liver as well. The liver, in addition to having hexokinase, also has another enzyme- glucokinase. These two enzymes catabolize the same reaction. The only difference is that glucokinase is found only in the liver.

That means hepatocytes have both hexokinase and glucokinase. Well, hexokinase is usually saturated under normal conditions in the liver, and so it isn’t much of a participator in glycolysis in the liver. What does glucokinase do then?

·       Glucokinase has a lower affinity for glucose compared to hexokinase

·       When hexokinase is saturated (and since the affinity for glucose is higher, it gets saturated earlier), essentially your body is saying, “I’m full! I don’t need any more of this glucose.” The remaining glucose enters the liver, is acted upon by glucokinase and goes in the direction of glycogenesis and lipogenesis.

Glucose-6-phosphate is then converted to fructose-6-phosphate by an isomerase.

The next step is known as the rate limiting step in glycolysis. It is a crucial step that often determines the rate of glycolysis taking place in the body.

Rate limiting step: The rate determining step is the slowest step of a chemical reaction that determines the speed (rate) at which the overall reaction proceeds. [1]

Fructose-6-phosphate gets a phosphate added to it, and becomes fructose-1,6-bisphosphate by the enzyme phosphofructokinase-1 (PFK-1) *Not to be confused with PFK-2, which converts fructose-6-phosphate to fructose-2,6-bisphosphate! Here, we have added in a phosphate. The creation of a bond requires energy- here, one ATP is used and converted to ADP.

Fructose 1,6 bisphosphate is a hexose sugar containing 6 carbons which is primed to get broken down. Next, we see the formation of two “triose phosphates”- glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP). DHAP is important because it is a link to lipid metabolic pathways. DHAP and glyceraldehyde-3-phosphate can be interconverted with the enzyme phosphotriose isomerase.

Glyceraldehyde-3-phosphate is then converted to 1,3-bisphosphoglycerate – an oxidation reaction. The removed hydrogens are transferred to NAD+, forming NADH.

The next reaction- 1,3 bisphosphoglycerate into 3-phosphoglycerate- is one that provides us with ATP. It is a substrate-level phosphorylation- i.e. phosphate groups are being transferred at the level of those specific compounds. (If you’ll remember, the other type of phosphorylation we’ve seen is ‘oxidative phosphorylation’)

How many ATP molecules have been formed so far? If you said two- you’re right. This is because two molecules of triose phosphate (glyceraldehyde-3-phosphate) are formed, and each undergoes subsequent reactions to give a total of 2 ATP moieties.

The next reaction forms PEP- phosphoenolpyruvate. This reaction is catalysed by enolase and requires either Mg2+ or Mn2+.

At this juncture I would like to raise a question. The rate limiting step in this process was mentioned above. The enzyme PFK-1 is irreversible and regulated by the amount of the substrate which is found in the cells. Other reactions we saw, including the one giving us ATP are reversible. Why can’t the reaction giving us ATP be the rate-limiting step?

The reaction catalysed by PFK-1 is irreversible. Any glucose molecule undergoing glycolysis that passes this reaction is going to be stuck in glycolysis until pyruvate or lactate is formed. Just imagine if the first reaction forming ATP, which is reversible, was the RLS- would the pathway go forward, forming pyruvate and lactate? Or would it go backward, and in the process convert ADP to ATP? It doesn’t have any advantage, does it? Thus, supposedly, evolutionary mechanisms have rightly selected the perfect reactions to regulate these metabolic processes. 

Next PEP is converted to pyruvate through pyruvate kinase to form 2 molecules of ATP.

This is also an irreversible reaction-

  • The amount of energy released is incredibly high
  • PEP is first converted to enol-pyruvate which immediately isomerises to pyruvate (so the first product of the reaction is not available to reverse)

This reaction is upregulated by fructose-1,6-bisphosphate (the product of our rate-limiting step). Can you guess what would down-regulate this reaction? That’s right, ATP. The more ATP that is produced, the lower the rate this reaction proceeds.

 
Glycolysis1.png
 

Now that we have pyruvate, how does the cell decide what to do with it? This depends on the available oxygen.

Glycolysis can operate under aerobic as well as anaerobic conditions. Under aerobic conditions, NADH gets oxidised through the respiratory chain (electron transport chain in the mitochondria) to O2 and finally to water, releasing a large amount of energy in turn.

In anaerobic conditions, pyruvate undergoes conversion to form lactic acid.

An interesting point to note here is that the amount of energy that is expelled through aerobic and anaerobic pathways is different. A large amount of ATP is made in aerobic – upto 32 mol of ATP, but anaerobic only yields 2 mol.

Irreversible reactions (usually ones that consume energy)

  1. Glucose to glucose-6-phosphate (ATP consumed)
  2. Fructose-6-phosphate to fructose-1.6-bisphosphate (ATP consumed)
  3. PEP to pyruvate

A few facts about this pathway:

  • Erythrocytes lack mitochondria, so they undergo only anaerobic glycolysis
  • Pyruvate is the link between glycolysis and the citric acid cycle
  • Deficiency of pyruvate kinase causes hemolytic anemia

Author: Shruthi Sivakumar