Glycolysis is the metabolic process by which glucose is converted to pyruvic acid. The liberated energy is used to synthesise the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NAD) (NADH). Glycolysis is a series of ten enzyme-catalysed processes.

Glycolysis is a non-oxygen-requiring metabolic pathway. Glycolysis is seen in a wide variety of different species, indicating that it is an ancient metabolic mechanism. Indeed, the events that comprise glycolysis and its parallel system, the pentose phosphate pathway, occur in the oxygen-depleted Archean oceans, as well as in the absence of enzymes catalysed by metals.

Glycolysis happens in the liquid portion of cells, the cytosol, in the majority of organisms. The Embden–Meyerhof–Parnas (EMP) pathway is the most prevalent kind of glycolysis. It was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also encompasses a variety of additional metabolic routes, including the Entner–Doudoroff pathway and a variety of heterofermentative and homofermentative pathways. The discussion here, however, will be limited to the Embden–Meyerhof–Parnas’s route. 

Steps Involved in Glycolysis

A molecule of glucose is destroyed in glycolysis through a sequence of enzyme-catalysed processes to yield two molecules of the carbon compound pyruvate. The glycolytic pathway fermentation of glucose can be separated into two stages, each of which requires multiple distinct enzyme events.

Phase I- Consists of reactions that serve as “precursors” to Phase II: These are not redox reactions and do not result in the release of energy; rather, they form a critical intermediate in the process.

Stage II- Involves the occurrence of redox reactions, the conservation of energy, and the formation of two molecules of pyruvate.

Phase I:  Energy investment phase (Preparatory phase)

• The pathway’s first five reactions.
• One glucose molecule is converted to two glyceraldehyde-3-phosphate molecules.
• Two ATP are consumed.
• Includes the rate-limiting step of fructose-6-phosphate conversion to fructose-1,6-bisphosphonate, which is mediated by phosphofructokinase.

Involved reactions

• Hexokinase phosphorylates glucose using ATP, resulting in glucose 6-phosphate.
• Phosphoglucose isomerase is then used to isomerize glucose 6-phosphate to fructose 6-phosphate.
• The second phosphorylation results in the synthesis of fructose 1,6-bisphosphate by the rate-limiting enzyme of glycolysis, phosphofructokinase 1 (PFK-1). This reaction consumes one ATP.
• Aldolase then separates fructose 1,6-bisphosphate into two 3-carbon molecules, glyceraldehyde 3-phosphate and its isomer, dihydroxyacetone phosphate, which is transformed back to glyceraldehyde 3-phosphate.

Phase II:  Energy production phase (Pay-off phase)

• Two G3P are converted to two pyruvates.
• Produces four adenosine triphosphates and two naphthalene diphosphates.

Involved reactions

• The first redox reaction occurs when glyceraldehyde 3-phosphate is oxidised to 1,3 bisphosphoglyceric acid using NAD + as a cofactor by glyceraldehyde 3-phosphate dehydrogenase
• Phosphoglycerate kinase converts 1, 3-bisphosphoglyceric acid to 3-phosphoglyceric acid. Per glucose molecule, this process generates two ATP
• Phosphoglycerate mutase catalyses the reversible conversion of 3-phosphoglyceric acid to 2-phosphoglyceric acid
• Enolase converts 2-phosphoglycerate to phosphoenolpyruvate (PEP) in a reversible manner.
• Regulated, irreversible reaction in which pyruvate kinase converts PEP to pyruvate. This process results in a net gain of two ATP per glucose molecule

ATP Generation

• Two ATP molecules are consumed and four ATP molecules are generated during Stages I and II of glycolysis
• Thus, glycolysis produces two molecules of ATP for every molecule of glucose fermented

However, peak ATP output from oxidation of glucose is 36 to 38 ATP.

The greatest generation of ATP per glucose molecule depends on coupling of glycolysis with the citric acid cycle by means of pyruvate dehydrogenase.

Significance of Glycolysis Pathway

• All tissues utilise the glycolytic pathway to break down glucose into energy in the form of ATP

• Significant avenue for energy production, particularly in anaerobic circumstances
• It is critical for energy synthesis in cells without mitochondria
• It produces intermediates for subsequent metabolic processes
• Glycolysis is involved in glycogen metabolism, the pentose phosphate pathway, amino sugar synthesis, triglyceride synthesis (by glycerol 3-phosphate), lactate synthesis (a dead-end reaction), and transamination with alanine

Regulation of Glycolysis

Glycolysis is an interesting metabolic route in that it is regulated at three distinct enzymatic points:

Glycolysis is regulated in a reciprocal manner to its anabolic counterpart, gluconeogenesis. Reciprocal regulation happens when the same chemical or therapy (phosphorylation, for example) affects both catabolic and anabolic pathways in opposite directions. Reciprocal control is critical when anabolic and catabolic pathways coexist in the same cell.

Consider the regulation of PFK. Numerous chemicals, most notably fructose-2,6-bisphosphate, activate it (F2,6BP). This chemical inhibits the gluconeogenesis enzyme fructose-1,6-bisphosphatase (F1,6BPase)

You may be wondering why pyruvate kinase, the pathway’s final enzyme, is regulated. The solution is straightforward. Pyruvate kinase catalyses glycolysis’s most energetically efficient process. The process is so heavily preferred in the forward direction that cells must take a ‘two-step’ around it while producing glucose. In gluconeogenesis, it requires two enzymes, two processes, and two triphosphates to convert pyruvate to PEP. When cells require glucose, they cannot be diverted by converting the PEP produced during gluconeogenesis directly back to pyruvate via pyruvate kinase. As a result, pyruvate kinase is inhibited during gluconeogenesis to avoid the occurrence of a “futile cycle.” “take place.

Pyruvate kinase is another intriguing regulatory mechanism known as feedforward activation. F1,6BP acts allosterically to activate pyruvate kinase. This molecule is a result of the PFK reaction and an aldolase substrate. It is worth noting that the aldolase reaction is energetically unfavourable (high +G°’), allowing for the accumulation of F1,6BP. When this occurs, a portion of the excess F1,6BP activates pyruvate kinase, initiating the conversion of PEP to pyruvate. The decrease in PEP levels that results has the effect of “pulling “on the processes that occur before to pyruvate kinase. As a result, the concentrations of G3P and DHAP decrease, assisting in the progression of the aldolase reaction.

Conclusion 

Glycolysis is a critical metabolic mechanism that involves the oxidative breakdown of one glucose into two pyruvates while capturing some energy in the form of ATP and NADH. Glycolysis is critical in the cell since glucose is the primary source of energy for the body’s tissues. For instance, glucose is the brain’s sole source of energy. The body needs to maintain a consistent supply of glucose in the blood in order to maintain optimal brain function. Glycolysis is also significant because it generates helpful intermediates for other metabolic pathways, such as amino acid or fatty acid production.