A Deep Dive Into Glycolysis — The Ancient Pathway That Powers Most Living Organisms
Glycolysis is how we convert our food into energy: You can picture it as food → energy
By Eva Fata
It is how our cells extract energy from sugar (glucose). Glycolysis is one of the oldest ancient pathways that most living organisms have as a mechanism in their body to convert food into energy.
The process at its core is that we break down a molecule of glucose, splitting it into 2-three carbon molecules called pyruvate.
Glycolysis is a living mechanism in living organisms for eons, for centuries if not hundreds of millions of years.
Glycolysis can be broken down into 2 phases. The first phase/half of glycolysis is the “energy-requiring steps” — also known as the preparatory phase, which gets the glucose prepared to get broken down.
The second phase/half is the “energy-releasing steps” also known as the payoff phase. This is when all the hard work pays off, and gains all the energy in the form of ATP and NADH.
The First Phase/Half Of Glycolysis “Energy Requiring Steps”
Step one → Hexokinase’s Kickstart: Turbocharging Glucose: the first phase of glycolysis, is catalyzed by hexokinase which is an enzyme which initiates the phosphorylation of six-carbon sugars. Hexokinase then adds a phosphate group to glucose using ATP which then produces glucose-6-phosphate which is a more reactive form of glucose. This reaction does not allow for the glucose molecule to react with the GLUT receptors and also does not allow it to leave the cell as it is negatively charged phosphate and cannot pass through the hydrophobic interior of the plasma membrane.
Step two → Phosphate Shuffle: From Glucose to Fructose: An isomerase which is an enzyme which initiates the transformation of a molecule into its isomer (a molecule with the same molecular formula but a different structural arrangement) converts the glucose-6–phosphate into one of its isomer which is fructose-6-phosphate. This will allow the split of the sugars into two 3-carbon molecules.
Step three → Fructose Boost: ATP’s Kickstart: Phosphorylation of fructose-6-phosphate which is catalyzed by the enzyme phosphofructokinase. During this phosphorylation, a molecule which contains high-energy phosphorus and oxygen atoms from ATP is moved to fructose-6-phosphate, which results in fructose-1,6-biphosphate and ADP (adenosine diphosphate).
Phosphofructokinase is a rate-limiting enzyme. This means that it regulates the overall speed at which this metabolic pathway proceeds. Therefore if the amount of ADP is high, it will be active, when ADP is low and ATP is high, it will be less active. This is a type of “end product inhibition” which regulates the metabolic process by the accumulation of its end product. This means that if ATP is too high it will give a signal saying it already has enough energy and can slow down the process.
Step four → Molecular Split: Aldolase’s Divide of Fructose-1,6-Bisphosphate: The newly added high-energy phosphate weakens the fructose-1,6-bisphosphate. A new enzyme is added aldolase, to break down 1,6- bisphosphate into three carbon isomers: dihydroxyacetone-phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P).
Step five → Triose Twist: Isomer Switch from Dihydroxyacetone-Phosphate to Glyceraldehyde-3-Phosphate: An isomerase, triose phosphate isomerase, converts the dihydroxyacetone-phosphate into its isomer, glyceraldehyde-3-phosphate. From here it will continue to proceed with two molecules of the same isomer, after the isomerization dihydroxyacetone-phosphate to glyceraldehyde-3-phosphate. At this point, the breakdown of glucose needs two ATP molecules for energy.
The Second Phase/Half Of Glycolysis “Energy-Releasing Steps”
Step six → Electron Harvest: NAD+ Gathering and Phosphorylation — Transforming G3P to 1,3-Bisphosphoglycerate: Oxidation of glyceraldehyde-3-phosphate which removes high energy electrons from glyceraldehyde-3-phosphate. These electrons are then picked up by NAD+ which further produces NADH. Glyceraldehyde-3-phosphate is then phosphorylated (adding a second phosphate group) which results in 1,3-bisphosphoglycerate.
There is another limiting to this pathway. The continuation of this reaction depends on what is available from the oxidized electron carrier NAD+. Therefore NADH must be constantly oxidized back into NAD+ to keep this step going. If NAD+ is not available, the second half (energy-releasing steps) will either slow down or stop. If oxygen is available (aerobic) the NADH will oxidize and the high-energy electrons from hydrogen will produce ATP. However, if no oxygen is available (anaerobic) there is an alternate pathway which is called fermentation that can provide the oxidation of NADH to NAD+.
Step seven → ATP Express: Phosphoglycerate Kinase’s Speedway — Shifting 1,3-Bisphosphoglycerate to 3-Phosphoglycerate: 1,3-bisphosphoglycerate is catalyzed by phosphoglycerate kinase which helps speed up the process of 1,3-bisphosphoglycerate donating high energy phosphate to ADP which results in ATP (substrate-level phosphorylation). A carbonyl group on the 1,3-bisphosphoglycerate is then oxidized to a carboxyl and therefore 3-phosphoglycerate is produced.
Step eight → Phosphate Shift: Rearranging 3-Phosphoglycerate into 2-Phosphoglycerate: The phosphate group from 3-phosphoglycerate catalyzed by mutase (isomerase) moves from the third carbon to the second carbon which then produces 2-phosphoglycerate.
Step nine → Water Out, Energy Up: Enolase’s Shift — Crafting Phosphoenolpyruvate (PEP) from 2-Phosphoglycerate: Enolase catalyzes this step, which causes 2-phosphoglycerate to lose water from this structure which results in a double bond, which then increases the energy in the remaining phosphate bond and produces phosphoenolpyruvate (PEP).
Step ten → Final Boost: Pyruvate Kinase’s Encore — Yielding ATP and Pyruvate: This final step is catalyzed by the enzyme pyruvate kinase, which results in the production of a second ATP molecule by substrate-level phosphorylation as well as pyruvic acid (or its salt form pyruvate).
The Outcomes of Glycolysis
Let’s talk about the importance of glycolysis for mammalian red blood cells. Without glycolysis, most mature mammalian blood cells would die or lead to premature cell death. Therefore without glycolysis, you will have cell death. Why is that? Because the absence of mitochondria in red blood cells means that they cannot perform aerobic respiration, which means that mammalian red blood cells depend on glycolysis for ATP production.
The lack of glycolysis and/or disruptions in glycolysis leads to cell death which is bad and can cause major problems.
Glycolysis starts with glucose and then ends with two pyruvate molecules, four ATP molecules and two molecules of NADH. The two ATP molecules were used in the first half (Energy-requiring steps) to prepare the six-carbon ring form of glucose for breaking down into 3 carbon sugars. The cell then has a net gain of two ATP molecules and 2 NADH molecules for its use in other cellular processes.
In the last step of glycolysis, if there is not enough pyruvate kinase, the step will not occur. However, the entire glycolysis pathway will keep going but only 2 ATP molecules will be made in the second half. This means that pyruvate kinase is a rate-limiting enzyme for glycolysis.
Summary
Glycolysis is the first step of cellular respiration. It is the first pathway which is used to break down glucose to get energy. There are two main parts the “energy-requiring steps” and the “energy-releasing steps”. The first half uses ATP to energize the separation of the 6-carbon ring form of glucose. The second half of glycolysis takes ATP and high-energy electrons from hydrogen atoms and attaches them to NAD+. Two ATP molecules are in the first half and four ATP molecules are formed in the second half by substrate phosphorylation. This further produces a net gain of two ATP and two NADH molecules!
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