Glycolysis

Image by JS W25

Glycolysis is defined as the biochemical processes that transform glucose into pyruvate. It is represented by the green shaded area in the image above. Pyruvate is converted to acetyl-CoA in the mitochondria. Cells generally prefer glycolysis as an initial source of energy, especially when glucose is readily available. This preference has a few reasons behind it:

Efficiency in Short-Term Energy Production: Glycolysis is a fast process that can quickly generate ATP, making it ideal for rapid energy needs. While glycolysis itself produces only 2 ATP per glucose molecule, it's sufficient to keep the cell going until more efficient pathways kick in.
Readiness and Accessibility: Glucose is typically more available and more easily broken down than fats or proteins, which require more complex processing. For example, in liver and muscle cells there is a supply of glycogen which can yield glucose molecules to immediately enter glycolytic pathways when demand is high for energy production.
Anaerobic Capability: Glycolysis can occur without oxygen, which is crucial for cells that might not have a steady oxygen supply, like muscle cells during intense exercise. In contrast, fats and proteins are almost exclusively broken down aerobically (with oxygen).

However, while glycolysis is convenient, it’s not the most efficient pathway for sustained energy production. When glucose levels are low or energy demands are prolonged (such as in endurance activities or fasting), cells shift to relying more on fats, which yield more ATP per molecule than glucose, and the cells can shift to mostly proteins as a last resort.

In essence, cells “prefer” glycolysis because it’s fast and simple, but they adapt to use fats and proteins when glucose is less available or when higher ATP demands arise. While the ratio of each substrate being used can depend on metabolic demand and regulation, the reality is that cells are likely using all three substrates, (carbohydrates, proteins, and fats) simultaneously most of the time.

How Glycolysis Works

Simple Overview: Glycolysis, or "sugar splitting," occurs in the cell’s cytoplasm. It breaks down one glucose molecule (6 carbons) into two molecules of pyruvate (3 carbons each). Energy released is captured as ATP or NADH.

Glucose Phosphorylation and Storage:

Glucose enters the cell and is phosphorylated by ATP, trapping it inside as glucose-6-phosphate.
If energy is sufficient, glucose-6-phosphate may be stored as glycogen for later use. Glycogen synthesis (glycogenesis) and breakdown (glycogenolysis) help regulate blood sugar levels, with the major storage occurring in liver cells. If energy is needed, glucose-6-phosphate will move on to step 3.

Conversion of of glucose to fructose and splitting to 3 carbon sugars:

Glucose-6-phosphate converts to fructose-6-phosphate, which is further phosphorylated to fructose-1,6-bisphosphate. fructose-1,6-bisphosphate has two phosphates bonded to it and this rapidly dissociates into two 3-carbon molecules (Glyceraldehyde-3-phosphate (G3P)), which continues through glycolysis.

Energy Capture (Redox Reaction)

Each G3P molecule undergoes dehydrogenation, losing two hydrogen atoms to form NADH from NAD+. This redox reaction bonds an inorganic phosphate (Pi) to G3P, forming 1,3-bisphosphoglycerate.

Substrate-Level Phosphorylation

Phosphate groups from the 3-carbon molecules transfer to ADP, forming ATP through substrate-level phosphorylation. With two G3P molecules from each glucose, this step generates four ATP, resulting in a net gain of two ATP per glucose after accounting for initial ATP use.

Formation of Pyruvate

The two 3-carbon molecules left after ATP production are now pyruvate, the end product of glycolysis. Pyruvate’s fate depends on oxygen availability:

Anaerobic (Low Oxygen): Pyruvate converts to lactate, regenerating NAD+ to sustain ATP production through glycolysis. Lactate is not a waste but is quickly recycled into pyruvate by other cells.
Aerobic (Oxygen Present): Pyruvate enters the mitochondria to produce acetyl-CoA.

Lactate: Likely Not What You Think

Lactate often gets a bad rap, mistakenly associated with muscle fatigue, soreness, and waste. The perception of lactate as a "waste product" has roots in early 20th-century research, notably Otto Meyerhof’s experiments on frog muscle contractions without oxygen, which led to the idea that lactate buildup resulted from oxygen deprivation and contributed to lactic acidosis. However, this experimental setup didn’t accurately reflect how muscles operate normally. While it’s true that lactate is produced when muscles work intensely (due to a temporary oxygen shortage), lactate itself doesn’t cause pain or fatigue. In fact, lactate is quickly absorbed and converted back to pyruvate by other cells in the body, and it doesn’t linger in the blood or act like a toxin. Today, we know that the body produces lactate, not lactic acid. Lactate actively supports muscle function and cellular energy production, especially during exercise. Rather than being a simple byproduct of anaerobic metabolism, lactate is a key player in energy metabolism, it fuels muscles and supports various cellular processes. Far from being a nuisance, lactate is crucial for meeting energy demands, particularly during bursts of intense activity.

Why Convert Pyruvate to Lactate? This conversion is vital to keep glycolysis going. During intense activity, cells generate NADH rapidly and must regenerate NAD+ to allow glycolysis (and thus ATP production) to continue. When NAD+ is used up, the reaction stalls, potentially compromising energy production and cellular function. Converting pyruvate to lactate frees up NAD+, which sustains glycolysis and enables further ATP production through anaerobic metabolism, a quick, if somewhat inefficient, way to produce energy under oxygen-limited conditions.