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Glycolysis

Glycolysis (from Greek glyk meaning sweet and lysis meaning dissolving) is the inital stage of glucose metabolism. The most common and well-known form of glycolysis is the Embden-Meyerhof pathway. The term can be taken to include alternative pathways, such as the Entner-Doudoroff pathway. However, glycolysis will be used here as a synonym for the Embden-Meyerhof pathway.

Glycolysis converts 1 molecule of glucose into 2 molecules of pyruvate, along with "reducing equivalents" in the form of NADH. Glycolysis proper is completely anerobic; that is, oxygen is not required. In eukaryotes it takes place within the cytosol of the cell (as opposed to the mitochondria, where reactions more closely connected to aerobic metabolism occur).

The ultimate fate of the pyruvate and NADH produced in glycolysis depends upon the organism and the conditions, most notably the presence or absence of oxygen or other external electron acceptors. In fermentation, the pyruvate and NADH are anerobically metabolized to yield any of a variety of products. For example, the bacteria involved in making yogurt simply reduce the pyruvate to lactic acid, whereas yeast produce ethanol and carbon dioxide. In aerobic organisms, the pyruvate typically enters the citric acid cycle, and the NADH is ultimately oxidized by oxygen. Although human metabolism is primarily aerobic, under anerobic conditions, for example in over-worked muscles that are starved for oxygen, pyruvate is converted to lactate, as in many microorganisms.

Glycolysis is the only metabolic pathway common to nearly all living organisms, suggesting great antiquity; it may have originated with the first prokaryotes, 3.5 billion years ago or more.

The first step in glycolysis is phosphorylation of glucose by hexokinase (in liver the enzyme is glucokinase which has slightly different properties). This reaction consumes 1 ATP molecule, but the energy is well spent: although the cell membrane is freely permeable to glucose because of the presence of glucose transport proteins, it is impermeable to glucose 6-phosphate. Glucose 6-phosphate is then rearranged into fructose 6-phosphate by phosphoglucose isomerase. (Fructose can also enter the glycolytic pathway at this point.)

Phosphofructokinase-1 then consumes 1 ATP to form fructose 1,6-bisphosphate. The energy expenditure in this step is justified in 2 ways: the glycolytic process (up to this step) is now irreversible, and the energy supplied to the molecule allows the ring to be split by aldolase into 2 molecules - dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. (Triosephosphate isomerase converts the molecule of dihydroxyacetone phosphate into a molecule of glyceraldehyde 3-phosphate.) Each molecule of glyceraldehyde 3-phosphate is then oxidized by a molecule of NAD+ in the presence of glyceraldehyde 3-phosphate dehydrogenase, forming 1,3-bisphosphoglycerate.

In the next step, phosphoglycerate kinase generates a molecule of ATP while forming 3-phosphoglycerate. At this step glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have been synthesized. This step, one of the two substrate-level phosphorylation steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP) this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway. Phosphoglyceromutase then forms 2-phosphoglycerate; enolase then forms phosphoenolpyruvate; and another substrate-level phosphorylation then forms a molecule of pyruvate and a molecule of ATP. This serves as an additional regulatory step.

After the formation of fructose 1,6 bisphosphate, many of the reactions are energetically unfavorable. The only reactions that are favorable are the 2 substrate-level phosphorylation steps that result in the formation of ATP. These two reactions pull the glycolytic pathway to completion.

So, for simple fermentations, the metabolism of 1 molecule of glucose has a net yield of 2 molecules of ATP. Cells performing respiration synthesize much more ATP. Eukaryotic aerobic respiration produces an additional 34 molecules (approximately) of ATP for each glucose molecule oxidized.

See also: Gluconeogenesis