7.7: Glycolysis

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Learning Objectives

Explain the purpose and products of glycolysis.
Describe the use and formation of ATP during glycolysis.

Introduction to Glycolysis

Glycolysis is a 10-step linear catabolic process in which glucose is converted into pyruvate via ten steps that are enzyme catalyzed.. The glucose molecules come from largely from the digestion of starch. The overall reaction is shown below.

\[\ce{Glucose + 2 NAD^{+} + 2 ADP + 2 Pi -> 2 pyruvate + 2 NADH + 2 ATP} \nonumber\]

Glycolysis is the only metabolic cycle that we will discuss that does not occur in the mitochondria; it occurs in the cytoplasm of the cell. This is an old cycle in terms of evolution and is common to animals, plants, fungi, and bacteria. Glycolysis can be divided into 2 stages: the 6-carbon stage and the 3-carbon stage.

There are also two phases of glycolysis:

the "preparatory phase" because it requires an input of energy in the form of 2 ATP's and
the "pay off phase" because energy is released in the form of 4 ATP's.

The end result of glycolysis is two pyruvate molecules which can be converted to acetyl-CoA under aerobic conditions which then feeds into the citric acid cycle (also known as the Kreb's cycle). The structures of glycolysis intermediates can be found in the following diagram:

Chart of glycolysis.png

Figure 1: Glycolysis pathway.

6-Carbon Stage:

Step 1: Glucose is phosphorylated at the sixth carbon by ATP via the enzyme hexokinase to yield glucose-6-phosphate. This step is requires energy from the hydrolysis of one ATP. Therefore this step is said to be coupled to ATP conversion to ADP which is an exothermic process. In a coupled reaction an exothermic reaction provides energy needed by an endothermic one. This step also serves to trap glucose in the cell by converting glucose into a charged compound. Glucose-6-phosphate is an anion at the phosphate end.

Step 2: This is an isomer forming reaction. A pyranose sugar is converted to a furanose sugar; glucose (an aldose) is converted into fructose (a ketose). This step is catalyzed by the enzyme phosphoglucose isomerase.

Step 3: This is another phosphorylation reaction like step 1. Fructose-6-phosphate is phosphorylated at the 1-carbon position by ATP via the enzyme phosphofructokinase. Like step 1 this step requires energy and must be coupled to ATP hydrolysis.

Step 4: This step takes a 6-carbon molecule and splits it into two different 3-carbon molecules. Only one of these 3-carbon molecules is a useful intermediate in glycolysis. The useful molecule is glyceraldehyde-3-phosphate. The other 3-carbon molecule, dihydroxyacetone phosphate, is not and must be converted into glyceraldehyde-3-phosphate in step 5.

Note

The 4 steps discussed so far forms the first phase of glycolysis which requires an input of energy in the form of ATP (adenosine triphosphate) and releases none of the energy stored in glucose.

3-Carbon Stage:

Step 5: This an isomer forming reaction. It converts dihydroxyacetone phosphate into glyceraldehyde-3-phosphate. This reaction is reversible and at equilibrium greatly favors (96%) the dihydroxyacetone phosphate; the reaction proceeds readily because of efficient removal of glyceraldehyde-3-phosphate by subsequent steps (removing a product shifts equilibrium to right—Le Chatelier Principle).

Note

From here, everything should multiplied by 2.

Step 6: This is a combination of oxidation-phosphorylation step that generates a high-energy phosphate bond and a NADH. Glyceraldehyde 3-phosphate is both oxidized and phosphorylated in a reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase, an enzyme that requires nicotinamide adenine dinucleotide (NAD⁺) as the oxidizing agent and inorganic phosphate as the phosphate donor. In the reaction, NAD⁺ is reduced to nicotinamide adenine dinucleotide (NADH), and 1,3-bisphosphoglycerate is formed.

Step 7: 1,3-bisphosphoglycerate has a high-energy phosphate bond joining a phosphate group to carbon atom 1. The high-energy phosphate bond is broken and that energy is harnessed to generate an ATP. The phosphate group is transferred directly to a molecule of ADP, thus forming ATP and 3-phosphoglycerate. The enzyme that catalyzes the reaction is phosphoglycerate kinase, which, requires magnesium ions to function. This is the first reaction to produce ATP in the pathway.

Step 8: In the next reaction, the phosphate group on 3-phosphoglycerate is transferred from the OH group of C3 to the OH group of C2, forming 2-phosphoglycerate in a reaction catalyzed by phosphoglyceromutase.

Step 9: A dehydration reaction catalyzed by enolase, forms phosphoenolpyruvate. An alcohol is converted into an alkene with loss of water. This generates another high-energy phosphate bond.

Step 10: The high-energy phosphate bond is cleaved in phosphoenolpyruvate and the energy is harnessed to produce another ATP. The reaction is catalyzed by pyruvate kinase, which requires both magnesium and potassium ions to be active.This final step generates pyruvate which is used in subsequent metabolic cycles.

Note

In the second phase of glycolysis, four molecules of ATP are produced per molecule of glucose. Because glucose is split to yield two molecules in step 4, each step in the "Pay Off" phase occurs twice per molecule of glucose. The two pyruvate molecules can be converted to acetyl-CoA under aerobic conditions which then feeds into the Citric Acid Cycle.

To Your Health: Diabetes

Although medical science has made significant progress against diabetes , it continues to be a major health threat. Some of the serious complications of diabetes are as follows:

It is the leading cause of lower limb amputations in the United States.
It is the leading cause of blindness in adults over age 20.
It is the leading cause of kidney failure.
It increases the risk of having a heart attack or stroke by two to four times.

Because a person with diabetes is unable to use glucose properly, excessive quantities accumulate in the blood and the urine. Other characteristic symptoms are constant hunger, weight loss, extreme thirst, and frequent urination because the kidneys excrete large amounts of water in an attempt to remove excess sugar from the blood.

There are two types of diabetes. In immune-mediated diabetes, insufficient amounts of insulin are produced. This type of diabetes develops early in life and is also known as Type 1 diabetes, as well as insulin-dependent or juvenile-onset diabetes. Symptoms are rapidly reversed by the administration of insulin, and Type 1 diabetics can lead active lives provided they receive insulin as needed. Because insulin is a protein that is readily digested in the small intestine, it cannot be taken orally and must be injected at least once a day.

In Type 1 diabetes, insulin-producing cells of the pancreas are destroyed by the body’s immune system. Researchers are still trying to find out why. Meanwhile, they have developed a simple blood test capable of predicting who will develop Type 1 diabetes several years before the disease becomes apparent. The blood test reveals the presence of antibodies that destroy the body’s insulin-producing cells.

Type 2 diabetes, also known as noninsulin-dependent or adult-onset diabetes, is by far the more common, representing about 95% of diagnosed diabetic cases. (This translates to about 16 million Americans.) Type 2 diabetics may produce sufficient amounts of insulin. But the insulin-producing cells in the pancreas do not release enough of it, or it is not used properly because of defective insulin receptors or a lack of insulin receptors on the target cells. In many of these people, the disease can be controlled with a combination of diet and exercise alone. For some people who are overweight, losing weight is sufficient to bring their blood sugar level into the normal range, after which medication is not required if they exercise regularly and eat wisely.

Diabetes information clipboard_e26453a54d73c58c9900b1dccca8cf8da.png

Those who require medication may use oral antidiabetic drugs that stimulate the islet cells to secrete insulin. First-generation antidiabetic drugs stimulated the release of insulin. Newer second-generation drugs, such as glyburide, do as well, but they also increase the sensitivity of cell receptors to insulin. Some individuals with Type 2 diabetes do not produce enough insulin and thus do not respond to these oral medications; they must use insulin. In both Type 1 and Type 2 diabetes, the blood sugar level must be carefully monitored and adjustments made in diet or medication to keep the level as normal as possible (70–120 mg/dL).

References

Garrett, H., Reginald and Charles Grisham. Biochemistry. Boston: Twayne Publishers, 2008.
Raven, Peter. Biology. Boston: Twayne Publishers, 2005.

Problems

What is the net yield of glycolysis as far as ATP?
Why is the priming phase necessary?