Question

Missing acyl CoA dehydrogenases. A number of genetic deficiencies in acyl CoA dehydrogenases have been described. A deficiency in acyl CoA dehydrogenase presents itself early in life or after a period of fasting. Symptoms include vomiting, lethargy, and, sometimes, coma. Not only are blood levels of glucose low (hypoglycemia), but also starvation-induced ketosis is absent. Provide a biochemical explanation for the last two observations.

Short answer

Deficient acyl CoA dehydrogenase limits fatty acid oxidation, leading to hypoglycemia and absence of ketosis due to impaired acetyl-CoA production.

Step-by-step solution

Understanding the Role of Acyl CoA Dehydrogenase

Acyl CoA dehydrogenases are enzymes that catalyze the initial step in the beta-oxidation of fatty acids. This process takes place in the mitochondria where fatty acids are broken down to acetyl-CoA, which can then enter the citric acid cycle to produce energy.

Impact on Energy Production

When acyl CoA dehydrogenase is deficient, the breakdown of fatty acids is impaired. As a result, there is decreased production of acetyl-CoA. This reduced production means less acetyl-CoA is available to generate energy in the citric acid cycle, especially during periods of fasting when the body relies on stored fat for energy.

Reason for Hypoglycemia

In individuals with this deficiency, the inability to effectively oxidize fatty acids reduces the energy supply during fasting, leading the body to consume more glucose for energy. Consequently, blood glucose levels drop (hypoglycemia) as the body tries to compensate for the lack of energy derived from fats.

Absence of Ketosis Explained

Ketosis occurs when acetyl-CoA is converted into ketone bodies in the liver, which happens during prolonged fasting or low carbohydrate intake. Due to the deficiency in acyl CoA dehydrogenase, there's a limited supply of acetyl-CoA, hampering the production of ketone bodies. Thus, even during fasting, ketosis does not occur.

Key concepts

Beta-Oxidation of Fatty Acids

Beta-oxidation is a vital metabolic process where fatty acids are broken down to generate energy. This occurs in the mitochondria, the powerhouse of the cell. Here, enzymes like acyl CoA dehydrogenase play a crucial role. It initiates the breakdown of fatty acids by removing electrons and transferring them to the electron transport chain, where they help produce ATP.
In cases where there's an acyl CoA dehydrogenase deficiency, this breakdown process is impaired. Without effective beta-oxidation, fatty acids accumulate and can't be used for energy, particularly during fasting periods when the body should rely on fat stores. This disruption not only affects energy production but also has downstream effects on other metabolic processes.

Citric Acid Cycle

The citric acid cycle, also known as the Krebs cycle, is a key energy-producing process that takes place in the mitochondria. Acetyl-CoA, a product of beta-oxidation, enters this cycle. Enzymes then transform acetyl-CoA through a series of reactions that release stored energy.
This energy is used to form ATP, the cell’s primary energy currency. ATP fuels various cellular activities, keeping organisms alive and functioning.
When acyl CoA dehydrogenase deficiency interrupts beta-oxidation, the production of acetyl-CoA falls short. With less acetyl-CoA entering the citric acid cycle, energy production declines. During fasting, this lack of energy becomes even more critical as glucose stores deplete, and the body struggles to compensate.

Hypoglycemia

Hypoglycemia refers to abnormally low blood glucose levels. In metabolic terms, it's often a result of impaired fatty acid oxidation. With acyl CoA dehydrogenase deficiency, fatty acids aren't being adequately broken down, leaving the body low on energy.
Instead of gaining energy from fats, the body must rely on glucose. However, during fasting or prolonged periods without food, glucose stores are quickly used up, leading to hypoglycemia.
Symptoms of hypoglycemia may include shakiness, confusion, and if severe, even coma. Understanding the connection between fatty acid oxidation and glucose levels is crucial for managing and diagnosing conditions like acyl CoA dehydrogenase deficiency.

Ketosis

Ketosis is a metabolic state where the body uses ketone bodies for energy, usually when glucose is scarce. This is common during fasting or low-carbohydrate diets. Ketone bodies are derived from acetyl-CoA, made during beta-oxidation of fatty acids.
In cases of acyl CoA dehydrogenase deficiency, the production of acetyl-CoA is reduced. This reduction inhibits the formation of ketone bodies, preventing ketosis despite fasting.
The absence of ketosis in such individuals indicates a disruption in fatty acid metabolism. While ketosis is a normal response to energy deficit from carbohydrates, the inability to enter ketosis during acyl CoA dehydrogenase deficiency signifies a deeper metabolic challenge.

Energy Metabolism

Energy metabolism encompasses the chemical reactions that convert foodstuffs into energy, primarily in the form of ATP. This involves various processes such as glycolysis, the citric acid cycle, and oxidative phosphorylation.
In a healthy state, the body efficiently cycles through these processes, drawing on different energy sources like glucose and fatty acids. A deficiency of acyl CoA dehydrogenase disrupts this balance, especially when fatty acids can't be oxidized.
Instead of smoothly transitioning to fat-derived energy, the body struggles, impacting metabolism overall. For students, understanding these dynamics is essential in grasping how enzyme deficiencies can lead to symptoms like hypoglycemia and a lack of ketosis.