Question

Medium-chain acyl-CoA dehydrogenase deficiency \((\mathrm{MCAD}),\) a defect in \(\beta\) -oxidation, usually produces symptoms within the first 2 years of life after a period of fasting. Typical symptoms include vomiting, lethargy, and hypoketotic hypoglycemia. Excessive urinary secretion of medium-chain dicarboxylic acids and medium-chain esters of glycine and carnitine help to establish the diagnosis. \(\beta\) -Oxidation of fatty acids A. generares ATP only if acetyl CoA is subsequently oxidized. B. is usually suppressed during starvation. C. uses only even-chain, saturated fatty acids as substrates. D. uses NADP \(^{+}\) E. occurs by a repeated sequence of four reactions.

Short answer

A) Generates ATP only if acetyl CoA is subsequently oxidized B) Is usually suppressed during starvation C) Uses only even-chain, saturated fatty acids as substrates D) Uses NADP+ E) Occurs by a repeated sequence of four reactions. Answer: B) Is usually suppressed during starvation (This statement about β-oxidation is false because β-oxidation increases during starvation to generate ATP from stored fats).

Step-by-step solution

Option A: Generates ATP only if acetyl CoA is subsequently oxidized

β-oxidation of fatty acids generates acetyl-CoA, which enters the citric acid cycle. The citric acid cycle produces ATP, NADH, and FADH2. NADH and FADH2 are later used in the electron transport chain to generate more ATP. Therefore, ATP production requires acetyl-CoA oxidation. Option A is true.

Option B: Is usually suppressed during starvation

During starvation, the body needs to produce energy, and it does this by breaking down stored fats through β-oxidation to generate ATP. Therefore, β-oxidation increases during starvation, not suppressed. Option B is false.

Option C: Uses only even-chain, saturated fatty acids as substrates

While it is true that β-oxidation primarily utilizes even-chain, saturated fatty acids, other fatty acids can serve as substrates as well, albeit with variations in the oxidation process. For example, odd-chain fatty acids produce propionyl-CoA, and unsaturated fatty acids require additional enzymes. Option C is not entirely true.

Option D: Uses NADP+

β-oxidation uses NAD+ as a cofactor to accept electrons during the oxidation reaction, not NADP+. Therefore, option D is false.

Option E: Occurs by a repeated sequence of four reactions

β-oxidation involves four sequential reactions: dehydrogenation, hydration, a second dehydrogenation, and thiolysis. These steps are repeated until the fatty acid is converted into multiple acetyl-CoA molecules. Option E is true. The correct answer is B: β-oxidation is usually suppressed during starvation. This statement is false because β-oxidation actually increases during starvation to generate ATP from stored fats.

Key concepts

Beta-oxidation of Fatty Acids

Understanding the beta-oxidation of fatty acids is key to grasping how our bodies utilize fat for energy. In simple terms, beta-oxidation is a metabolic process that involves breaking down fatty acids into smaller molecules called acetyl-CoA, which then enter the Krebs cycle, also known as the citric acid cycle, to produce energy.

During beta-oxidation, each fatty acid undergoes a cycle of four reactions: first, a dehydrogenation that forms a double bond; second, water is added across this double bond; next, another dehydrogenation occurs to form a keto group; and finally, the fatty acid is cleaved by a molecule of coenzyme A to release acetyl-CoA and a fatty acid that is two carbons shorter.

This shortened fatty acid undergoes the same four-step cycle repeatedly until the entire chain is converted into units of acetyl-CoA. These reactions depend on enzymes that are designed to process these fats. It's like unpacking a long train where each carriage is separated and sent off to be used for energy.

Importantly, beta-oxidation primarily uses even-chain, saturated fatty acids. However, contrary to what some might think, it is not limited to these. The body indeed has mechanisms to oxidize odd-chain and unsaturated fatty acids, although these processes are slightly different due to their unique structures.

An error in any step of this metabolism, such as seen with MCAD deficiency, impedes the body's ability to break down fatty acids, which can cause serious health issues including energy deficits and accumulation of partially oxidized fatty acids.

Hypoketotic Hypoglycemia

When it comes to managing energy, the human body is a bit like a hybrid car that can switch fuel sources. Typically, glucose is the body's preferred energy source. However, during times of fasting or starvation, the body starts to rely more on fat breakdown, a process that not only generates ATP or energy but also produces ketone bodies—a sort of alternative fuel.

Hypoketotic hypoglycemia refers to a low blood sugar condition (hypoglycemia) with lower-than-normal levels of ketones. Normally, if you run out of glucose (like after not eating for an extended period), you'd expect to see high levels of ketones since your body would be breaking down fats instead. But in hypoketotic hypoglycemia, this isn't the case.

This can happen in metabolic conditions like MCAD deficiency, where the body cannot efficiently break down fatty acids due to a lack of specific enzymes. This leads to an energy production crisis: glucose is low since it's not being replenished through eating, and ketone production is low since fat breakdown is impaired. The result is a double whammy of energy shortage and low blood sugar levels; it's like running out of gas with no backup battery charge. For children with MCAD deficiency, this situation can lead to serious symptoms such as vomiting and lethargy.

Medium-chain Dicarboxylic Acids

Medium-chain dicarboxylic acids might not be everyday terms, but they play a significant role in understanding metabolic disorders. These acids are typically byproducts of incomplete fatty acid oxidation in the mitochondria. When beta-oxidation functions correctly, fatty acids are fully broken down into acetyl-CoA. However, in conditions like MCAD deficiency, the fatty acids aren't properly processed, leading to an accumulation of medium-chain dicarboxylic acids.

The 'medium-chain' refers to the length of the carbon chain within the compound—the 'middle-sized' fatty acids, you could say. 'Dicarboxylic' indicates that there are two carboxyl groups (COOH) in the molecule—one at each end. Because these compounds are not usually present in high levels, their excessive urinary excretion can be a red flag for metabolic disorders.

In the context of MCAD deficiency, these medium-chain dicarboxylic acids, along with esters of glycine and carnitine, become alternative products that the body tries to get rid of through urine. Testing for the presence of these unusual compounds can help diagnose MCAD deficiency early, allowing for prompt management to prevent serious complications.