Question

Mutant Acetyl-CoA Carboxylase What would be the consequences for fat metabolism of a mutation in acetyl-CoA carboxylase that replaced the Ser residue normally phosphorylated by AMPK with an Ala residue? What might happen if the same Ser were replaced by Asp?

Short answer

Ala mutation leads to continuous fat synthesis, while Asp mutation prevents fat synthesis.

Step-by-step solution

Understanding Acetyl-CoA Carboxylase

Acetyl-CoA carboxylase (ACC) is an enzyme crucial in fat metabolism. Its primary role is to catalyze the carboxylation of acetyl-CoA to malonyl-CoA, which is the first step in fatty acid synthesis. The activity of ACC is regulated by phosphorylation. When phosphorylated by AMP-activated protein kinase (AMPK), ACC becomes inactive, which decreases fat synthesis.

Effect of Serine to Alanine Mutation

Replacing the serine (Ser) residue with alanine (Ala) prevents the phosphorylation on that site. Since AMPK can no longer phosphorylate this site, ACC will remain in its active form, leading to continuous fat synthesis regardless of the energy status of the cell.

Implication of Continuous ACC Activity

With ACC constantly active, cells may synthesize excess fatty acids even when energy is low, potentially leading to metabolic imbalances such as increased fat storage in cells and tissues, contributing to obesity-related issues.

Effect of Serine to Aspartic Acid Mutation

Replacing the serine with aspartic acid (Asp) is often intended to mimic the negative charge that comes with phosphorylation. In this case, the ACC could become constantly inactive, as if it were always phosphorylated, suppressing fat synthesis even when it is required.

Consequences of Constant Inactivation

The inability to activate ACC (due to the constant inactive form) could result in insufficient fatty acid synthesis, impacting energy storage, membrane synthesis, and overall energy homeostasis, which can be detrimental to cellular function.

Key concepts

Fat Metabolism

Fat metabolism is an essential process that allows your body to efficiently convert food into energy and store excess energy as fat. It involves several steps and enzymes working in harmony. Acetyl-CoA Carboxylase (ACC) plays a pivotal role in this process by catalyzing the conversion of acetyl-CoA to malonyl-CoA—with malonyl-CoA being the building block for synthesizing fatty acids. This step is crucial because it determines whether energy will be stored as fat or used for other purposes.
In the context of fat metabolism:

• ACC activity is essential for starting fatty acid synthesis.
• Fatty acids are either stored as fat or used as energy sources.
• Proper regulation of ACC ensures balance between energy storage and expenditure.

This balance is vital for maintaining a healthy body weight and preventing metabolic disturbances such as obesity or fatty liver disease.

Enzyme Regulation

Enzyme regulation refers to the various mechanisms that control the activity of enzymes like Acetyl-CoA Carboxylase (ACC). These mechanisms ensure that enzymes function optimally and are activated or deactivated when necessary. The regulation of ACC is particularly important in fat metabolism as it needs to be turned on or off according to the cell's energy needs.
To regulate ACC, some of the following factors come into play:

• Phosphorylation and dephosphorylation events.
• Allosteric regulation by metabolites such as citrate or fatty acids.
• Hormonal controls, including insulin and glucagon.

When enzyme regulation is disrupted, either by mutation or other factors, it can lead to metabolic imbalance, affecting processes like fat synthesis and energy production.

Phosphorylation

Phosphorylation is a key regulatory mechanism for many enzymes, including Acetyl-CoA Carboxylase (ACC). It involves the addition of a phosphate group to an enzyme, often resulting in a change in enzyme activity. In the case of ACC, phosphorylation typically leads to its inactivation, reducing fat synthesis when energy is scarce.
Here's how phosphorylation affects ACC:

• AMP-Activated Protein Kinase (AMPK) phosphorylates ACC, which inactivates it.
• Inactivation of ACC reduces fatty acid production, conserving energy.
• This is particularly important when the body's energy supply is low, such as during fasting or intense exercise.

Phosphorylation thus acts like a molecular switch, enabling cells to modulate metabolic pathways in response to changing energy needs.

AMP-Activated Protein Kinase

AMP-Activated Protein Kinase (AMPK) is a vital enzyme that serves as an energy sensor in cells, helping to maintain energy balance. When activated, AMPK triggers a cascade of events that help conserve energy, including the phosphorylation of enzymes like Acetyl-CoA Carboxylase (ACC).
Here's how AMPK functions:

• AMPK is activated when cellular energy levels are low, indicated by high AMP:ATP ratios.
• Upon activation, AMPK phosphorylates ACC, causing its inactivation.
• This reduces fat and cholesterol synthesis, directing energy towards essential processes.

Through its action, AMPK plays a critical role in controlling metabolism, promoting energy efficiency, and protecting against energy deficits in cells.