Principles of metabolic regulation for the MCAT

Medistudents Team
May 3, 2023

The principles of metabolic regulation are covered in the Biological and Biochemical Foundations of Living Systems section of the MCAT. To prepare effectively for the exam, it’s essential that you have a clear understanding of the topic and can answer questions related to it. This guide will provide a comprehensive overview of the principles of metabolic regulation as detailed in the MCAT syllabus. This includes a breakdown of the following:

  • Regulation of metabolic pathways
  • Regulation of glycolysis and gluconeogenesis
  • Metabolism of glycogen
  • Regulation of glycogen synthesis and breakdown
  • Analysis of metabolic control

Regulation of metabolic pathways

Metabolic pathways are controlled in various ways, with them all being grouped under the term metabolic regulation. Regulation tends to be seen at the beginning of pathways, rate limiting steps in a pathway (the slowest step in a pathway, that determines the rate of reaction) and irreversible reactions.

There are two ways that pathways can be regulated and positive feedback leads to the amplification of a certain output. If this output then causes further amplification, for example by activating more enzymes, then this process would be classed as a positive feedback loop. You can also have negative feedback which results in a certain output being decreased and again if this is induced by reactants/products of the pathway in question, then a negative feedback loop would be formed.

A requirement for something to be classed as living is for it to be able to perform homeostasis, this is where a dynamic steady state is maintained through the regulation of metabolic pathways. A dynamic steady state is important to keep the internal environment of an organism at a constant level, also known as equilibrium, whereby quantities of all substances remain constant whilst reactions are still taking place.

Regulation of glycolysis and gluconeogenesis

Glycolysis is a metabolic pathway that splits glucose into two pyruvate molecules without the use of oxygen (thus can be seen in both aerobic and anaerobic respiration). The rate limiting enzymes of this pathway are hexokinase, phosphofructokinase and pyruvate kinase. The purpose of glycolysis is to turn glucose into pyruvate so it can enter the TCA (also known as Krebs or citric acid) cycle to eventually generate ATP (energy).

Gluconeogenesis is a metabolic pathway that is almost the reverse of glycolysis as it generates glucose from non-carbohydrate carbon like pyruvate, lactate etc. This process is also anaerobic. The rate limiting enzymes in this process are fructose-1,6-bisphosphatase, PEP carboxylase and pyruvate carboxylase. The purpose of gluconeogenesis is to provide glucose to the body when there is not enough glucose being dietarily consumed.

MCAT: Glycolysis pathway (from glucose to pyruvate)
Figure 1 – Glycolysis pathway (from glucose to pyruvate). Please note that step 1, 3 and 10 are the rate limiting steps.
MCAT: Gluconeogenesis pathway (pyruvate to glucose)
Figure 2 – Gluconeogenesis pathway (pyruvate to glucose). Rate limiting enzymes are fructose-1,6-bisphosphatase, PEP carboxykinase and pyruvate carboxylase.

Glycolysis and gluconeogenesis are controlled by the level of ATP and ADP in the body to determine whether more glucose needs to be broken down in order to supply the body with sufficient energy. When there are high levels of ATP and low levels of ADP there is no need to break down more glucose and therefore you can store it by inhibiting glycolysis and activating gluconeogenesis. When there are high levels of ADP and low levels of ATP, glucose needs to be broken down to obtain more ATP and thus glycolysis is activated and gluconeogenesis is inhibited.

There are many molecules that are used to regulate the levels of glycolysis and gluconeogenesis in the body. Glucagon decreases glycolysis and increases gluconeogenesis, overall increasing blood sugar levels. Insulin, however, causes an increase in glycolysis and a decrease in glucagon thus a decrease in blood sugar levels. Epinephrine elevates in periods of stress (where the fight or flight response is activated) and causes an increase in muscle glycolysis as well as an increase in gluconeogenesis, overall increasing blood sugar levels. Fructose-2,6-bisphosphate activates glycolysis and inhibits gluconeogenesis, overall promoting the breakdown of glucose.

Metabolism of glycogen

Glycogen can be broken down with glucose-6-phosphate which can then feed into glycolysis, the pentose phosphate pathway or convert to glucose using glucose-6-phosphatase.

  1. Glycogen breaks down into glucose-1-phosphate using the enzyme glycogen phosphorylase
  2. Glucose-1-phosphate is then turned into glucose-6-phosphate using the enzyme phosphoglucomutase
  3. Glucose-6-phosphate can then be used in the various pathways mentioned above

Regulation of glycogen synthesis and breakdown

Glycogen metabolism can be regulated either hormonally or allosterically. For example, epinephrine and glucagon are hormones that can promote glycogen breakdown. Hormones can also create a cAMP cascade which would lead to allosteric effects.

Cyclic AMP (cAMP) activates protein kinase A which promotes glycogen breakdown and inhibits glycogen synthesis by triggering a series of phosphorylations. Low levels of cAMP activate phosphorylases, activating glycogen synthase (needed in glycogen synthesis) and inhibiting glycogen phosphorylase (needed in glycogen breakdown).

Analysis of metabolic control

In order to find out what type of regulation a specific pathway is under you need to identify the steps of that pathway that control it. You can do this by altering different variables of the certain pathway and then recording any differences that are seen. You can quantify these differences into measurements (depending on what variable you have changed) and it allows you to generate specific mathematical models. Some examples of variables that can be changed include the abundance of metabolite or the concentration/activity of enzymes.

Hopefully this has provided you with a good understanding of the principles of metabolic regulation for the MCAT. If you’re looking for more useful revision tools, we cover a wide range of MCAT topics in our blogs, including the metabolism of fatty acids and proteins.


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