HMP Shunt Pathway

Introduction

The HMP shunt pathway, also known as the pentose phosphate pathway, is a metabolic alternative to glycolysis that works alongside it in some cells. Instead of focusing solely on energy production, the HMP shunt prioritizes producing two key things: building blocks for nucleic acids (RNA and DNA) and a special molecule called NADPH. NADPH is a powerful antioxidant that helps protect cells from damage and is crucial for fatty acid synthesis. Red blood cells and the liver rely heavily on the HMP shunt for these essential functions. In this article we will see HMP pathway and its significance.

Table of Contents

Pathway

The HMP shunt, or pentose phosphate pathway, operates in the cytoplasm of various cells, particularly red blood cells and the liver. It functions alongside glycolysis but has a different focus. Here’s a breakdown of the pathway.

The Oxidative Phase

Glucose-6-Phosphate Dehydrogenase (G6PD): This enzyme is the rate-limiting step of the pathway. It takes glucose-6-phosphate (G6P), a product of glucose breakdown, and removes a phosphate group while transferring two electrons to NADP+, converting it to NADPH. This reaction also generates a molecule called 6-phosphoglucono-δ-lactone.
6-Phosphogluconolactonase: This enzyme hydrolyzes the lactone ring in 6-phosphoglucono-δ-lactone, converting it to 6-phosphogluconate (6PG).
6-Phosphogluconate Dehydrogenase: This enzyme removes another phosphate group from 6PG and transfers two electrons to NADP+, again generating NADPH. This reaction also produces ribulose-5-phosphate (Ru5P).

The Non-Oxidative Phase

This phase uses the Ru5P generated in the oxidative phase to produce various intermediates used for different purposes.

Pentose Phosphate Isomerase: This enzyme can convert Ru5P into other pentose sugars like ribose-5-phosphate, a crucial building block for RNA and DNA synthesis.
Transketolase and Transaldolase: These enzymes work together to rearrange the carbon skeletons of the pentose sugars, allowing the pathway to generate intermediates for glycolysis (e.g., glyceraldehyde-3-phosphate) or regeneration of G6P for the cycle to continue.

Significance

NADPH Production: The HMP shunt is a significant source of NADPH, which plays a vital role in:
- Antioxidant defense: NADPH helps regenerate glutathione, a key antioxidant that protects cells from free radical damage.
- Fatty acid synthesis: NADPH is required for the synthesis of fatty acids, essential for energy storage and cell membrane structure.
Pentose Sugar Production: The pathway provides ribose-5-phosphate for the synthesis of nucleotides (RNA and DNA), crucial for cell function and growth.
Regulation of Glycolysis: The HMP shunt can be regulated based on cellular needs. When NADPH or pentose sugars are abundant, the pathway slows down. Conversely, when these molecules are in high demand, the pathway is activated.

Additionally, Defects in enzymes of the HMP shunt can lead to various health problems, such as favism (a severe reaction to fava beans) and haemolytic anaemia (destruction of red blood cells).

Glucose-6-Phosphate dehydrogenase (G6PD) deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder affecting red blood cells. People with G6PD deficiency lack enough of the G6PD enzyme, which plays a crucial role in protecting red blood cells from oxidative stress. This deficiency can lead to a condition called hemolytic anemia when triggered by certain factors.

Here’s a breakdown of G6PD deficiency:

The G6PD Enzyme

Located in red blood cells, G6PD is the first enzyme in the pentose phosphate pathway (HMP shunt).
This pathway helps generate NADPH, a molecule essential for protecting red blood cells from damage caused by free radicals (unstable molecules).
G6PD also participates in the production of ribose-5-phosphate, a building block for RNA and DNA synthesis.

The Problem with G6PD Deficiency

In individuals with G6PD deficiency, the lack of sufficient G6PD enzyme leads to a decreased production of NADPH.
This decrease weakens the red blood cells’ defense system against oxidative stress, making them more susceptible to damage and premature destruction.

Triggers of Hemolytic Anemia

Certain factors can trigger a rapid breakdown of red blood cells in individuals with G6PD deficiency, leading to a condition called hemolytic anemia. These triggers include:
- Fava beans: Consuming fava beans (also called broad beans) is a common trigger for hemolytic episodes. A substance in fava beans, vicine, can increase oxidative stress within red blood cells.
- Infections: Bacterial or viral infections can increase the production of free radicals, overwhelming the weakened defense system of red blood cells with G6PD deficiency.
- Certain medications: Some medications, like antibiotics and antimalarial drugs, can generate oxidative stress and trigger hemolysis in individuals with G6PD deficiency.
- Oxidative stress from other sources: Exposure to certain chemicals or environmental toxins can also increase oxidative stress and trigger hemolysis.

Symptoms of Hemolytic Anemia

Fatigue and weakness
Pale skin, jaundice (yellowing of the skin and whites of the eyes)
Dark urine
Shortness of breath
Rapid heartbeat
Abdominal pain
Severity of G6PD Deficiency:

The severity of G6PD deficiency varies significantly among individuals. Some people may not experience any symptoms unless exposed to a trigger, while others may have chronic anaemia.

Diagnosis

G6PD deficiency can be diagnosed through a simple blood test that measures the activity of the G6PD enzyme.

Management

There is no cure for G6PD deficiency, but it can be effectively managed by avoiding triggers like fava beans and certain medications.
During a haemolytic crisis, supportive care may be needed, including fluids, pain management, and potentially blood transfusions in severe cases.
Genetic counselling can be helpful for individuals and families affected by G6PD deficiency.

Additional Points

G6PD deficiency is the most common enzyme deficiency affecting red blood cells globally.
It is more prevalent in people of African, Mediterranean, Middle Eastern, and Asian descent.
G6PD deficiency can be inherited from one or both parents, depending on the specific genetic mutation.

Summary

The HMP shunt, operating alongside glycolysis, prioritizes building blocks for RNA and DNA synthesis through ribose-5-phosphate production. It also generates NADPH, a crucial antioxidant and player in fatty acid synthesis. This pathway functions mainly in red blood cells and the liver, with two phases: the oxidative phase producing NADPH and an intermediate, and the non-oxidative phase using intermediates for ribose-5-phosphate or potentially feeding back into glycolysis. Deficiencies in HMP shunt enzymes can lead to health problems.