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  • Writer's pictureDr Edin Hamzić

Part 1: Shortly About The G6PD Gene

Updated: May 13, 2023

This is the first blog post in the series of posts focused on the G6PD gene and G6PD deficiency. In this blog post, I would like to describe the G6PD gene and its role shortly. This blog post is followed by four other posts, each covering specific G6PD-related topics.

What does the G6PD gene do? What does the G6PD gene encode?

The G6PD gene is located on the X chromosome's long arm, roughly 16.183 MB long. The G6PD gene is a housekeeping gene [citation] present in every cell and serves as protection from oxidative stress more about this in the rest of the post. The G6PD gene encodes an enzyme called the glucose-6-phosphate 1-dehydrogenase (G6PD).

When increased oxidative stress is present in cells, the activity of G6PD arises, increases, protecting cells from oxidative stress.

What is the G6PD enzyme? What does the G6PD enzyme do?

The glucose-6-phosphate dehydrogenase (G6PD) is one of the critical enzymes in the pentose phosphate pathway, which in essence converts glucose into ribose-5-phosphate.

  • What is Glucose?

    • Glucose is a building block of most carbohydrates and an essential energy source in the body.

  • What is Ribose-5-phosphate (R5P)?

    • Ribose-5-phosphate is a building block of DNA and RNA. The R5P is composed of sugar ribose and a phosphate group.

  • What is the pentose phosphate pathway?

    • The pentose phosphate pathway is a biochemical process that generates NADPH and pentoses (5-carbon sugars). For most organisms, the pentose phosphate pathway happens in the cytosol. There are two main steps in the pentose phosphate pathway. In the first step, NADPH is generated, which is considered an oxidative step, and the second step is the non-oxidative in which the synthesis of 5-carbon sugars happens.

Nicotinamide adenine dinucleotide phosphate (NADPH) is the essential product of the pentose phosphate pathway and, more specifically, this is the reaction that is catalyzed by G6PD.

The NADPH is produced from nicotinamide adenine dinucleotide (NADP+) in the following reaction:

Figure 1: The pentose phosphate pathway reaction catalyzed by the G6PD enzyme

The above figure illustrates the reaction where G6PD acts as an enzyme which is the first reaction in the pentose phosphate pathway where glucose (in the form of phosphorylated glucose) gets converted into gluconolactone (an intermediate product of the pentose phosphate pathway) by G6PD.

During this process, NADPH is produced from its oxidized version NADP+. Production of NADPH, or the conversion of NADP+ into NADPH, is vital as NADPH is used as a reducing agent protecting cells from oxidative stress.

What are the functions of NADPH?

In most cells of the human body, NADPH is the key electron donor required for many biosynthetic processes, including several reactions in the pathways of fatty acid synthesis, cholesterol, and steroid hormone synthesis, as well as in the formation from ribose of deoxyribose required for DNA synthesis [citation], but also in erythrocyte synthesis, oxidative stress, positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel, negative regulation of cell growth involved in cardiac muscle cell development, negative regulation of protein glutathionylation, etc. [citation].

Generally, the primary source of NADPH in animals and other non-photosynthetic organisms is the pentose phosphate pathway produced by glucose-6-phosphate dehydrogenase (G6PDH), as illustrated in the above figure.

As mentioned, NADPH protects cells from potentially harmful molecules (products of normal cell function) and essential components for red blood cells (RBC) since the pentose phosphate pathway is the only source of NADPH in RBC [citation].

The G6PD, besides the central role of conversion of glucose to ribose phosphate, is also involved in the following:

  • Production of fatty acid

  • Production of cholesterol and steroid hormones

  • Production of deoxyribose from ribose that is necessary for DNA synthesis.

Why is the G6PD enzyme important?

The biology of G6PD has been a model system in biochemical genetics and understanding how the red cell responds to oxidative attack. Serving for many studies related to X-chromosome inactivation and enzymopathies [citation].

Cells can function normally even without the G6PD enzyme, as other factors produce NADPH in a cell. However, the situation is different in red blood cells (RBCs), which lack mitochondria and have no other NADPH-generating enzymes to protect them against oxidative stress [citation]. Therefore, deficiency of G6PD directly affects the integrity of red blood cells (RBCs) as they are not protected from oxidative stress that leads to premature breakdown and acute hemolysis [citation] [citation].

In the case of G6PD deficiency, the NADPH produced is sufficient for the normal functioning of red blood cells. Still, the problem arises due to the reduction of its lifespan, which cannot increase the additional production of NADPH. The consequence can result in damage to hemoglobin so that red blood cells can be caught by macrophages or may succumb to hemolysis [citation].

What happens when the G6PD gene is mutated?

Mutations in the G6PD gene cause G6PD deficiency, which occurs in around 400 million people worldwide (11% African males) [citation], [citation].

Nearly all people with this trait have no disease, no signs or symptoms, unless and until they are exposed to an agent that triggers acute hemolytic anemia, which may be severe and even life-threatening [citation].

If you are interested in the G6PD gene mutations, please check my second blog post Part 2: The G6PD Gene Mutations & G6PD Deficiency which covers topics on G6PD gene mutations.


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