Trait: Cardiovascular Health (GLUL)
Dr Haran Sivapalan
May 18, 2020
What is glutamic acid?
Glutamic acid is a non-essential amino acid that is important for making various proteins, regulating metabolic processes and sending nerve signals in the brain.
The term “non-essential amino acid” warrants further explanation.
“Amino acids” are the building blocks of proteins. Glutamic acid, along with glutamine, proline, histidine, arginine and ornithine, belongs to a family of related amino acids known as the glutamate amino acids.
The term ‘non-essential’ means that our body can synthesize glutamic acid itself. Glutamic acid is also abundant in foodstuffs, either as a free amino acid, or as part of larger protein chains. Both plant and animal proteins are rich in glutamic acid, with meat, fish, eggs, dairy products, and protein-rich legumes (e.g. beans and lentils) being good sources.
While the body can make enough glutamic acid to meet our needs in most situations, major trauma, sepsis, chemotherapy and radiotherapy can all deplete glutamic acid, meaning that supplementation is required. In this respect, it may be more accurate to classify glutamic acid as a “conditionally essential” amino acid.
In the body, glutamic acid quickly donates a H+ ion to form glutamate. Consequently, we often use the terms glutamic acid and glutamate interchangeably.
- Glutamic acid is a non-essential amino acid found in plant and animal protein.
- Glutamic acid plays a role in several metabolic reactions and is needed for making proteins and brain function.
- Glutamic acid forms glutamate in the body. The terms 'glutamate' and 'glutamic acid' are often used interchangeably.
- Our body normally produces enough glutamic acid to meet our needs, but some conditions (e.g. illness, trauma) mean that supplementation is required.
Why is glutamic acid (glutamate) important?
Glutamic acid plays a number of roles in the body, including: the manufacture of proteins, the production of neurotransmitters, making the antioxidant glutathione, and being used as an energy source.
Glutamic acid is widely used to build larger protein chains. In many instances, glutamic acid is often converted into other amino acids before being made into larger proteins. For example, glutamic acid is easily converted into proline, which is used significantly in proteins such as collagen.
Neurotransmitters are chemical messengers used to convey a signal from one nerve (or ‘neuron’) to another. In the body, glutamic acid quickly becomes a closely related molecule called glutamate. (For this reason, the terms “glutamic acid” and “glutamate” are often used interchangeably.)
Glutamate is an important excitatory neurotransmitter in the brain. This means it stimulates neurons, making them more likely to fire nerve signals. It also plays a role in the growth and development of synapses – the connections between neurons. Accordingly, glutamate is very important for learning and memory.
Glutamic acid is also made into another neurotransmitter called GABA (gamma-aminobutyric acid). Unlike glutamate, GABA is an inhibitory neurotransmitter – it reduces the likelihood of a neuron firing a signal. GABA plays a role in the control of movement, sleep and mood.
Glutamic acid (or glutamate) is involved in several important metabolic reactions in the body. For example, glutamate plays a key role in a series of reactions called the γ-glutamyl cycle. This cycle is responsible for the production and recycling of glutathione.
Glutathione (GSH) is an important antioxidant that neutralises harmful free radical and reactive oxygen species (ROS) substances and prevents against oxidative stress. For more on oxidative stress, please refer to the GPx-1 and oxidative stress, and SOD2 and oxidative stress blogs.
Glutamate can also be used as an energy source, particularly by skeletal muscles and the gut. It can be converted into a molecule called alpha-ketoglutarate, which can then enter a stage of aerobic respiration known as the citric acid (TCA or Kreb’s) cycle. This process leads to the generation of ATP – the chemical energy currency used by cells to power various functions.
Through a process known as gluconeogenesis, glutamate can also be converted into glucose, which is our cells’ main energy source.
- Glutamic acid (glutamate) is used to build proteins
- Glutamic acids is used to make two key neurotransmitters in the brain: glutamate and GABA.
- Glutamic acid (glutamate) is involved in several metabolic reactions, including: the production of the antioxidant glutathione, aerobic respiration and production of glucose.
What is glutamine?
Glutamine is another amino acid in the glutamate family of amino acids. It is the most abundant amino acid in the human body, with the liver and skeletal muscles having a particularly high concentration of glutamine.
Our body can make glutamine itself, by converting it from glutamic acid (or glutamate). This reaction is catalysed by an enzyme called glutamine synthetase (GS).
Although our body can usually make enough glutamine to meet our needs, certain catabolic states (e.g. disease, sepsis, major trauma, chemotherapy) mean that glutamine supplementation is required. In this respect, glutamine, like glutamic acid, is considered to be a conditionally essential amino acid.
- Glutamine is the most abundant amino acid in the body.
- Glutamine is used in various metabolic reactions.
- Glutamine is a conditionally essential amino acid - we normally make enough of it to meet our needs, but in some cases (e.g. illness) we may require supplementation.
Why is glutamine important?
Glutamine plays several important roles in the body, both on its own and via its conversion to glutamic acid (glutamate).
As an amino acid, glutamine is incorporated into larger protein chains. Glutamine also stimulates protein synthesis by activating a signalling pathway known as the mTOR pathway. To read more about this pathway, please consult the Protein synthesis and hypertrophy (mTOR) blog.
For cells and enzymes to function properly, the pH (a measure of acidity/alkalinity) of our blood and tissue fluid has to be kept within a strict range.
We call this our body’s acid-base balance. The way our body regulates pH is complicated, but partly involves the movement of acids and bases (alkaline substances) by our kidneys. One of these bases is ammonia (NH3), which acts to neutralise or “buffer” acids and prevent our blood from becoming too acidic.
Ammonia is generated from ammonium (NH4), which in turn is made from glutamine. By creating ammonium, glutamine helps to maintain a healthy acid-base balance and keep our blood pH within normal range.
As with glutamic acid (glutamate), glutamine is involved in many metabolic reactions within cells. For example, glutamine is used to make molecules called purines. Purines include the nucleotide bases adenine (A)and guanine (G), which are important components of our DNA.
Glutamine (GLN) can also be converted in glutamic acid (glutamate). This reaction is catalysed by the enzyme glutaminase. By providing a supply of glutamate (GLU), glutamine is also indirectly involved in many metabolic reactions, such as the production of glutathione and the generation of energy in the citric acid cycle (both explained earlier).
Protection against oxidative stress
Oxidative stress refers to the damaging process whereby free radicals and reactive oxygen species (ROS) accumulate and cause damage to cells. You can read more about oxidative stress in the GPx-1 and oxidative stress, and SOD2 and oxidative stress blogs.
Glutamine is important in protecting cells against damage from oxidative stress. We’ve already mentioned that glutamic acid (glutamate), which can be formed from glutamine, is used in the production of glutathione – an important antioxidant.
Glutamine also stimulates the production of specialized proteins called heatshock proteins. These proteins are produced by cells in response to various stressors in the environment, such as heat, infection and oxidative stress. Heatshock proteins act as "molecular chaperones” – they protect, transport and assist with the refolding of damaged proteins.
By stimulating the manufacture of heatshock proteins, glutamine may help to prevent and repair damage caused by oxidative stress.
Oxidative stress can damage cells lining our arteries and other blood vessels (known as endothelial cells). This damage prevents endothelial cells from functioning properly - a phenomenon termed "vascular endothelial dysfunction." In turn, vascular endothelial dysfunction is implicated in the development of cardiovascular diseases, such as heart attack, stroke and atherosclerosis (the narrowing of arteries caused by the build up of fatty plaques).
Glutamine plays a role in various signalling pathways by which cells communicate with each other and coordinate key functions. On this note, glutamine is involved in the secretion of insulin.
As we learned in the Insulin and your blood glucose levels blog, insulin is a hormone that allows glucose to be taken up from the bloodstream into cells. Glutamine is therefore important for the control of blood sugar levels.
- Glutamine is important for building proteins, making DNA, regulating our body's acid-base balance, participating in metabolic reactions and control of blood sugar levels.
- Glutamine plays a crucial role in protecting cells from oxidative stress.
- Oxidative stress can negatively affect the health of our cardiovascular system.
How is glutamic acid (glutamate) converted into glutamine?
Glutamic acid (glutamate) is combined with ammonia (NH3) to form glutamine.
This reaction is catalysed by the glutamine synthetase (GS) enzyme. The GS enzyme is encoded by your GLUL gene.
As we’ll explain in the next section, variants of your GLUL gene affect how much GS enzyme you produce (express). This influences how effectively your cells make glutamine and (as it can be derived from glutamine by hydrolysis) glutamate.
- Glutamine is made from glutamic acid (glutamate) by the glutamine synthetase (GS) enzyme.
- The glutamine synthetase enzyme is encoded by the GLUL gene.
- Variants of the GLUL gene affect the expression and activity of the GS enzyme.
How do GLUL gene variants affect cardiovascular health?
Different GLUL gene variants
A SNP (Single Nucleotide Polymorphism) near the GLUL gene causes a change in the DNA sequence from the letter ‘C’ to the letter ‘T’.
This SNP (given the code rs10911021) therefore creates two gene variants or alleles – the ‘C’ allele and the ‘T’ allele.
Studies suggest that the ‘C’ allele of the GLUL gene is associated with decreased expression (i.e. production) of the glutamine synthetase (GS) enzyme.
People carrying two copies of the ‘C’ allele (i.e. having the CC genotype) were shown to have 32% reduced expression of the GS enzyme. Similarly, people with one copy of the ‘C’ allele (i.e. the CT genotype) demonstrated 19% reduced expression.
By contrast, people with two copies of the ‘T’ allele (i.e. the TT genotype) had normal GS expression and enzyme activity.
These alterations in GS activity are likely to affect the production and metabolism of glutamine and glutamate, which can have further effects on our health.
GLUL variants and cardiovascular health
Some GLUL gene variants have also been linked to an increased risk of cardiovascular health problems, such as coronary artery disease, heart attack and stroke. Importantly, this link was only found in subjects with Type 2 diabetes.
For example, a large analysis of subjects from the Nurses Health Study and other studies found that diabetic subjects who carried the ‘C’ allele of the GLUL gene were more likely to have coronary heart disease. No association, however, was found between GLUL gene variants and heart disease in people without Type II diabetes.
It’s not clear how exactly GLUL gene variants affect the risk of cardiovascular disease. It is possible that, by interrupting the production of glutamine and glutamate, the risk ‘C’ allele makes people more susceptible to oxidative stress, particularly the oxidative stress caused by high blood sugar levels (as seen in Type II diabetes).
On this note, a study of Pakistani patients with coronary heart disease and Type II diabetes found that the ‘C’ allele was significantly associated with markers of oxidative stress and damage to arterial lining (vascular endothelial dysfunction).
- A SNP (rs10911021) creates two variants (alleles) of the GLUL gene - 'T' and 'C'.
- The 'C' allele is associated with reduced GS enzyme activity.
- Reduced GS enzyme activity can impair the production and metabolism of glutamine and glutamate.
- The 'C' allele is associated with an increased risk of cardiovascular disease in people who have Type II diabetes.
- By affecting glutamine and glutamate metabolism, the 'C' allele may make people more susceptible to oxidative stress caused by poorly controlled blood sugar levels.