The Biological Importance of Magnesium ions

By V. Sai Kalyani

Bioinorganic Chemistry of Magnesium


Magnesium is an indispensable element that plays a crucial role in various physiological and biochemical processes within living organisms. It is essential for vital cellular functions including intermediary metabolism, DNA replication and repair, RNA transcription and protein translation, as well as potassium and calcium ion transport, cell proliferation, and signal transduction. Magnesium is also involved in chlorophyll synthesis, photoassimilate production, transportation, and utilization, enzyme activation, and protein synthesis. The human body typically contains 21-28 grams of magnesium, which is vital for the proper functioning of all biological processes. Deficiency of magnesium can lead to various health disorders such as cardiovascular diseases, gastrointestinal tract issues, DNA mutations, and diabetes mellitus. In our latest blog article, we delve into the bioinorganic chemistry of magnesium, offering a comprehensive exploration of the role and significance of magnesium ions in biological processes.


Table of contents


  1. Distribution of Magnesium in human body

  2. Biological importance of Magnesium ions

  3. Magnesium in human nutrition

  4. Factors influencing magnesium absorption in the human body

  5. Factors that influence the excretion of magnesium from the human body

  6. Magnesium deficiency in humans

  7. Adverse effects of excess magnesium ions on biological system

  8. FAQs on bioinorganic chemistry of Magnesium

  9. MCQs on bioinorganic chemistry of Magnesium


Distribution of Magnesium in human body


Magnesium, the second most prevalent cation in the intracellular fluid after potassium, holds the position of the fourth most abundant essential element in the human body, following calcium, potassium, and sodium.

Within the human body, around 60-65% of the total 21-28 grams of magnesium is mineralized in bones, while 33-34% is distributed among muscles and soft tissues. A mere 1% of magnesium can be found in blood plasma and erythrocytes.

Among the total concentration, approximately 10% exists in a free form, while the remaining 90% is bound to nucleic acids, ATP, negatively charged phospholipids, and proteins. The highest concentrations of magnesium are observed in microsomes that encompass ribosomes, endoplasmic reticulum, mitochondria, and nuclei.

In the blood, magnesium is partially bound to proteins, with about 1/3 being protein-bound and the remaining 2/3 existing in an ionic state under normal physiological pH conditions.

Notably, concentrations of magnesium in cerebrospinal fluid (CSF) are typically higher than those in magnesium plasma ultrafiltrate due to active transport across the blood-brain barrier.


Biological importance of Magnesium ions


1. Approximately 70% of the total magnesium in the body is found in bones, dental enamel, and dentin.

2. In the realm of plant biology, magnesium ions (Mg2+) hold significant importance in chlorophyll, particularly in the green parts of plants. The overall process of photosynthesis involves the conversion of carbon dioxide and water into carbohydrates and oxygen.

                                                               Chlorophyll

                       nCO2 + nH2O ----------------------→ (CH2O)n + nO2

                                                               light

3. Magnesium serves as an essential cofactor in the synthesis and salvage of purine and pyrimidine nucleotides, which are crucial components of DNA and RNA.

4. Metal-enzyme complexes, specifically those containing Mg2+ ions, serve as catalysts in phosphorylation reactions that play a crucial role in the formation and cleavage of phosphate bonds. These reactions are fundamental for supplying energy to a wide range of biochemical processes.

One notable example is the conversion of ATP to ADP, which is facilitated by the phosphorylase enzyme in the presence of an Mg2+ complex. Mg2+ ions form complexes with ATP and are essential components of phosphotransfer and phosphohydrolase enzymes, which are responsible for reactions involving ATP and the release of energy. (Refer FAQ no-1 of this blog post for additional information)

The conversion of ATP to ADP is an exergonic process (proceeds with the release of energy)

                                                  Kinase enzyme

Adenosine triphosphate +H2O   -------------→    Adenosine diphosphate + HPO42- + H++ 30.543 KJ/mole

The conversion of ADP to ATP is an endergonic process (proceeds with the intake of energy)

                                                                         Kinase enzyme

Adenosine diphosphate + HPO42-+ Energy    ----------------→    Adenosine triphosphate +H2O

5. Furthermore, Magnesium plays a vital role in the structure of nucleic acids, influencing their interactions with proteins and other ligands.

6. Enzymes such as Glycyl-L-leucine dipeptidase, aminopeptidase, and carboxypeptidase rely on Mg2+ ion-complexes to facilitate the metabolic breakdown of proteins into amino acids. It shows the crucial role of Mg2+ ion-complexes in the cleavage of peptide bonds.

                                     Pepsin                                       Carboxypeptidase

   Dietary protein ---------------→  Polypeptides    ------------------→  Tripeptides & Dipeptides     

                                    Acidic pH                                        Aminopeptidase

 

      ------------------→    Amino acids                                    

     Peptidases, pH=7

7. Decarboxylation and carboxylation reactions, such as the conversion of oxalosuccinic acid to α-ketoglutaric acid and α-ketoglutaric acid to succinic acid, are facilitated by carboxylase enzymes that involve magnesium and manganese complexes.

                                        CO2

Oxalosuccinic acid     ⇌     α-Ketoglutaric acid  (Carboxylation reaction)

                                       Mg2+             

                                                           Mg2+

α- Ketoglutarate + NAD++CoA-SH   ⇌   Succinyl-CoA + CO2 + NaOH (Decarboxylation reaction)

                                                                    TPP                  


Succinyl-CoA + GDP + ip+ H2O → Succinic acid +CoA+ GTP     

8. The activity of contractile protein by actomyosin also involves an Mg2+ complex.

9. The synthesis of citric acid from oxaloacetic acid enol, facilitated by Coenzyme-A, is dependent on the presence of Mg2+ ions. Acetyl CoA acts as the bridge between glycolysis and the Krebs cycle. Through the action of citrate synthase enzyme and a water molecule, acetyl-CoA combines with oxaloacetic acid to produce citric acid, while CoA is released.

                                                                                       Mg2+

Acetyl CoA + Oxaloacetic acid + H2O   ------------------------→     Citric acid + CoA.

                                                                               Citrate synthase 

10. Mg2+ ions play a critical role in maintaining the stability of the genome by ensuring the accuracy of DNA replication and repair mechanisms. Furthermore, the presence of Mg2+ ions leads to a more compact structure of DNA molecules.

11. Mg2+ cations are also known to regulate the transport of ions through pumps, carriers, and ion channels. This suggests that Mg2+ may act as a modulator of signal transduction and influence the cytosolic concentrations of electrolytes like Ca2+ and K+.

12. Additionally, Mg has similar effects on neuromuscular irritability as Ca2+. Elevated levels of Mg2+ can depress nerve conduction, while low levels may lead to tetany, a condition characterized by increased muscle excitability (hypomagnesemic tetany).

13. The reversible dehydration of 2-phosphoglycerate to phosphoenolpyruvate, catalyzed by the glycolytic enzyme enolase, relies on the presence of Mg2+ ions.

                                                    Enolase

              2- Phosphoglycerate   ⇌     Phosphoenolpyruvate + H2O

The reaction catalyzed by enolase occurs in two steps:

Step 1: At the active site, two magnesium ions coordinate with the carboxyl group of 2-PGA (2-Phosphoglycerate). The base catalyst Lys345 abstracts a proton from 2-PGA, leading to the formation of an enolic intermediate.

Step 2: The enolic intermediate is stabilized by Mg2+ ions. An acid catalyst Glu211 facilitates the elimination of the -OH group from the enolic intermediate, resulting in the formation of phosphoenolpyruvate.


Magnesium in human nutrition


Magnesium-rich foods such as cocoa, nuts, almonds, whole seeds, unground grains, legumes, green leafy vegetables, and potatoes are valuable dietary sources of magnesium. The presence of chlorophyll makes the green parts of plants particularly abundant in magnesium. Additionally, hard water can also serve as a good source of magnesium.

The recommended daily intake of magnesium is 370 mg for adult men and 300 mg for adult women (non-pregnant). However, the specific magnesium requirement varies based on factors such as overall activity level, type of work, lifestyle, and any underlying health conditions.

Assimilating magnesium ions can be challenging as they are primarily absorbed in the ileum and jejunum of the small intestine. The absorption process involves two mechanisms: passive diffusion and facilitated diffusion. Approximately 30% of the supplied magnesium is typically absorbed, with 10% occurring through passive diffusion. The facilitated diffusion process relies on metabolic energy supply and the concentration of magnesium ions.

Magnesium absorption from dietary sources is notably enhanced in cases of magnesium deficiency. In regular conditions, the absorption of magnesium is optimized when it is provided in small doses spread across multiple meals, rather than a large amount in a single dose. It is worth noting that magnesium is more effectively absorbed as a component of food compared to oral magnesium supplements.


Factors influencing magnesium absorption in the human body


  • Magnesium absorption is enhanced by various factors, such as an acidic environment, diets containing animal proteins, unsaturated fats, vitamin B6, vitamin D, sodium, and lactose.
  • Hormonal factors, including insulin, parathyroid hormone, and growth hormone, also contribute to increased magnesium absorption.
  • Interestingly, neomycin therapy has been found to increase magnesium absorption.
  • Furthermore, diets deficient in calcium tend to promote magnesium absorption. If the amount of calcium in diet is twice the level of magnesium, then it favours the absorption of magnesium.

In contrast, let's explore the factors that hinder magnesium absorption:


  1. Diets high in fat, particularly those containing fatty meat, can reduce magnesium absorption.
  2. A low-protein and high-fiber diet may decrease the absorption of magnesium in the intestines.
  3. Consuming foods rich in phosphates and having a high calcium intake can also reduce magnesium absorption.
  4. Certain components in foods, such as saturated fatty acids, phytates, and oxalic acid, can interfere with magnesium absorption.
  5. Conditions that result in hurried bowel absorption or damage to the mucosal lining can also impede the absorption of magnesium by the human body.


Factors that influence the excretion of magnesium from the human body


Magnesium is eliminated from the body through various routes, including feces, sweat, and urine. When magnesium is taken orally, approximately 60 to 80% of it is eliminated in the feces. Through perspiration, about 0.75 milliequivalents (mEq) of magnesium is lost daily in individuals with normal health and a normal diet. In the case of a normal healthy adult with a regular diet, the urinary excretion of magnesium ranges from 3 to 14 mEq. These pathways contribute to the overall elimination of magnesium from the body.


Here are the factors collectively determine the excretion of magnesium from the human body.


➤ Renal function plays a significant role in the excretion of magnesium. Impaired kidney function can lead to reduced magnesium excretion.

➤ Hormonal regulation, particularly through the action of parathyroid hormone, can affect magnesium excretion. Increased levels of parathyroid hormone can enhance magnesium excretion. Hence, Hyperthyroidism leads to a significant increase in the level of exchangeable magnesium, resulting in higher excretion of magnesium. Conversely, the opposite effect is observed in hypothyroidism.

➤ Certain medications, such as diuretics, amino-glycoside antibiotics, sedatives and cytostatic drugs can increase magnesium excretion by promoting its elimination through urine.

➤ Dietary factors, including high intake of alcohol, caffeine, and certain medications, can contribute to increased magnesium excretion. The enhanced excretion of magnesium plays a role in the magnesium deficiency observed in chronic alcoholics experiencing Delirium tremens.

➤ Health conditions such as gastrointestinal disorders or prolonged diarrhea can result in excessive magnesium excretion.

➤ Acid-base balance in the body can influence magnesium excretion, with alkalosis leading to increased excretion and acidosis reducing excretion.


Magnesium deficiency in humans


The availability of magnesium in the body is greatly influenced by the form of food we consume. Fresh and unprocessed foods like fruits, vegetables, and unrefined whole grains are rich sources of magnesium compared to processed foods.

Furthermore, the consumption of calorie-dense foods that lack essential micronutrients contributes to a magnesium imbalance in the body. This deficiency can lead to impaired functioning of vital organs such as the brain, heart, and muscles, which require adequate amounts of magnesium for optimal performance.

As a result, insufficient magnesium levels in the body can lead to various health conditions including cardiovascular issues (such as thrombosis, atherosclerosis, ischemic heart disease, myocardial infarction, hypertension, arrhythmias, and congestive heart failure), diabetes mellitus, gastrointestinal tract disorders, liver cirrhosis, and thyroid and parathyroid diseases.

In children, inadequate magnesium intake has been linked to the development and worsening of ADHD (Attention Deficit Hyperactivity Disorder).

Here are several signs and symptoms that indicate a potential magnesium deficiency: persistent weakness, fatigue, difficulty concentrating, increased susceptibility to stress, tingling and trembling sensations in the hands, excessive physical hyperactivity, restlessness, anxiety, irregular heartbeat, and headaches.

Individuals who live in hot climates or engage in strenuous physical activity often experience significant magnesium loss through sweat. Furthermore, older individuals, due to decreased efficiency of gastrointestinal and renal processes, are more susceptible to magnesium deficiencies.

The relationship between magnesium and cancer formation is intricate, as various experimental studies have indicated that imbalances in magnesium homeostasis are frequently observed in tumour cells. Both magnesium deficiency and supplementation have the potential to influence the progression of existing tumours.

Furthermore, magnesium deficiency has been associated with inflammatory mediators and elevated levels of free radicals, which can contribute to oxidative DNA damage and the development of cancer. Magnesium plays a crucial role in stabilizing the structure of nucleic acids and acts as a vital co-factor for enzymes involved in DNA replication and repair. Therefore, magnesium deficiency can contribute to the occurrence of DNA mutations and the accumulation of genomic alterations, leading to tumorigenesis.

At the early stages of carcinogenesis, magnesium appears to have a protective effect. However, in later stages, it can promote the growth of existing tumors. Additionally, magnesium deficiency seems to favor invasion and the colonization of metastatic tumors.


Adverse effects of excess magnesium ions on biological system


When the concentration of magnesium exceeds the normal level in the human body, it is referred to as hypermagnesemia.

Excessive levels of magnesium ions can have adverse effects on biological systems. These effects include:

Gastrointestinal disturbances: High levels of magnesium can cause diarrhea, nausea, and abdominal cramps. It can also act as a laxative, leading to increased bowel movements.

Electrolyte imbalances: Excess magnesium can disrupt the balance of other electrolytes in the body, such as calcium and potassium. This imbalance can have various consequences on nerve and muscle function.

Cardiovascular effects: Excessive magnesium can affect heart function, leading to a decrease in heart rate, low blood pressure, and cardiac arrhythmias.

Respiratory issues: In rare cases, an excess of magnesium can result in respiratory depression, causing difficulty in breathing.

Impaired kidney function: High levels of magnesium can put a strain on the kidneys and may lead to impaired kidney function, particularly in individuals with pre-existing kidney conditions.

Central nervous system effects: Excessive magnesium can cause symptoms such as drowsiness, lethargy, confusion, and even coma in severe cases.

Renal system effects:  Excess magnesium levels can contribute to the progression of advanced and acute renal failure.

It is important to note that the adverse effects of excess magnesium are rare and typically occur in individuals with pre-existing health conditions or in cases of extremely high magnesium intake, such as from supplementation without medical supervision.


FAQs on bioinorganic chemistry of Magnesium


1. What is the role of magnesium ion in ATP hydrolysis?

ATP (Adenosine triphosphate) serves as the primary energy source for various cellular processes, including muscle contraction, cell signaling, DNA and RNA synthesis, and carbon fixation. 

The energy derived from the oxidation of carbohydrates and respiratory substrates is captured and stored in the form of ATP. When energy is needed, ATP is hydrolyzed to ADP (Adenosine diphosphate), releasing the necessary energy to drive these biological processes.

The polyphosphate linkage in ATP acts as an energy storage unit. When required, ATP molecules undergo hydrolysis catalyzed by the kinase enzyme, resulting in the production of ADP, inorganic phosphate, and 30.543 KJ/mole of energy.

                                                  Kinase enzyme

Adenosine triphosphate +H2O   -------------→    Adenosine diphosphate + HPO42- + H++ 30.543 KJ/mole

The hydrolysis of ATP, resulting in the release of energy, is considered an exergonic process. The enzyme kinase, which contains Mg2+ ion, facilitates the transfer of phosphate from ATP to a substrate.

 The presence of Mg2+ ion may play a role in properly orienting the enzyme protein for interaction with ATP during its breakdown into ADP and phosphate, as well as the transfer of phosphate to the substrate.

 This suggests that the protein itself has the enzymatic function, while Mg2+ ion functions as a coenzyme.


2. Why is Mg2+ needed in DNA replication?

DNA polymerase is an essential enzyme that plays a key role in the replication of DNA. DNA replication is a fundamental cellular process that involves the creation of an identical copy of an existing DNA molecule. 

During this process, DNA polymerase reads the template DNA strand and synthesizes a complementary DNA strand using the four deoxyribonucleoside triphosphates (mononucleotides). 

The activity of DNA polymerase is facilitated by the presence of Mg2+ ions and a primer DNA, which serves as a starting point for the polymerization reaction.


3. What is the role of magnesium in enzyme activity?

Mg2+ ions play a crucial role in biochemical processes by interacting with substrates, enzymes, or both. When interacting with substrates, Mg2+ ions typically engage in inner sphere coordination, providing stability to anions or reactive intermediates. 

They also bind to molecules like ATP, activating them for nucleophilic attack. In the case of enzymes and other proteins, Mg2+ ions can bind using inner or outer sphere coordination, influencing the enzyme's conformation or participating in the catalytic reaction. 

Interestingly, the presence of Mg2+-associated water molecules may be more important than the ion itself, as complete dehydration of Mg2+ is rare during ligand binding. 

The Lewis acidity of Mg2+ (pKa =11.4) is leveraged to enable hydrolysis and condensation reactions, such as phosphate ester hydrolysis and phosphoryl transfer, at physiological pH values. This avoids the need for extreme pH conditions that deviate significantly from physiological levels.


MCQs on bioinorganic chemistry of Magnesium


1. What are the functions of Magnesium ion in living organisms?

  1. Keep bones strong and healthy

  2. Ensures the proper functioning of nerves and muscles

  3. Keeps the heartbeat steady

  4. All the above

Answer: All the above

2. Which of the following statements accurately describes the role of magnesium in living systems?

  1. It is an atom

  2. It is an electrolyte

  3. It is a molecule

  4. It is a metal-complex

Answer: It is an electrolyte

3. Which food has the highest magnesium content?

  1. Pumpkin seeds

  2. Chia seeds

  3. Sesame seeds

  4. Sunflower seeds

Answer: Pumpkin seeds

4. By whom was magnesium discovered?

  1. Joseph Black

  2. Humphrey Davy

  3. Robertson

  4. Michael Thomas

Answer: Humphrey Davy

5. Which of these indicates low magnesium levels in the body?

  1. Anxiety

  2. Schizophrenia

  3. Phobia

  4. Bipolar disorder

Answer: Anxiety