Transamination

Transamination is the most important reaction in the metabolism of amino acids. It is the first step in amino acid catabolism23, and it plays a crucial role in both the synthesis and breakdown of amino acids. All amino acids, except lysine, threonine, proline, and hydroxyproline, can undergo transamination.

Definition and Mechanism:

• Transamination is defined as the transfer of an amino group from an α-amino acid to an α-keto acid.

• This process results in the conversion of the amino acid to its corresponding α-keto acid, and the α-keto acid to its corresponding amino acid.

• The amino group acceptor in transamination reactions is always α-ketoglutarate.

• Transamination reactions are reversible.

Enzymes and Coenzymes:

• • Transamination is catalyzed by a family of enzymes called transaminases or aminotransferases.

  • Each transaminase is specific for a particular amino acid.

  • All transaminases require pyridoxal phosphate (PLP) as a coenzyme359. PLP is the active form of vitamin B6.

Mechanism of Transamination:

• • Stage 1: The amino group from the amino acid is transferred to the enzyme, releasing the corresponding α-keto acid.

  • Stage 2: The amino group from the enzyme is transferred to α-ketoglutarate, producing glutamate and regenerating the PLP-enzyme complex.

Significance of Transamination:

• • Transamination plays a vital role in several metabolic processes:

  • Collecting amino groups: Transamination reactions collect amino groups from various amino acids and funnel them into glutamate.

  • Redistributing amino groups: This process helps to balance the amino acid pool by interconverting different amino acids.

  • Synthesizing non-essential amino acids: Transamination allows for the synthesis of non-essential amino acids from their corresponding α-keto acids.

  • Degradation of amino acids: Transamination is the first step in the breakdown of amino acids.

Transaminases in Clinical Diagnosis:

• • Serum levels of certain transaminases are elevated in some disease states, particularly those affecting the heart and liver.

  • The two most frequently assayed transaminases in clinical laboratories are aspartate aminotransferase (AST), also known as serum glutamate-oxaloacetate transaminase (SGOT), and alanine aminotransferase (ALT), also known as serum glutamate-pyruvate transaminase (SGPT)41213. Elevated levels of these enzymes can be indicative of liver damage or heart disease.

Examples of Transamination Reactions:

• The sources list several specific transamination reactions11, including:

  • Alanine transaminase (ALT): alanine + α-ketoglutarate ⇄ pyruvate + glutamate

  • Aspartate transaminase (AST): aspartate + α-ketoglutarate ⇄ oxaloacetate + glutamate

Transdeamination:

• Transdeamination is the combined process of transamination and oxidative deamination.

• This coupled reaction efficiently removes the amino group from most amino acids.

• It involves transamination in all cells of the body, followed by the transport of the amino group to the liver as glutamate, where it is oxidatively deaminated

Transaminases: 

Transaminases, also known as aminotransferases, are a family of enzymes crucial for amino acid metabolism. These enzymes catalyze transamination, a reversible reaction that involves the transfer of an amino group from an α-amino acid to an α-keto acid12. Each transaminase is specific for a particular amino acid, meaning it only facilitates the transfer of the amino group from that specific amino acid34. The α-keto acid acceptor in transamination is always α-ketoglutarate34.

All transaminases require pyridoxal phosphate (PLP), the active form of vitamin B6, as a coenzyme125. PLP plays a central role in the transamination mechanism, acting as a temporary carrier for the amino group during the transfer process67. The transamination reaction takes place in two stages:

1. Transfer of the amino group from the amino acid to the enzyme, releasing the keto acid.

2. Transfer of the amino group from the enzyme to the keto acid (α-ketoglutarate), releasing the amino acid (glutamate) and regenerating the PLP-enzyme complex.

Clinical Utility of Transaminases

The clinical utility of transaminases stems from their presence in various tissues and their release into the bloodstream upon tissue damage. Measuring the levels of specific transaminases in serum can provide valuable insights into the health of organs like the liver and heart.

Aspartate aminotransferase (AST), also called serum glutamate-oxaloacetate transaminase (SGOT), and alanine aminotransferase (ALT), also called serum glutamate-pyruvate transaminase (SGPT), are the two most frequently assayed transaminases in clinical laboratories89.

• Elevated levels of AST and ALT are often indicative of liver damage, as these enzymes are abundant in liver cells. Conditions such as hepatitis, cirrhosis, and liver cancer can cause a significant release of these enzymes into the blood.

• While AST is present in both the cytoplasm and mitochondria of liver cells, ALT is primarily located in the cytoplasm. Therefore, a predominantly elevated ALT level suggests more severe or acute liver injury affecting the cell's cytoplasm.

• AST is also found in heart muscle, skeletal muscle, kidneys, and red blood cells. Thus, elevated AST levels may also indicate heart damage, muscle injury, or other conditions affecting these tissues.

Examples of Transamination Reactions

The sources provide examples of specific transamination reactions catalyzed by AST and ALT3:

AST: aspartate + α-ketoglutarate ⇄ oxaloacetate + glutamate

ALT: alanine + α-ketoglutarate ⇄ pyruvate + glutamate

In these reactions, AST and ALT facilitate the transfer of amino groups from aspartate and alanine, respectively, to α-ketoglutarate, resulting in the formation of oxaloacetate and pyruvate, along with glutamate.

By measuring the serum levels of these transaminases, clinicians can assess the extent of tissue damage and monitor the progression of diseases affecting the liver, heart, and other organs.

Sources of Ammonia in the Human Body

Ammonia (NH3) is a toxic waste product constantly produced in the body during the metabolism of amino acids and other nitrogen-containing compounds. The sources list several pathways and processes that contribute to ammonia formation:

1. Transamination and Deamination of Amino Acids:

• Transamination is the transfer of an amino group from an amino acid to an α-keto acid, primarily α-ketoglutarate, resulting in the formation of glutamate. This process is the first step in amino acid catabolism and occurs in various tissues throughout the body.

• Deamination is the removal of an amino group from an amino acid, producing ammonia (NH3) and a keto acid. The primary site of deamination is the liver, although it also occurs in the kidneys.

  • Oxidative deamination primarily acts on glutamate, which acts as a "collection center" for amino groups gathered through transamination. The enzyme glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of glutamate, releasing ammonia and regenerating α-ketoglutarate.

    • Other types of deamination include non-oxidative deamination, which occurs for hydroxy amino acids, and hydrolytic deamination, which applies to glutamine and asparagine.

• The combined process of transamination and deamination, termed transdeamination, efficiently removes amino groups from most amino acids. Transamination occurs in various tissues, and the resulting glutamate transports the amino group to the liver, where it undergoes oxidative deamination, releasing ammonia.

2. Metabolism of Biogenic Amines:

• Biogenic amines are nitrogen-containing compounds derived from amino acids, such as histamine, serotonin, and catecholamines. The breakdown of these amines, catalyzed by the enzyme monoamine oxidase, also releases ammonia.

3. Catabolism of Purines and Pyrimidines:

• The degradation of purine and pyrimidine nucleotides, the building blocks of DNA and RNA, releases ammonia from their amino groups.

4. Action of Intestinal Bacteria:

• The bacteria residing in the large intestine possess the enzyme urease, which hydrolyzes urea into ammonia and carbon dioxide. This process contributes to the ammonia levels in the portal vein, which carries blood from the intestines to the liver.

Detoxification of Ammonia and Associated Inborn Errors

The body has developed efficient mechanisms to detoxify ammonia due to its toxicity, particularly to the central nervous system (CNS). The primary defense mechanism involves the formation of glutamine, while the secondary defense relies on the urea cycle.

Glutamine Synthesis: A Primary Defense

Ammonia is produced in all cells, and intracellular ammonia is immediately trapped by glutamic acid to form glutamine, especially in the brain3. This reaction is catalyzed by the mitochondrial enzyme glutamine synthetase4 and occurs primarily in the liver, brain, and muscles.

Glutamine serves as a major transport and temporary storage form of ammonia4. Its ability to readily pass through cell membranes allows it to carry ammonia safely to the liver and kidneys for further processing4. In addition to its role in ammonia detoxification, glutamine also plays a crucial role in:

• Regulation of acid-base balance in the kidneys

• Removal of toxic ammonia effects in the brain

• Serving as a source of nitrogen for purine base synthesis4

The Urea Cycle: The Ultimate Detoxification Pathway

The urea cycle, primarily located in the liver, is the main pathway for ammonia detoxification. In this cycle, ammonia is converted into urea, a non-toxic compound that can be safely excreted in urine. The urea cycle involves a series of enzymatic reactions that convert ammonia and aspartate into urea. The sources do not provide a detailed explanation of the urea cycle steps.

Inborn Errors of Ammonia Detoxification

Genetic defects in the enzymes or transporters involved in ammonia detoxification can lead to inherited hyperammonemia, a condition characterized by elevated ammonia levels in the blood. The sources list two inborn errors associated with ammonia detoxification:

1.Ornithine Transcarbamoylase Deficiency: This is the most common urea cycle disorder and is X-linked, meaning it primarily affects males. This deficiency leads to a buildup of ammonia and other metabolites in the blood. Affected individuals exhibit symptoms like:

• Aversion to high-protein diets

• Elevated blood ammonia levels

• Increased glutamine levels in blood, cerebrospinal fluid (CSF), and urine

• Orotic aciduria (increased orotic acid in the urine)

2.N-Acetyl Glutamate Synthase (NAGS) Deficiency: NAGS is crucial for the activity of carbamoyl phosphate synthetase 1 (CPS-I), the first enzyme in the urea cycle. NAGS catalyzes the formation of N-acetyl glutamate (NAG) from glutamate and acetyl-CoA, and NAG acts as an activator of CPS-I. A deficiency in NAGS results in severe hyperammonemia, and individuals with this condition may benefit from administered N-acetylglutamate.

Other Urea Cycle Defects and Associated Disorders

●HHH Syndrome (Hyperornithinemia, Hyperammonemia, Homocitrullinuria): Caused by a defect in the ornithine transporter, leading to a failure in ornithine transport6. It's a rare autosomal recessive disorder.

●Hyperinsulinism/Hyperammonemia (HI/HA): Characterized by hypoglycemia and hyperammonemia due to mutations in the GLUD1 gene8. These mutations cause a "gain of function" in glutamate dehydrogenase, leading to hyperinsulinemia and hyperammonemia.

Hyperammonemia Type I and Type II: Urea Cycle Defects

Hyperammonemia, a condition characterized by elevated blood ammonia levels, can arise from acquired factors like liver failure or inherited deficiencies in enzymes or transporters involved in ammonia detoxification. The sources specifically mention Hyperammonemia Type I and Type II, both linked to defects in the urea cycle.

Hyperammonemia Type I: CPS-I Deficiency

Hyperammonemia Type I results from a deficiency in carbamoyl phosphate synthetase I (CPS-I), the first enzyme in the urea cycle. This enzyme catalyzes the condensation of ammonia with bicarbonate to form carbamoyl phosphate, the initial step in urea synthesis. This condition as an autosomal recessive disorder, leading to very high ammonia levels in the blood.

Hyperammonemia Type II: Ornithine Transcarbamoylase Deficiency

Hyperammonemia Type II is caused by a deficiency in ornithine transcarbamoylase (OTC), another key enzyme in the urea cycle. OTC catalyzes the transfer of a carbamoyl group from carbamoyl phosphate to ornithine, forming citrulline. In contrast to Type I, this condition is X-linked, making it more prevalent in males. Individuals with this disorder may exhibit:

• Aversion to high-protein diets: This is because protein breakdown leads to increased ammonia production, which cannot be efficiently detoxified due to the OTC deficiency.

• Elevated blood ammonia levels: The inability to convert ammonia to urea results in its accumulation in the bloodstream.

• Increased glutamine levels in blood, CSF, and urine: Elevated ammonia levels stimulate glutamine synthesis as a primary defense mechanism234.

• Orotic aciduria: The accumulation of carbamoyl phosphate due to OTC deficiency leads to its diversion into pyrimidine synthesis, resulting in increased orotic acid production and excretion.

Similarities and Differences Between Type I and Type II

Both Hyperammonemia Type I and Type II are inherited metabolic disorders caused by defects in urea cycle enzymes. This leads to an inability to efficiently detoxify ammonia, resulting in hyperammonemia. However, they differ in their inheritance pattern, the specific enzyme deficiency, and some associated symptoms.

Other Inborn Errors and Acquired Causes

Other inborn errors of ammonia detoxification like N-acetyl glutamate synthase (NAGS) deficiency and HHH syndrome, caused by a defect in the ornithine transporter78. These disorders can also lead to hyperammonemia.

While the query specifically focuses on inherited causes, it's important to remember that acquired hyperammonemia can also occur, typically due to liver dysfunction. Conditions like cirrhosis and hepatitis can impair the liver's ability to perform the urea cycle, leading to ammonia buildup.