Catabolism of Amino Acids

Overview

Amino acids (AAs) follow 3 main metabolic pathways for their metabolism:

1. Synthesis of new proteins
2. Formation of amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids derivatives
3. Catabolism of AAs
   • Catabolism consists of the breakdown of complex molecules into smaller units to produce energy or to be used in anabolic reactions
   • Removal or exchange of functional groups
     • Involves transamination, deamination, and decarboxylation
     • Releases excess nitrogen in the form of ammonium (NH4⁺), which then enters the urea cycle Urea Cycle The catabolism of amino acids results in the release of nitrogen in the form of ammonium. This excess nitrogen is transported to the liver and kidneys and eliminated from the body in the form of urea via the urine. The urea cycle (or ornithine cycle) takes place mainly in the liver and comprises the synthesis of urea from ammonium, CO2, aspartate, and bicarbonate. Urea Cycle, is converted into urea, and excreted through the urine
   • Catabolism of the remaining carbon skeleton
     • In general, all 20 AAs can be broken down into 1 of 6 intermediates: pyruvate, acetyl-CoA, oxaloacetate, alpha-ketoglutarate, succinyl-CoA, and fumarate.
     • Ketogenic AAs metabolize to acetyl-CoA, later used in the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle, ketogenesis, or fatty acid synthesis.
     • Glucogenic AAs are converted into glucose through gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis.
     • Some AAs are both glucogenic and ketogenic.

Amino Acid Derivatives

Amino acids can be used to assemble many substances. The image below shows the most important AA-derived substances in humans.

Transamination

Transamination is the transfer of an amino group from an alpha-AA to an alpha-keto acid, which is an AA with an alpha-keto group (=O) instead of an alpha-amino group (NH₂).

• The original AA loses an amino group and gains a keto group, becoming an alpha-keto acid.
• The original alpha-keto acid loses its keto group and gains an amino, becoming a nonessential AA.
• The reaction is catalyzed by aminotransferase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • Can be specific for a particular AA pair or a group with similar chemical compositions
  • Requires coenzyme pyridoxal phosphate (PLP, the active form of vitamin B6)
  • Found in high concentrations in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver

This process is need-dependent. If there is an excess of a type of AA, the amino group of that type can be transferred to make other types of AAs that the body currently needs.

All of the common AAs participate in transamination, except lysine, threonine, proline, and hydroxyproline, which catabolize via a dehydrogenase.

Transaminases

• Alanine transaminase (ALT or ALAT) transfers an amino group from alanine to alpha-ketoglutarate, forming pyruvate and glutamate. 
• Aspartate transaminase (AST or ASAT) transfers an amino group from aspartate to alpha-ketoglutarate, forming oxaloacetate and glutamate.  

Both enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes catabolize reversible reactions, which are essential for the transport of nitrogen from tissues to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and into the urea cycle Urea Cycle The catabolism of amino acids results in the release of nitrogen in the form of ammonium. This excess nitrogen is transported to the liver and kidneys and eliminated from the body in the form of urea via the urine. The urea cycle (or ornithine cycle) takes place mainly in the liver and comprises the synthesis of urea from ammonium, CO2, aspartate, and bicarbonate. Urea Cycle.

Steps:

1. PLP reacts with the amino group of the AA, releasing H₂O.
2. A Schiff base is formed, destabilizing the AA.
3. Hydrogen atoms migrate, double-bond shifts, and aldimine → ketimine.
4. H₂O is added, yielding PMP and an alpha-keto acid.
5. In reverse, PMP reacts with an alpha-keto acid, generating an AA and reconstituting PLP.

Deamination

Deamination is the process through which amino groups are stripped from AAs, releasing free cytotoxic ammonia: ammonia → ammonium → urea or uric acid via the urea cycle Urea Cycle The catabolism of amino acids results in the release of nitrogen in the form of ammonium. This excess nitrogen is transported to the liver and kidneys and eliminated from the body in the form of urea via the urine. The urea cycle (or ornithine cycle) takes place mainly in the liver and comprises the synthesis of urea from ammonium, CO2, aspartate, and bicarbonate. Urea Cycle in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver.

Three types of deamination

1. Oxidative deamination

• Oxidation turns the amino group into an imino group.
• NAD⁺ or NADP⁺ is reduced to NADH/H or NADPH/H, respectively.
• Water is added to the amino group, converting it to an alpha-keto group, releasing ammonia.

2. Hydrolytic deamination

Water reacts with the amino group, irreversibly attaching an OH group and eliminating the amino group in the form of ammonia.

3. Eliminative deamination: 

• Small AAs (serine or cysteine) release water (or hydrogen sulfide for sulfurous amino acids).
  • PLP is a necessary coenzyme.
• Through hydrolysis, the amino group is cleaved, resulting in pyruvate.

Decarboxylation

• Cleavage of a carboxyl group from an AA, releasing CO₂
• Catalyzed by the enzyme decarboxylase 
• Uses PLP as a coenzyme
• Resulting amines fulfill important functions in the body = biogenic amines
  • Histamine is formed through decarboxylation from histidine, and plays a vital role in immediate hypersensitivity reactions. 
  • Other examples: gamma-aminobutyric acid from glutamine acid and dopamine (from 3,4-dihydroxyphenylalanine).

Catabolism of the Carbon Skeleton

The catabolism of AAs involves anaplerotic reactions (chemical reactions that form intermediates of metabolic pathways).

The breakdown of the carbon skeleton of AAs can be classified by the metabolic pathways to which their catabolic products will serve as intermediates. 

• Glucogenic AAs → gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis intermediates
• Ketogenic AAs → ketogenesis intermediates
• Glucogenic and ketogenic AAs → both pathways

All AAs are broken down into 1 of 6 intermediates (see green boxes in the images below): pyruvate, acetyl-CoA, oxaloacetate, alpha-ketoglutarate, succinyl-CoA, and fumarate.

Glucogenic AAs

Metabolized to pyruvate or metabolites of the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle (CAC):

• Pyruvate (from serine, cysteine, glycine, alanine, and threonine)
  • Threonine first → glycine → serine → pyruvate
• Succinyl-CoA (from methionine, isoleucine, valine, and threonine via propionyl-Coa and methylmalonyl-CoA
• Propionyl-CoA (intermediate of succinyl-CoA pathway)
• Oxaloacetate (from asparagine via aspartate)
• α-Ketoglutarate (from glutamine, arginine, histidine, proline via glutamate)
• Fumarate

Catabolic products either move into the CAC to produce energy or are used as substrates for gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis.

Ketogenic AAs

Metabolized directly to acetyl-CoA, then enter 1 of 3 metabolic pathways:

• Enter the CAC to produce ATP/energy
• Ketogenesis (production of ketone bodies)
• Synthesis of fatty acids or cholesterol

Glucogenic and Ketogenic AAs

Metabolized to intermediates of lipidic as well as glucogenic pathways:

• Isoleucine → propionyl-CoA (→ methylmalonyl-CoA → succinyl-CoA) and acetyl-CoA
• Phenylalanine → tyrosine → fumarate and acetyl-CoA
• Threonine → propionyl-CoA and pyruvate as well as acetyl-CoA (via glycine + acetaldehyde)
• Tryptophan → alanine and acetyl-CoA

Mnemonic Device

To recall the metabolic pathways of the carbon skeletons of amino acids, remember:

• Glucogenic: “I Met His Valentine, she is so sweet.”
  • Methionine
  • Histidine
  • Valine
• Ketogenic: “The onLy pureLy ketogenic amino acids.”
  • Leucine
  • Lysine

Clinical Relevance

The following conditions are disorders of amino acid metabolism Disorders of amino acid metabolism Amino acids are the building blocks of proteins, whose production is a tightly regulated enzymatic cascade. Disorders of the enzymes involved in amino acid metabolism are often serious and present early in life. Congenital errors in amino acid metabolism are due to either impaired synthesis or degradation. Disorders of Amino Acid Metabolism. Depending on the country and the individual U.S. state, newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn infants may be routinely screened for these disorders (except for alkaptonuria).

• Phenylketonuria: a defect of phenylalanine hydroxylase that results in the impairment of the conversion of phenylalanine to tyrosine and subsequent accumulation of phenylalanine. Presents as psychomotor delay and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Maple syrup urine disease: a defect in dehydrogenase that results in the accumulation of branched-chain AAs. Presents as cognitive disability, sweet-smelling urine, and dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia 
• Homocystinuria: a defect in the enzyme cystathionine β-synthase, which leads to an accumulation of homocysteine. Presents as flushing, developmental delay, lens dislocation, vascular disease, and osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Tyrosinemia: a deficiency of fumarylacetoacetate hydrolase, the last enzyme in the tyrosine catabolism. Presents as liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease, deficient weight gain, peripheral nerve disease, and kidney defects
• Alkaptonuria: a deficiency of homogentisic acid dioxygenase, which impairs the normal degradation of tyrosine to fumarate. Presents as a bluish-black discoloration of connective tissues, arthritis, and calcifications of various tissues.