Amino acids are organic compounds that consist of a carbon atom attached to a carboxyl group, a hydrogen atom, an amino group, and a variable R group (side chain). In humans (and other eukaryotes), there are 21 different proteinogenic amino acids, 20 of which are encoded for protein synthesis by the genetic code, as well as selenocysteine, which is integrated via a special translation mechanism. They can be divided into essential amino acids (cannot be synthesized by the body) and nonessential amino acids (can be synthesized by the body). Amino acid derivatives include glycine, glutamate, histidine, arginine, tryptophan, and phenylalanine. Amino acid catabolism can occur via different metabolic routes, each with a specific purpose, including the production of metabolic fuels (e.g., pyruvate, acetyl-CoA), reuse in the synthesis of new proteins, and the creation of amino acid derivatives. Deficiencies in these metabolic routes can lead to a variety of conditions, which are covered in more detail in “Disorders of amino acid metabolism,” “Hyperphenylalaninemia,” and “Hyperammonemia.”
- Amino acid (AA) consists of a carbon atom attached to a/an:
- Carboxyl group (-COOH)
- Hydrogen atom
- Amino group (-NH2)
- Variable R group (side chain): determines unique properties
- Only L-form amino acids are incorporated into proteins during translation.
- There are 21 standard proteinogenic amino acids in humans
- 20 are encoded for protein synthesis by the genetic code
- Selenocysteine is incorporated via a mechanism known as translational recoding
Essential or nonessential
|Essential vs. nonessential amino acids|
|Group||Amino acid||Synthesis||Catabolic product|
Essential amino acids
|Nonessential amino acids|| |
|Tyrosine** (Tyr)|| |
|Conditional amino acids|
*Arginine and Histidine may become essential (thus require supplementation) during times of increased demand (e.g., during illness, growth phases such as pregnancy or childhood).
**Cysteine and Tyrosine are synthesized from essential AAs.
For essential AAs, think PVT (Private) TIM HALL: Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Arginine, Leucine, Lysine
To remember glucogenic AAs, think: Arges Met His Valentine and gave her sweets.
For his movie roles, Brad PITT may eat a lot (glucogenic) or diet (ketogenic): Phenylalanine, Isoleucine, Threonine, Tryptophan
For ketogenic AAs, visualize 2 L-shaped keys: Leucine and Lysine.
Hydrophobic or hydrophilic
|Hydrophobic vs. hydrophilic amino acids|
|Features||Hydrophobic amino acids||Hydrophilic amino acids|
|Location during protein folding|| || |
|R groups|| || |
|Examples|| || |
- The net charge and thus polarity of AAs can change according to the surrounding pH and availability of H+ available for protonation. When charged, AAs become polar/hydrophilic.
Acid dissociation constant (pKa)
- Indicates the strength of a weak acid or base
- Defined as the pH at which the ionized and unionized forms exist in equal concentrations
All AAs have at least two ionizable groups, each with its own acid dissociation constant (pKa).
- pKa of the α-carboxyl group = 2
- pKa of the α-amino group = 9–10
- Acidic/basic AAs have another pKa for their ionizable side chain group, which varies.
Acidic amino acids: Side groups are negatively charged at body pH (both have a pKa of ∼ 4). ;
- Basic amino acids
His (histidine) lies (lysine) are (arginine) base (basic amino acids).
Amino acid derivatives
- (+ Succinyl CoA + pyridoxine) → Porphyrin → Heme
- (+ Aspartate + glutamine) → Purines
- (+ pyridoxine) → GABA
- (+ Glycine + cysteine) → Glutathione
- Histidine: (+ pyridoxine) → Histamine + CO2(decarboxylation)
- (+ NADPH + THB) → Nitric oxide
- Creatinine is synthesized from arginine + glycine
- (+ pyridoxine + riboflavin) → Niacin (= vitamin B3) → NAD+/NADP+
- (+ THB + pyridoxine) → Serotonin → Melatonin
- (+ THB) → Tyrosine (+ THB) → L-Dopa (+ pyridoxine) → Dopamine (+ vitamin C) → Norepinephrine (+ S-Adenosylmethionine) → Epinephrine
Catabolism of amino acids
Metabolic routes: During protein catabolism, amino acids may undergo different metabolic routes for different purposes, including:
AA catabolism, leading to the creation of
- Metabolic fuels (e.g., forming pyruvate, acetyl-CoA)
- Urea for excretion of excess nitrogen
- Reuse in the synthesis of new proteins (See “Translation and protein synthesis.”)
- Creation of amino acid derivatives (See above.)
- See “Protein degradation.”
- AA catabolism, leading to the creation of
Sites of metabolism
- Essential AAs: primarily the liver
- Nonessential AAs: throughout the body
Processes of AA metabolism
- Biochemical reactions of AA
- Splitting of the amino group (via transamination or deamination)
- Splitting of the carboxyl group (via decarboxylation)
- Pyridoxal phosphate (PLP) is an important cofactor, a derivative of vitamin B6, used in transamination, decarboxylation, and deamination of serine.
- Catabolism of the carbon skeleton of amino acids: can be reused as part of carbohydrate or lipid metabolism, or the citric acid cycle
- The urea cycle: Excess nitrogen is converted into urea via the urea cycle and excreted in urine.
- Biochemical reactions of AA
Biochemical reactions of amino acid metabolism
- Description: transfer of an amino group from an AA to an α-ketoacid for breakdown, or to an α-ketoacid to form a nonessential AA
- Transaminases, particularly
- Important cofactor: pyridoxal phosphate (PLP), a derivative of vitamin B6, for transamination and decarboxylation reactions
- Location: Transaminases are found in most cells of the body, but they have greater concentrations in the liver and heart.
Most common examples
- ALT: alanine + α-ketoglutarate ⇄ pyruvate + glutamate
- AST: aspartate + α-ketoglutarate ⇄ oxalacetate + glutamate
- All AAs (except threonine and lysine) undergo transamination at some point in their catabolism.
Glutamate is involved in most transamination reactions and a very important part of AA metabolism.
- Description: reaction in which an amino group from an AA is released as ammonium
- Glutamate dehydrogenase: glutamate + NAD(P)+ + H2O ⇄ α-ketoglutarate + NH4+ + NAD(P)H + H+
- Serine dehydratase: serine + PLP ⇄ NH4+ + pyruvate
- Glutaminase: glutamine + H2O → glutamate + ammonium (irreversible)
- Asparaginase: asparagine + H2O → aspartate + ammonium (irreversible)
Glutamate dehydrogenase can use either NAD+ or NADP+ as a cofactor.
- Description: release of the α-carboxyl group of an AA via splitting of CO2
- Example: : synthesis of biogenic amines via aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), which also uses PLP
Catabolism of the carbon skeleton of amino acids
|Overview of the amino acid carbon skeleton metabolism|
|Category||Amino acids||Metabolism routes|
|Glucogenic amino acids|| |
|Mixed glucogenic/ketogenic amino acids|| |
|Ketogenic amino acids|| |
Routes of AA carbon skeleton metabolism
Glucogenic amino acids
- Are metabolized to pyruvate and to metabolites of the citric acid cycle, then either:
- Oxidized to CO2 in the CAC for production of energy OR
- Utilized as a substrate for gluconeogenesis
- Methionine and valine: metabolized to succinyl-CoA via propionyl-CoA and methylmalonyl-CoA
Methionine cycle: Methionine → S-adenosylmethionine (SAM) → S-adenosylhomocysteine → Homocysteine → Methionine
- S-adenosylmethionine (SAM): plays an important role as a cofactor for methylation reactions (It donates its methyl group for anabolic pathways.)
- S-adenosyl methionine synthase: an enzyme that catalyzes the conversion of methionine and ATP to S-adenosylmethionine; deficiency of this enzyme causes hypermethioninemia
- Homocysteine: Demethylation of SAM results in homocysteine, which can be metabolized to cystathionine and then cysteine.
Ketogenic amino acids
Lysine and leucine are metabolized to acetyl-CoA, then either:
- The acetyl group is oxidized to CO2 in the citric acid cycle for production of energy OR
- Used to synthesize ketone bodies OR
- Used to synthesize fatty acids or cholesterol
Mixed gluconeogenic/ketogenic amino acids
Tyrosine and phenylalanine: metabolized to fumarate and acetyl-CoA
- Tyrosine: transamination through tyrosine transaminase, that is then metabolized through multiple steps to fumarate and acetyl-CoA
- Phenylalanine: first metabolized to tyrosine via phenylalanine hydroxylase (requires O2 and the reducing agent tetrahydrobiopterin), then further metabolized as described above
- Tryptophan: metabolized to alanine and acetyl-CoA, thereby also creating nicotinamide
- Transamination to propionyl-CoA and acetyl-CoA
- Propionyl-CoA is further metabolized to methylmalonyl-CoA to succinyl-CoA
- Glucogenic routes
- → Ketobutyrate → propionyl-CoA (via dehydratase)
- → Amino acetone → pyruvate (via dehydrogenase)
- Ketogenic routes
- → Glycine + acetaldehyde → acetyl-CoA (via aldolase)
- + CoA → glycine + acetyl-CoA (via dehydrogenase coupled with a lyase)
- Glucogenic routes
Lysine and leucine are the only pure ketogenic AAs.
- A cycle of reactions that produce urea; ((NH2)2CO) from ammonia (NH3), bicarbonate (HCO3−), and the amino group of aspartate
- Requires 3 ATP for energy
- Measured as blood urea nitrogen (BUN) for clinical use
- Function: renal excretion of nitrogen in form of urea
- Location: primarily occurs in the cytosol and mitochondria of liver cells and also in kidney cells
Origin of ammonia
- Ammonia develops as a product of various metabolic pathways throughout the body.
- Because of its toxicity, ammonia must be bound to glutamine or alanine for transportation.
Glutamine cycle (most common): transport of ammonia as an amine group attached to glutamine to the liver
- Glutamine synthetase attaches free ammonia to glutamate to form glutamine
- Ammonia is then split from glutamate via oxidative deamination in hepatocytes
- Alanine cycle
- Glutamine cycle (most common): transport of ammonia as an amine group attached to glutamine to the liver
|Urea cycle reactions|
|Reaction||Substrate||Enzyme (+ site of reaction)||Product(s)||Special features|
|1. Entry into the urea cycle: creation of carbamoyl phosphate from HCO3− and NH3|| || || || |
2. Creation of citrulline from carbamoyl phosphate and ornithine
| || || || |
|3. Creation of argininosuccinate from citrulline and aspartate|| || || || |
|4. Hydrolysis of argininosuccinate to arginine and fumarate|| |
|5. Hydrolysis of arginine to urea and ornithine|| || || |
Urea cycle steps (Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, and Urea): “Outrageously Cynical Criticism Antagonizes All my Friends At University”
The rate-limiting step of the urea cycle involves CPS1.
Location of the CPS1 enzyme is “M1tochondria.”
NH2 groups for urea production are derived from carbamoyl phosphate and aspartate, whereas the carbon group comes from bicarbonate.
The mitochondrial carbamoyl phosphate synthetase 1 of the urea cycle should not be confused with the cytosolic carbamoyl phosphate synthetase 2, which is an important enzyme for pyrimidine biosynthesis.
Do not confuse urea with uric acid from purine metabolism.
Synthesis of nonessential amino acids
|Overview of nonessential AA synthesis|
|Development from||Responsible enzyme(s)|
|Asparagine|| || |
|Arginine and Proline|| || |
|Cysteine|| || |
|Serine|| || |
- Synthesis of nonessential AAs occurs mainly in the liver.
- The carbon skeleton is taken from either the citric acid cycle or from carbohydrate catabolism.
Conditions associated with amino acid metabolism
- See “Disorders of amino acid metabolism” for details of the following conditions
Normal intracranial ammonia physiology
- Glutamate and ammonia exist in a chemical equilibrium with glutamine, mediated by the enzyme glutamine synthetase.
- Glutamate serves as a substrate for glutamate decarboxylase to form GABA.
- This mechanism controls GABA concentration and, thus, GABAergic tone.
Elevated serum ammonia levels disrupt the balance between glutamine, glutamate, α-ketoglutarate, and GABA through the actions of glutamate dehydrogenase and glutamine synthetase, resulting in increased glutamine and decreased glutamate levels → low GABA synthesis and GABAergic tone → typical features of hyperammonemic encephalopathy:
- Excess glutamine → osmotic damage to astrocytes → cellular swelling and dysfunction → cerebral edema
- Imbalance of the neurotransmitters → Inhibition of excitatory neurotransmission and activation of inhibitory neurotransmission
- Low α-ketoglutarate → inhibition of TCA cycle
- Elevated serum ammonia levels disrupt the balance between glutamine, glutamate, α-ketoglutarate, and GABA through the actions of glutamate dehydrogenase and glutamine synthetase, resulting in increased glutamine and decreased glutamate levels → low GABA synthesis and GABAergic tone → typical features of hyperammonemic encephalopathy:
Acquired: most common in adults
- Liver failure: naturally occurring nitrogenous wastes in the blood accumulate to toxic levels secondary to impaired urea cycle function in damaged hepatocytes and/or shunting of blood from the portal vein to collateral circulations→ hepatic encephalopathy
- Kidney failure: inability to excrete excess ammonia as urea
- Severe dehydration
- Small intestinal bacterial overgrowth: urease-producing organisms in the gut produce excess ammonia
- Medications (e.g., valproic acid toxicity → carnitine deficiency)
- Reye syndrome
Hereditary: most often in children but heterozygotes can present as older children or adults
- Urea cycle disorders, especially ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase 1 deficiency, N-acetylglutamate synthase deficiency
- Organic acidemias: most commonly methylmalonic acidemia
- Other rare causes including congenital lactic acidosis conditions, dibasic amino aciduria conditions, inborn errors of mitochondrial fatty acid oxidation
- Acquired: most common in adults
- Pediatric patients
- Poor feeding, lethargy
- Respiratory distress
- Flapping tremor (asterixis)
- Blurred vision, slurred speech
- Cerebral edema (caused by osmotic shifts due to change in glutamine levels), seizures, somnolence, and coma
- Pediatric patients
- Depends on the underlying cause and should be conducted ASAP to prevent central nervous system morbidity and possible mortality
- Reduction of protein intake
Medications that lower serum ammonia level
- Lactulose: lowers gastrointestinal pH levels and thereby fixes NH4+ and promotes its excretion
- Antibiotics i.e., rifaximin or neomycin: diminish bacterial population in the gut that produces excess ammonia
- Phenylbutyrate, phenylacetate, or benzoate: form water soluble products with glycine or glutamine that can be excreted through kidneys