Toxic action of ammonia
Ammonia (NH₃) is a highly toxic compound formed during the deamination of amino acids, biogenic amines, and nucleotides, as well as by intestinal bacterial flora. Ammonia poses a particular danger to the central nervous system: blood concentrations above 60 µmol/L lead to encephalopathy, tremor, and impaired consciousness ranging up to coma.
The mechanisms of ammonia neurotoxicity are diverse, acting primarily through the disruption of neuronal energy metabolism and neurotransmitter imbalance.
Mechanisms of neurotoxicity
- Depletion of α-ketoglutarate. Ammonia is actively bound by glutamate dehydrogenase to form glutamate from α-ketoglutarate. A decrease in α-ketoglutarate inhibits the Krebs cycle and leads to energy deficit in neurons.
- Decreased ATP synthesis. Suppression of the TCA cycle is accompanied by a drop in NADH and FADH₂ production, which reduces electron flow into the respiratory chain.
- Accumulation of glutamine. In astrocytes, glutamine synthetase attaches ammonia to glutamate to form glutamine. Excess glutamine increases osmotic pressure, causing astrocyte swelling and intracranial hypertension.
- Impairment of neurotransmitter balance. Glutamate levels as an excitatory neurotransmitter decrease, GABA synthesis is disrupted, and the pool of glycine, an inhibitory neurotransmitter of the spinal cord, is depleted.
- Alkalosis. NH₃ binds protons to form NH₄⁺, which shifts pH toward alkalinity and reduces oxyhemoglobin dissociation.
Pathways of ammonia detoxification
The body has several mechanisms for binding and excreting ammonia:
- Glutamine synthesis via glutamine synthetase is the primary transport mechanism for ammonia from peripheral tissues and the brain to the liver and kidneys.
- The urea cycle in hepatocytes with urea formation is the main pathway of nitrogen excretion in humans.
- Renal ammoniagenesis involves the hydrolysis of glutamine by glutaminase with the release of NH₄⁺ into the urine, simultaneously maintaining acid-base balance.
- Reductive amination of α-ketoglutarate to form glutamate.
Folic acid and one-carbon units
Folic acid (vitamin B9) consists of a pteridine ring, para-aminobenzoic acid (PABA), and glutamate residues. The active form is tetrahydrofolate (THF, H₄-folate), formed by a two-step reduction catalyzed by dihydrofolate reductase.
THF carries one-carbon fragments in various oxidation states: methyl (–CH₃), methylene (–CH₂–), methenyl (=CH–), formyl (–CHO), and formimino. Sources of these fragments include serine, glycine, histidine, and formate.
THF derivatives are essential for the synthesis of purines, thymidylate (dTMP from dUMP), methionine, and the regeneration of glycine.
Antifolate and antibacterial drugs
- Sulfonamides are structural analogs of PABA; they competitively inhibit bacterial dihydropteroate synthase, disrupting folate synthesis. Because humans obtain folate through diet, the selectivity of action is high.
- Trimethoprim selectively inhibits bacterial dihydrofolate reductase.
- Methotrexate blocks human DHFR and is used as an antineoplastic agent.
Methionine metabolism and the methylation cycle
Methionine is an essential sulfur-containing amino acid. Its active form is S-adenosylmethionine (SAM), formed by methionine adenosyltransferase in the presence of ATP. SAM is a universal methyl group donor in reactions of DNA and histone methylation, as well as the synthesis of creatine, phosphatidylcholine, adrenaline, and the inactivation of catecholamines.
After donating its methyl group, SAM is converted to S-adenosylhomocysteine and then to homocysteine. The subsequent fate of homocysteine is twofold:
- Remethylation to methionine involving methionine synthase; cofactors include methyl-THF and vitamin B12 (methylcobalamin).
- Transsulfuration leading to cystathionine and further to cysteine with the participation of cystathionine β-synthase (cofactor: pyridoxal phosphate, B6).
Hyperhomocysteinemia
Deficiency of folate, B12, or B6, as well as genetic enzyme defects (e.g., methylenetetrahydrofolate reductase, MTHFR), leads to the accumulation of homocysteine. Hyperhomocysteinemia damages the vascular endothelium, activates oxidative stress and thrombogenesis, thereby increasing the risk of atherosclerosis, myocardial infarction, stroke, and venous thrombosis. In pregnant women, folate deficiency is associated with fetal neural tube defects.
Key points
- Ammonia toxicity is linked to the depletion of α-ketoglutarate, accumulation of glutamine, and astrocyte swelling.
- Glutamine is the primary transport form of ammonia; urea is the main pathway of its excretion.
- Tetrahydrofolate carries one-carbon fragments in reactions of purine, thymidylate, and methionine synthesis.
- Sulfonamides, acting as PABA analogs, selectively block bacterial folate synthesis.
- S-adenosylmethionine is a universal methyl group donor in the body.
- Homocysteine remethylation requires folate and vitamin B12, whereas transsulfuration requires vitamin B6.
- Hyperhomocysteinemia is a risk factor for atherosclerosis, thrombosis, and neural tube defects.