Manganese is an essential trace mineral that is the cofactor for multiple enzymes in diverse metabolic pathways — including the arginase (which is the final enzyme of the urea cycle and which converts the arginine to the ornithine and the urea), the glutamine synthetase (which is the enzyme that synthesises the glutamine from the glutamate and the ammonia in the brain and in the astrocytes), the pyruvate carboxylase (which is the enzyme that carboxylates the pyruvate to the oxaloacetate in the gluconeogenesis pathway), the manganese superoxide dismutase (MnSOD, which is the primary defence against the superoxide radical in the mitochondrial matrix), and the glycosyltransferases (which are required for the synthesis of the proteoglycans and of the glycoproteins). This remarkable diversity of the manganese-dependent enzymes reflects the central role of the manganese as a cofactor in the nitrogen metabolism, in the glucose metabolism, in the antioxidant defence, and in the connective tissue synthesis — and it explains why the manganese deficiency produces such a wide range of clinical manifestations, from the neurological dysfunction to the impaired urea excretion to the hypoglycaemia. The typical dietary manganese intake is 2-5mg daily (from the whole grains, the nuts, the seeds, the tea, and the leafy green vegetables), and the estimated safe and adequate intake is 2-3mg daily for adults — the manganese deficiency is rare in the general population (because the manganese is present in a wide variety of plant-based foods), but it can occur in people with the severe malnutrition, with the chronic alcoholism, with the malabsorption syndromes, and with the genetic disorders of the manganese metabolism.
Arginase and the Urea Cycle
The arginase is the final enzyme of the urea cycle — it hydrolyses the arginine to the ornithine and the urea, and it is the enzyme that is responsible for the disposal of the nitrogen that is generated by the protein catabolism. The urea cycle is the primary pathway for the detoxification of the ammonia (which is the nitrogen byproduct of the amino acid catabolism) — the ammonia is converted to the urea (which is non-toxic and water-soluble) and is excreted by the kidneys. The arginase requires manganese as a cofactor — the manganese ion is located at the active site of the enzyme, where it coordinates the arginine substrate and facilitates its hydrolysis. Without adequate manganese and functional arginase, the urea cycle is impaired at its final step, the urea synthesis is reduced, the ammonia accumulates in the blood (hyperammonemia), and the neurological damage develops (because the ammonia is neurotoxic and because the ornithine depletion disrupts the ammonia-shuttling function of the urea cycle). The manganese-dependent arginase deficiency is one of the primary mechanisms of the impaired urea excretion and of the hyperammonemia that are associated with the manganese deficiency.
The clinical importance of the manganese for the arginase function is underscored by the observation that the manganese deficiency impairs the urea cycle function and produces the hyperammonemia — particularly in people with the genetic defects in the urea cycle enzymes (such as the arginase deficiency, which is one of the urea cycle disorders that is characterised by the hyperammonemia, the intellectual disability, and the epilepsy). The management of the urea cycle disorders involves the dietary restriction of the protein (to reduce the ammonia production), the supplementation with the essential amino acids (to prevent the nutritional deficiencies that would result from the protein restriction), and the supplementation with the manganese and the other cofactors of the urea cycle enzymes (to maximise the residual activity of the defective enzymes).
Glutamine Synthetase and the Brain Ammonia Detoxification
The glutamine synthetase (GS) is the enzyme that synthesises the glutamine from the glutamate and the ammonia in the astrocytes of the brain — it is the primary enzyme that detoxifies the ammonia in the central nervous system, and it is therefore essential for the prevention of the ammonia neurotoxicity. The astrocytes are the most important cells for the ammonia detoxification in the brain — they take up the glutamate (which is released by the neurons during the synaptic transmission) and the ammonia (which is generated by the astrocytes during the glutamate metabolism) and convert them to the glutamine by the glutamine synthetase reaction. The glutamine is then released by the astrocytes and taken up by the neurons, where it is converted back to the glutamate (for the neurotransmitter synthesis) — this glutamine-glutamate cycle is the primary mechanism for the recycling of the glutamate and for the detoxification of the ammonia in the brain. Without adequate manganese and functional glutamine synthetase, the astrocytes cannot convert the glutamate and the ammonia to the glutamine, the glutamate accumulates in the synaptic cleft (producing the excitotoxicity), the ammonia accumulates in the brain (producing the neurotoxicity), and the cognitive impairment, the seizures, and the coma develop — which are the hallmarks of the severe hyperammonemia.
Practical Application
For general manganese supplementation, the evidence-based approach is to supplement with 2-5mg of manganese daily (as manganese gluconate, manganese citrate, or manganese aspartate — the forms that are well absorbed and well tolerated). Most people achieve adequate manganese from a varied diet — manganese is found in whole grains, nuts, seeds, tea, and leafy green vegetables. The RDA of manganese has not been established (because the manganese deficiency is so rare), but the estimated safe and adequate intake is 2-3mg daily for adults. The tolerable upper intake level is 11mg daily for adults — above which the manganese can interfere with the iron absorption and produce the neurological symptoms of the manganese toxicity (which are similar to the symptoms of the Parkinson’s disease, because the manganese accumulates in the basal ganglia). For comprehensive nitrogen metabolism and neurological support, manganese pairs well with the zinc (which is required for the arginase activity and for the immune function), with the magnesium (which is a cofactor for many of the enzymes of the nitrogen metabolism), with the vitamin B6 (which is required for the transamination reactions that generate the glutamate from the amino acids), and with the alpha-lipoic acid (which has antioxidant effects and which protects the astrocytes from the oxidative stress).
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