Amino acid 3( transport of ammonia) parrt1

Reduced N enters the human body as dietary free amino acids, protein and as ammonia produced by intestinal tract bacteria.

glutamate dehydrogenase and glutamine synthatase effect the conversion of ammonia into the amino acids glutamate and glutamine.

Glu and Gln precursos for non essential aa, neurotransmitters, urea

Gln co substrate for formation of asparagine

The Glu and Gln synthesis reaction uniquely incorporates free ammonium ions and is important for ammonia metabolism and detoxification.

Compounds from transamination can be oxidatively deaminated, producing ammonia, or their amine groups are converted to urea by the urea cycle .

GLUTAMATE DEHYDROGENASE, GLUTAMINE SYNTHETASE &

GLUTAMINASE REACTION

The metabolic pathway for the synthesis of glutamate and glutamine involves:

i) Conversion of alpha-ketoglutarate to glutamate by enzyme glutamate dehydrogenase, an NADPH requiring an enzyme that incorporates free ammonia into alpha-ketoglutarate.

ii) Conversion of glutamate to glutamine is catalyzed by Glutamine synthetase which incorporates ammonium ion and utilizes ATP as energy.

iii) Glutamine when combined with water in the presence of glutaminase can form glutamate and NH4+

GLUTAMINE SYNTHETASE

Plays a vital role in regulating nitrogen levels in molecules such as DNA & aa

GS ensures that nitrogen is efficiently transferred to nitrogen-deficient molecules and slows down the transfer to nitrogen-rich molecules.

Plants: GS detoxifies ammonia.

Animals: GS recycles amino acid neurotransmitters and detoxifies ammonia.

GS is primarily found in astrocytes, which protects neurons against excitotoxicity by converting excess ammonia and neurotoxic glutamate into less harmful glutamine.

Malfunction of GS can lead to neurological diseases like Alzheimer’s, epilepsy, and glioblastoma multiforme

GLUTAMATE DEHYDROGENASE AND GLUTAMINE SYNTHASE REACTION

Liver contains both glutamine synthetase and glutaminase which are localized in different cellular segments.

Differences in cellular location allows the liver to scavenge ammonia that has not been incorporated into urea.

Urea cycle enzymes are located in the same cells as glutaminase.

Differential distribution of these two hepatic enzymes enables the liver to control ammonia incorporation into either urea or glutamine.

Glutamine is the major carrier of NH3 from peripheral tissues to the kidney.

In acidosis, the body will divert more glutamine from the liver to the kidney allowing for the conservation of bicarbonate ion since the incorporation of ammonia into urea in the liver requires bicarbonate.

When glutamine enters the kidney, glutaminase releases one mole of NH3 from glutamate and then glutamate dehydrogenase releases another mole of ammonia generating -ketoglutarate.

The ammonia will ionizes to ammonium ion (NH4+) which is excreted. The net effect is a reduction in the pH.

In peripheral tissues excess ammonia is converted to non toxic compounds before transport to the liver and kidney

In many peripheral tissues, ammonia is converted to glutamine in a reaction catalyzed by glutamine synthetase

Glutamine is then transported in the blood to the liver where it is converted to glutamate by glutaminase in the mitochondria

In the skeletal muscle, ammonia is transported as alanine via the alanine-glucose cycle

Alanine is transported in the blood to the liver where it is converted to pyruvate and glutamate in a transamination reaction

Glutamate may be converted to urea whereas pyruvate may be converted to glucose via gluconeogenesis

The glucose may be transported to the skeletal muscle for its contractile activity

The alanine-glucose cycle thus imposes the burden of gluconeogenesis on the liver rather than the muscle.

Ammonia is toxic to mammalian cells for the following reasons:

Accumulated ammonia reverses the glutamate dehydrogenase reaction thus depleting the cell of α-ketoglutarate

This will lead to depressed synthesis of ATP which will thus affect active transport systems.

Impaired active transport will lead to loss of electrochemical gradient which is paramount to the transfer of impulses.

The accumulation of ammonia may also impede the synthesis of GABA which is a neurotransmitter.

Accumulated ammonia may also result in acid-base disturbances

It may also inhibit amino acid transport and the Na+-K+ ATPase system