Reaction direction: The direction of the reaction depends on the relative concentrations of glutamate, α-ketoglutarate, and ammonia and the ratio of oxidized to reduced coenzymes. For example, after ingestion of a meal containing protein, glutamate levels in the liver are elevated, and the reaction proceeds in the direction of amino acid degradation and the formation of ammonia (see Fig. 19.12A). High ammonia levels are required to drive the reaction to glutamate synthesis.
c.
Allosteric regulators: Guanosine triphosphate is an allosteric inhibitor of GDH, whereas adenosine diphosphate is an activator. Therefore, when energy levels are low in the cell, amino acid degradation by GDH is high, facilitating energy production from the carbon skeletons derived from amino acids.
2. d-Amino acid oxidase: D-Amino acids (see p. 5) are supplied by the diet but are not used in the synthesis of mammalian proteins. They are, however, efficiently metabolized to α-keto acids, ammonia, and hydrogen peroxide in the peroxisomes of liver and kidney cells by flavin adenine dinucleotide–dependent D-amino acid oxidase (DAO). The αketo acids can enter the general pathways of amino acid metabolism and be reaminated to L-isomers or catabolized for energy. [Note: DAO degrades D-serine, the isomeric form of serine that modulates N-methylD-aspartate (NMDA)-type glutamate receptors. Increased DAO activity has been linked to increased susceptibility to schizophrenia. DAO also converts glycine to glyoxylate (see p. 263).] L-Amino acid oxidases are found in snake venom.
C. Ammonia transport to the liver
Two mechanisms are available in humans for the transport of ammonia from peripheral tissues to the liver for conversion to urea. Both are important in, but not exclusive to, skeletal muscle. The first uses glutamine synthetase to combine ammonia with glutamate to form glutamine, a nontoxic transport form of ammonia (Fig. 19.13). The glutamine is transported in the blood to the liver where it is cleaved by glutaminase to glutamate and ammonia (see p. 256). The glutamate is oxidatively deaminated to ammonia and α-ketoglutarate by GDH. The ammonia is converted to urea. The second transport mechanism involves the formation of alanine by the transamination of pyruvate produced from both aerobic glycolysis and metabolism of the succinyl coenzyme A (CoA) generated by the catabolism of the BCAA isoleucine and valine. Alanine is transported in the blood to the liver, where it is transaminated by ALT to pyruvate. The pyruvate is used to synthesize glucose, which can enter the blood and be used by muscle, a pathway called the glucose–alanine cycle. The glutamate product of ALT can be deaminated by GDH, generating ammonia. Thus, both alanine and glutamine carry ammonia to the liver.
V. UREA CYCLE is the major disposal form of amino groups derived from amino acids and accounts for ~90% of the nitrogen-containing components of urine. One nitrogen of the urea molecule is supplied by free ammonia and the other nitrogen by aspartate. [Note: Glutamate is the immediate precursor of both ammonia (through oxidative deamination by GDH) and aspartate nitrogen (through transamination of oxaloacetate by AST).] The carbon and oxygen of urea are derived from CO2 (as HCO3−). Urea is produced by the liver and then is transported in the blood to the kidneys for excretion in the urine.