Metabolic Fates of Amino Groups:- Glutamate Releases Its Amino Group as Ammonia in the Liver
As we have seen, the amino groups from many of theα -amino acids are collected in the liver in the form of the amino group of L-glutamate molecules. These amino groups must next be removed from glutamate to pre pare them for excretion. In hepatocytes, glutamate is transported from the cytosol into mitochondria, where it undergoes oxidative deamination catalyzed by L glutamate dehydrogenase (Mr330,000). In mammals, this enzyme is present in the mitochondrial matrix. It is the only enzyme that can use either NAD+ or NADP+ as the acceptor of reducing equivalents (Fig. 18–7). The combined action of an aminotransferase and glutamate dehydrogenase is referred to as transdeamination. A few amino acids bypass the transdeamination pathway and undergo direct oxidative deamination. The fate of the NH+4 produced by any of these deamination processes is discussed in detail in Section 18.2. The -ketoglutarate formed from glutamate deamination can be used in the citric acid cycle and for glucose synthesis.
Glutamate dehydrogenase operates at an important intersection of carbon and nitrogen metabolism. An allosteric enzyme with six identical subunits, its activity is influenced by a complicated array of allosteric modulators. The best-studied of these are the positive modulator ADP and the negative modulator GTP. The metabolic rationale for this regulatory pattern has not been elucidated in detail. Mutations that alter the allosteric binding site for GTP or otherwise cause permanent activation of glutamate dehydrogenase lead to a human genetic disorder called hyperinsulinism-hyperammonemia syndrome, characterized by elevated levels of ammonia in the bloodstream and hypoglycemia.
MECHANISM FIGURE 18–6 Some amino acid transformations at the α carbon that are facilitated by pyridoxal phosphate. Pyridoxal phosphate is generally bonded to the enzyme through a Schiff base (see Fig. 18–5b, d). Reactions begin (top left) with formation of a new Schiff base (aldimine) between the -amino group of the amino acid and PLP, which substitutes for the enzyme-PLP linkage. Three alternative fates for this Schiff base are shown: A transamination, B racemization, and C decarboxylation. The Schiff base formed between PLP and the amino acid is in conjugation with the pyridinering, an electron sink that permits delocalization of an electron pair to avoid formation of an unstable carbanion on the α carbon (inset). A quinonoid inter mediate is involved in all three types of reactions. The transamination route (A) is especially important in the pathways described in this chapter. The pathway highlighted here (shown left to right) represents only part of the overall reaction catalyzed by aminotransferases. To complete the process, a second α -keto acid replaces the one that is released, and this is converted to an amino acid in a reversal of the reaction steps (right to left). Pyridoxal phosphate is also involved in certain reactions at the β and γ carbons of some amino acids (not shown).
FIGURE 18–7 Reaction catalyzed by glutamate dehydrogenase. The glutamate dehydrogenase of mammalian liver has the unusual capacity to use either NAD+ or NADP+ as cofactor. The glutamate dehydrogenases of plants and microorganisms are generally specific for one or the other. The mammalian enzyme is allosterically regulated by GTP and ADP.
