Biochemistry - The Chemical Reactions of Living Cells, Volume 3 - D. Metzler 1980

Nitrogen Compound Metabolism
Compounds Derived from Aspartate

Aspartate, a four-carbon molecule, serves as the starting point for the Biosynthesis of Pyrimidines and several Amino Acids, including Lysine, Methionine, isoleucine, and asparagine. These Metabolic pathways are summarized in Fig. 14-6. Note the several branching points present. Aspartate can be directly converted into asparagine, carbamoylaspartate (a pyrimidine precursor), β-aspartyl phosphate, or aspartate semialdehyde. The latter can be channeled into one pathway to yield lysine or another to yield homoserine. Homoserine can then be converted into either homocysteine and methionine, or Threonine. Although threonine is a final product incorporated directly into Proteins, it can be further metabolized to α-ketobutyrate, the precursor of isoleucine.

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FIG. 14-6. Selected biosynthetic pathways of aspartic acid; a minus sign in a circle denotes inhibition, and a minus sign in a square denotes repression (feedback regulation).

Most of these chemical steps have been discussed previously. The reduction of aspartate via β-aspartyl phosphate proceeds in a standard manner. The conversion to methionine can follow two routes. In E. coli, homoserine is succinylated by succinyl-CoA. The γ-succinyl group is subsequently displaced by a Cysteine molecule via a PLP-dependent γ-replacement reaction (Fig. 14-6). The product of this reaction, cystathionine [Equation (8-22)], undergoes β-elimination to yield homocysteine. Alternatively, in Neurospora, a more direct γ-replacement of the homoserine hydroxyl group by a sulfide ion takes place. The methylation of homocysteine to form methionine was discussed earlier [Equation (8-45)], as was The conversion of homoserine to threonine catalyzed by PLP-dependent threonine synthetase (Chap. 8, Sec. D, 3, g). A standard PLP-dependent β-elimination converts threonine into α-ketobutyrate, the precursor of isoleucine (Fig. 14-10).

The formation of asparagine proceeds analogously to that of glutamine. However, E. coli asparagine synthetase [45] cleaves ATP to AMP and PP_i without forming ADP. It is widely accepted that a β-aspartyl adenylate intermediate is formed during the process. In higher animals, glutamine serves as the primary ammonia donor for asparagine synthesis, although free NH⁺₄ can also be utilized directly [46].

L-asparaginase, a bacterial hydrolytic enzyme, has proven to be an effective therapeutic agent against leukemia; when injected into the bloodstream, it depletes the exogenous asparagine required by tumor Cells for their rapid proliferation [47]. However, this enzyme also affects Tissues with low asparaginase synthetase activity, which limits its clinical application.