Metabolism of Asparagine, Aspartate, Glutamine, and Glutamate in Lymphoid Tissue: Basis for Immunosuppression by L-Asparaginase

Abstract Metabolic properties of lymphoid tissue were examined with a view to elaborating a mechanism by which l-asparaginase acts as an immunosuppressive agent. The study consisted of a) examining the ability of lymphoid tissue to incorporate asparagine, aspartate, glutamine, and glutamate from an exogenous source into cell protein, and b) determining the capacity of the tissue to synthesize these amino acids endogenously. All four amino acids were incorporated into cell protein during shortterm incubations. Under the conditions of study glutamine and glutamate were incorporated to the same degree, but depending on cell density, asparagine was incorporated from 1.3 to 6.3 times as readily as aspartate. The most marked difference was in the biosynthetic capacity of lymphoid tissue with respect to the four amino acids. Asparagine synthetase, as an indicator of the capacity to make asparagine, was barely detectable (0.01 milli-international units (mIU)/mg protein). In contrast, the capacity for glutamine (GSase) was 2200 times as high and for aspartate and glutamate (GOT) 7000 times as great. The limited capacity for asparagine formation implies that it must be supplied from the circulation, and since asparaginase destroys circulating asparagine, immunosuppression results.