The presence in many animal tissues of enzymes that catalyze the synthesis of glutamine from glutamate and also the hydrolysis of glutamine to glutamate and ammonia was first reported by Krebs in 1935 (1). These classic studies alluded to a metabolic role for this amino acid apart from its function as a protein constituent. A central role for glutamine in nitrogen metabolism soon became evident. The early studies dealing with mammalian glutamine metabolism have been excellently reviewed by Archibald (2) and Meister (3). Glutamine is found in high concentration in many animal cells, where it serves, on the one hand, as an ammonia scavenger and, on the other hand, as an amide nitrogen or amino nitrogen donor in reactions leading to the biosynthesis of a number of important metabolites, including the pyridine, purine, and pyrimidine nucleotides, amino sugars, asparagine, and other amino acids (4). Glutamine in most animals is also the most abundant amino acid in the blood. Functionally, circulating glutamine has been viewed as an important vehicle (a) whereby nitrogen, during metabolic acidosis, is delivered to the kidneys for the production of urinary ammonia (5) and (b) whereby in ureotelic species, waste nitrogen derived from catabolic reactions in peripheral tissues is delivered directly to the liver for the biosynthesis of urea. This latter concept emerged from the results of a variety of studies. When glutamine, labeled in the amide group with 15N, was injected intravenously into rats, the label was rapidly cleared from the circulation and 66% of it was recovered in urinary urea (6). A massive intravenous glutamine injection produced an accumulation of the amino acid in the liver and kidneys (7). When infused intravenously into dogs, glutamine produced a larger increment in the urinary output of urea than did any other amino acid (8). Finally, liver was found to contain several enzymes catalyzing glutamine catabolism:(a) an a-keto acid-stimulated enzyme (9), later