“a 
GLUTAMIC ACID METABOLISM IN BRAIN AND LIVER 72 
than by a regulation of its transport. Glucose is the respiratory substrate of the 
brain, and its oxidation provides all the utilizable energy, the major portion by direct 
oxidation and the rest through alternate routes such as the metabolism of amino 
acids or lipid constituents into which the intermediates of glucose metabolism have 
been incorporated. In the oxidation of glucose and in the utilization of the generated 
adenosine triphosphate (ATP), we are faced with the major problem of metabolic 
pools on all levels of cell organization, since ATP is generated in the mitochondrial 
compartment but is utilized for rejuvenation of structure and support of function in 
various compartments to differing degrees. For the purpose of this discussion the 
yield of ATP derived from glycolysis may be neglected. The resynthesis of ATP willalso 
TABLE I 
NERVOUS-SYSTEM COMPARTMENTS ON DIFFERENT LEVELS 
OF ORGANIZATION 
Arrow indicates increasing degree of attempted biochemical 
interpretation. 



Level of organization Compartments 


Organ CNS, Blood 
Tissue Extracellular space, neuron, glia 
Cell Cell body, dendrites, axon, synapse 
+ Subcellular Nucleus, mitochondria, endoplasmic reticulum 

depend on the flow of the necessary substrates and coenzymes into the compartment 
of oxidative phosphorylation. The most significant consequence of the compart- 
mentation of ATP formation and utilization is the control and regulation of these 
processes. 
The concept of metabolic compartments as a tool for the understanding of inter- 
mediary metabolism was forced upon us when we were unable to interpret experi- 
mental results obtained 7m vivo by the conventional assumptions? ‘. It also pointed 
to a way to study metabolic compartments in the intact mammalian organism, and 
in particular, in the brain 7 vivo. Practically all experimental results obtained in 
other laboratories concerned with regulation and controls of metabolism, and thereby 
indirectly with metabolic compartments, were obtained either on tissue preparations, 
yeast, or ascites cells. All our experiments dealt with the metabolism of glutamic 
acid in the central nervous system, and in particular, with the conversion of glutamic 
acid to glutamine. They serve as a model of how the compartmentation of metabolic 
events may be demonstrated and studied 7m vivo. Glutamic acid occupies a central 
position in the intermediary metabolism of all tissues but particularly in the nervous 
system. Indicative of this fact may be the exceptionally high concentration of 10-12 
umoles/g of brain. Besides the participation in the metabolism of the citric acid cycle, 
by virtue of ketoglutarate, and in the metabolism of amino acids, glutamic acid is the 
precursor of y-aminobutyric acid (GABA). The conversion of glutamic acid to glutamine 
represents, as will become apparent, the major removal mechanism for ammonia in ner- 
vous tissue. This conversion is catalyzed by glutamine synthetase and isan AT P-depen- 
dent synthesis of the amide linkage of the y-carboxyl of glutamic acid. This pathway is, 
as far as we know (and this will be of significance later on), the only way by which glu- 
References p. 730 
