Nutrition and Metabolism of Proteins 57In bacteria and plant chloroplasts, glutamate is
produced by the action of glutamate synthase, accord-
ing to the reaction:
α-Ketoglutarate + glutamine + NADPH + H+
→ 2 Glutamate + NADP (4.3)The sum of the glutamate synthase (eqn 4.3)
and glutamine synthetase (eqn 4.1) reactions is,
therefore:
α-Ketoglutarate + NH+ 4 + NADPH + AT P
→ Glutamate + NADP + ADP + Pi (4.4)
Hence, the two reactions combined (eqn 4.4) give
a net synthesis of one molecule of glutamate. However,
because glutamate synthetase is not present in animal
tissues, a net incorporation of ammonia nitrogen via
this nitrogen cycle arises primarily from glutamate
rather than from glutamine. A net accumulation of
glutamine would be achieved via the glutamine syn-
thetase reaction that uses ammonia, which would be
derived from various sources including glutamate or
other amino acids or via hydrolysis of urea by the
microfl ora on the intestinal lumen.
A net incorporation of ammonia into glycine might
also be achieved via the glycine synthase (glycine
cleavage) reaction, as follows:
CO 2 + NH+ 4 H+ + NAD + N 5 ,N 10 -
Methylenetetrahydrofolate
∫ Glycine + NAD+^ + Tetrahydrofolate (4.5)The glycine could then be incorporated into proteins
and into such compounds as glutathione, creatine,
and the porphyrins, as well as being converted to
serine. The nitrogen of serine would then either be
available for cysteine (and taurine) synthesis or be
released as ammonia via the serine dehydratase reac-
tion. However, the glycine cleavage reaction appears
to be more important in glycine catabolism than for
its synthesis. Therefore, the glycine–serine pathway of
ammonia incorporation into the amino acid economy
of the organism would appear to have only a limited
effect on a net nitrogen input into the amino acid
economy of the body. Serine can be formed from
glucose via 3-phosphoglycerate, which comes from
carbohydrate metabolism, and its nitrogen obtained
from glutamic acid synthesis via transamination with
2-ketoglutarate.
This suggests, therefore, the possibility that gluta-
mate is a key amino acid in making net amino
nitrogen available to the mammalian organism; this
glutamate would be derived ultimately from plant
protein. In this sense, glutamate or its lower homo-
logue, aspartic acid, which could supply the α-amino
nitrogen for glutamate, or its derivative, glutamine,
would be required as a source of α-amino nitrogen.
While additional research is necessary to determine
whether glutamate, or one of these metabolically
related amino acids, would be the most effi cient
source of α-amino nitrogen, these considerations
potentially offer a new perspective on the NSN com-
ponent of the total protein requirement. In 1965, a
United Nations expert group stated:
The proportion of nonessential amino acid
nitrogen, and hence the E/T [total essential or
indispensable amino acids to total nitrogen]
ratio of the diet, has an obvious infl uence on
essential amino acid requirements .... To make
the best use of the available food supplies there
is an obvious need to determine the minimum
E/T ratios for different physiological states ....
Finally, the question arises whether there is an
optimal pattern of nonessential amino acids.
This statement can just as well be repeated today,
but clearly recent studies are beginning to provide
deeper metabolic insights into the nature of the NSN
needs of the human body.“Conditional” indispensability
A contemporary nutritional classifi cation of amino
acids in human nutrition is given in Table 4.5 and
some points should be made here about the “condi-
tionally” indispensable amino acids, a term that is
used to indicate that there are measurable limitations
to the rate at which they can be synthesized. There are
several important determinants. First, their synthesis
requires the provision of another amino acid, either as
the carbon donor (e.g., citrulline in the case of argi-
nine synthesis or serine in the case of glycine synthe-
sis) or as a donor of an accessory group (e.g., the sulfur
group of methionine for cysteine synthesis). The
ability of the organism to synthesize a conditionally
essential amino acid is, therefore, set by the availabil-
ity of its amino acid precursor. Second, some of these
amino acids are synthesized in only a limited number
of tissues. The best example of this is the crucial
dependence of the synthesis of proline and arginine
on intestinal metabolism. Third, most evidence sug-