Experiments That Changed Nutritional Thinking - TUUM EST

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FIGURE 1 Intermediates in the conversion of tryptophan to niacin
in N. crassa and rats.
Trp / AA (Thr or Lys) r Protein
f
Niacin
When an essential amino acid, such as threonine, is supplied
at just below the optimum level, moderately good growth oc-
curs and the marginal tryptophan level meets the needs for
both protein and niacin synthesis. When the threonine in the
The most likely explanation for the interchangeability of
niacin, required at 1 mg% of the diet, and tryptophan, required
at 40 times that molar concentration, was the conversion of
tryptophan to niacin. The fact that 2% acid-hydrolyzed casein
(tryptophan destroyed) could replace 40% corn grits in causing
the deficiency suggested that an increase in the levels of other
amino acids was inducing the deficiency. This effect was
termed ‘‘amino acid imbalance.’’ The amino acids most effective
in producing the deficiency were threonine and lysine
(Hankes et al. 1948), but additional sulfur amino acids were
needed to maximize the effect. Therefore, in subsequent studies
0.2% L-cystine was added to the basal diet (Table 1). The
explanation offered for the effect of other amino acids on the
growth of rats fed the 9% casein / 0.2% L-cystine diets is
illustrated as follows:
diet is elevated, protein synthesis increases, tryptophan is
drawn into this function at the expense of the alternate pathway
to niacin, and the vitamin deficiency results. That this
explanation for the effect of threonine is valid is supported by
the results of similar imbalance studies that showed that lysine,
valine, leucine and isoleucine also produce growth inhibition
that is reversed by tryptophan or niacin (Koeppe and Henderson
1955).
Many isotopic labeling studies with rats have confirmed
the conversion of tryptophan to niacin. The first evidence
regarding the reactions involved came from experiments with
mutants of the mold Neurospora crassa (Fig. 1). The first four
compounds in this scheme were verified in animal systems,
and quinolinic acid was added when it was identified as an
excretory product of tryptophan in mammals and a rather
ineffective niacin substitute in rats and a niacin-less mutant
of N. crassa (Henderson 1949).
Quinolinic and picolinic acids are formed by the incubation
of 3-hydroxyanthranilate with mammalian liver (Fig. 2). Nei-
ther is degraded to carbon dioxide even in vivo. That they
arise from intermediates in the degradation of tryptophan to
glutarate was established by the report of Gholson et al.
(1962). It is evident that picolinate and quinolinate arise by
formation of cyclic Shiff’s bases from intermediates in the
degradation of tryptophan, and they can be considered side
reaction products of the degradative pathway.
The limited activity of exogenous quinolinate as a dietary
replacement for niacin cast doubt on its intermediary role in
the formation of niacin. This limited activity probably results
from the failure of the salts of quinolinic acid to penetrate the
cells in which it normally arises. It is a strong acid and because
it is obliged to enter cells in the undissociated form, a proper
pH for its penetration is much below physiological pH values.
The role of quinolinate in the formation of niacin was clarified
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FIGURE 2
Simplified scheme for the total metabolism of tryptophan and its conversion to pyridinium compounds, including niacin.
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