216 
NATURE 
[OcTOBER 16, 1913 
hippuric acid in animal fluids, these authors proved, 
by a method of exclusion, that, in the dog at least, 
the kidney is the seat of the hippuric synthesis. When, 
in their carefully controlled experiments, blood con- 
taining benzoic acid and glycine was circulated 
through that organ, after its isolation from the body, 
the production of hippuric acid followed. Schmiede- 
berg, a little later, convinced himself that the reaction 
in the kidney was a balanced one; the organ can not 
only synthesise hippuric acid, it can also hydrolise it. 
As with reactions elsewhere, so in the kidney cell, 
the equilibrium of the reaction depends on the relative 
concentration of the products concerned. Schmiede- 
berg then separated from the tissues of the kidney 
what he believed to be an enzyme capable of inducing 
the hydrolysis. Mutch, with improved methods, has 
recently shown that a preparation from the kidney, 
wholly free from intact cells, can, beyond all doubt, 
hydrolise hippuric acid under rigidly aseptic condi- 
tions, the reaction being one which comes to an 
equilibrium point when some 97 per cent. of the sub- 
stance is broken down. The occurrence of this equili- 
brium, and the form of the reaction-velocity curve as 
obtained by Mutch, suggested that synthesis under 
the influence of the enzyme was to be expected, and, 
on submitting the mixture of benzoic acid and glycine 
to its influence, Mutch obtained a product which, 
though too small in amount for analysis, was almost 
certainly hippuric acid. I have myself obtained 
evidence which shows that the synthesis does certainly 
occur under these conditions. 
The significance of this earliest known synthesis in 
the body is no limited one. The amide linkage estab- 
lished by it is one with which the body deals widely, 
and is, of course, of the type which is dominant in 
tissue complexes, since it is one which unites the 
amino-acids in the protein molecule. 
Seeing, from the nature of the material supplied 
for the synthesis by the body itself, that the foreign 
substances administered must intrude themselves into 
the machinery of protein metabolism, it is not sur- 
prising that many have turned their minds to consider 
how far a detailed study of the phenomena might 
throw light upon this machinery. How far can the 
body extend its supply of glycine when stimulated 
by increasing doses of benzoic acid? What effects 
follow when administration is pushed to its limits? 
How is the fate in metabolism of the whole molecule 
of protein affected when one particular amino-acid is 
inharmoniously removed? Can the amino-acid be 
itself synthesised de novo in response to the call for 
it? These and similar questions clearly arise. I can 
only stop to remind you that there is evidence that, 
in connection with this, particular chemical synthesis, 
the carnivore reacts differently to the herbivore. If 
the body of the former be flooded with benzoic acid, 
only a proportion undergoes condensation. Only so 
much glycine is supplied as would correspond, roughly, 
at any rate, with that rendered available by the normal 
contemporary breakdown of protein, whereas, in the 
herbivorous animal, pushing the administration of 
benzoic acid may lead to the excretion of so much 
conjugated glycine that it may contain more than half 
of the whole nitrogen excreted. This is, of course, 
much more than could come from the protein of the 
body, and it would seem that the amino-acid is pre- 
pared de novo for an express purpose, a significant 
thing. But I must not stop to consider questions 
which are still in course of study. Before the hippuric 
synthesis was first observed synthetic powers were 
thought to be absent from the animal. Since then 
we have been continuously learning of fresh instances 
of synthesis in the body, not only in connection with 
its treatment of foreign substances, with which I am 
NO. 2294, VOL. 92] 
| 
just now concerned, but in connection with all it 
normal processes. ‘ af 
Another most interesting group of syntheses i 
which substances are so dealt with in the body as to 
reappear in conjugation with protein derivatives ar 
those in which the sulphur group plays its part. In 
1876 Baumann first introduced us to the ethereal 
sulphates of the urine, and, from much subsequen 
work, we know how great a group of substances, 
chiefly those of phenolic character, are, after adminis- 
tration, excreted linked to sulphuric acid. We have 
evidence to show that, in all prebability, the original 
condensation is not with sulphuric acid itself, but 
that oxidation of a previously formed sulphur contain- 
ing conjugate has preceded excretion, and we know 
that another group of substances leave the body com- 
bined with unoxidised sulphur. Certain cyanides—_ 
the aliphatic nitriles, for example—reappear as sulpho- 
cyanides; but, above all in interest, is the case de-— 
scribed by Baumann, in which the intact cystein 
complex of protein, after suffering acetylation of its 
amino group, is excreted as a conjugate. The ad- 
ministration of halogen-benzene compounds is followed 
by the appearance of the so-called mercapturic acids 
in which the cystein is linked by its sulphur atom 
to the ring of chlor-, bromo-, or iodi-benzene. That 
large amounts of these conjugates can be formed 
during the twenty-four hours is certain, but it would 
be interesting to know what limit is set to this loss — 
of cystin from the body. 
I will now recall to you syntheses in which the © 
substance supplied by the body is derived, not from 
protein, but from carbohydrate. The study of the 
fate of camphor in the body, carried out by Schmiede- 
berg and Hans Meyer in 1878, if it stood by itself, 
would abundantly illustrate the significance of this 
type of experiment. As you are aware, these workers 
proved that, after the administration of camphor, the 
urine contains a conjugate formed between an oxidation 
product of the camphor and an oxidation product of 
glucose. Both substances were then new to chem- 
istry, and the latter—glycuronic acid—has_ since 
proved itself of great physiological interest. After 
Schmiedeberg’s and Hans Meyer’s experiments it was 
realised for the first time that the sugar molecule 
might play a part in metabolism quite distinct from 
its function as fuel, a fact that has much of cogency 
at the present time. We have good reason to believe 
that though, as a matter of fact, glycuronic acid is a 
normal metabolite, the actual synthesis concerns sugar 
itself, the oxidation of the glucose molecule occurring 
later. The compound formed is of the glucoside 
type, and the analogy with the formation of gluco- 
sides in the plant is unmistakable. Already the 
number of substances known to suffer this particular 
synthesis is legion. Almost every organic group 
yields an example. 
Lastly, in illustration of a quite different type of 
synthesis (I can only deal with a few of the man 
known cases) we may recall the methylation whi 
certain compounds undergo. The mechanism of this 
process, as it occurs in the body, is obscure, and its 
explanation would be of the greatest chemical interest. 
I must mention only one particular instance inves- 
tigated by Ackermann. When nicotinic acid is fed 
to animals, it is excreted as trigonellin, a known 
vegetable base. This conversion involves methyla- 
tion, and is of striking character as an instance of 
the artificially induced production of a plant alkaloid 
in the animal body. ; 
The full significance of all such happenings will not 
be understood unless it be remembered that a nice 
adjustment of molecular structure is in many cases 
necessary to prepare the foreign substance for syn- 
