The discovery of nature's biosynthetic pathways

Uro'gen-III is a key intermediate on the biosynthetic pathways to the vitally important natural pigments haem, chlorophyll and the cytochromes. How the unexpected structure of uro'gen-III is synthesized by living things has long been a major puzzle. Studies based on 13C-labelling are described which show a) that a single intramolecular rearrangement occurs and b) that this step occurs after the open-chain linear tetrapyrrole system has been built. A second study involves stereospecific labelling with deuterium and tritium to elucidate the absolute stereochemistry of the enzymic reaction sequence which produces the vinyl groups of haem. The third and last section of the lecture is focussed on the biosynthetic intermediates lying between uro'gen-III and cobyrinic acid on the pathway to vitamin B12. An octacarboxylic isobacteriochlorin is isolated from a vitamin B12-producing organism and this is shown to be identical with sirohydrochlorin, previously obtained by Kamin and Siegel as the metal-free prosthetic group of certain sulphite-reducing bacteria. The structure and absolute stereochemistry of sirohydrochlorin are studied and comment is made on the evolutionary interest of these findings.     

The discovery of antidepressants: A winding path

Summary Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, reversal of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

The discovery of antidepressants: a winding path

Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, 'reversal' of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

Structural biology of the purine biosynthetic pathway

Purine biosynthesis requires ten enzymatic transformations to generate inosine monophosphate. PurF, PurD, PurL, PurM, PurC, and PurB are common to all pathways, while PurN or PurT, PurK/PurE-I or PurE-II, PurH or PurP, and PurJ or PurO catalyze the same steps in different organisms. X-ray crystal structures are available for all 15 purine biosynthetic enzymes, including 7 ATP-dependent enzymes, 2 amidotransferases and 2 tetrahydrofolate-dependent enzymes. Here we summarize the structures of the purine biosynthetic enzymes, discuss similarities and differences, and present arguments for pathway evolution. Four of the ATP-dependent enzymes belong to the ATP-grasp superfamily and 2 to the PurM superfamily. The amidotransferases are unrelated, with one utilizing an N-terminal nucleophileglutaminase and the other utilizing a triad glutaminase. Likewise the tetrahydrofolate-dependent enzymes are unrelated. Ancestral proteins may have included a broad specificity enzyme instead of PurD, PurT, PurK, PurC, and PurP, and a separate enzyme instead of PurM and PurL. Received 26 May 2008; received after revision 30 June 2008; accepted 9 July 2008     

The pre-history of hemocyanin. The discovery of copper in the blood of molluscs

The presence of copper in molluscs was discovered in 1833 by Bartolomeo Bizio, a Venetian chemist, who found copper in marine gastropods of the family Muricidae during his studies on the purple dye he had isolated from these animals. Bizio was so surprised by this finding that he extended his analysis to several other invertebrate species in which he identified the metal.     

The discovery of atmospheric condensation nuclei by Paul-Jean Coulier in 1875

Zusammenfassung 1875 hatPaul-Jean Coulier, Professor für Chemie und Hygiene an der Medizinischen Militärschule Val de Grâce in Paris, mit einfachen Mitteln die Rolle der atmosphärischen Kondensationskerne bei der Nebelbildung entdeckt und viele wesentliche Tatsachen beschrieben. Erst 5 Jahre später erfolgte die erste Arbeit vonAitken. Die Geschichte dieser Entdeckung und die Ursache dafür, dass sie nicht besser bekannt wurde, wird besprochen.     

The isotope effect: Prediction,discussion, and discovery

The precise position of a spectral line emitted by an atomic system depends on the mass of the atomic nucleus and is therefore different for isotopes belonging to the same element. The possible presence of an isotope effect followed from Bohr's atomic theory of 1913, but it took several years before it was confirmed experimentally. Its early history involves the childhood not only of the quantum atom, but also of the concept of isotopy. Bohr's prediction of the isotope effect was apparently at odds with early attempts to distinguish between isotopes by means of their optical spectra. However, in 1920 the effect was discovered in HCl molecules, which gave rise to a fruitful development in molecular spectroscopy. The first detection of an atomic isotope effect was no less important, as it was by this means that the heavy hydrogen isotope deuterium was discovered in 1932. The early development of isotope spectroscopy led to successes as well as problems. At the end of the paper I briefly comment on the relationship between theory, experiment and prediction in this area of spectral physics.     

The conceptual import of Carnot's theorem to the discovery of the entropy

Summary Among many other things, Carnot stated a principle and proved a theorem. In 1850, Clausius corrected Carnot's theory, modifying it according to Joule's principle. He might have considered a corollary of the theorem as the mathematical formulation of Carnot's principle. We challenge the corollary: it is based on hidden assumptions, nor is it true for all cycles. Clausius realized the corollary's lack of generality, but on different grounds. In 1854, he generalized the theorem, and gave an (other) expression to Carnot's principle. We analyze Clapeyron's account of Carnot's theory, Thomson's account of 1849 and some of Clausius belated comments on his 1850 paper, as well Clausius' paper of 1854. We hope that they shed light on the corollary's tacit hypotheses and on the meaning of Carnot's principle. It is our contention: Clausius took seriously a contemporary meaning of the principle, and looked for a condition of integrability that could express recovery of the initial conditions of the reservoirs. Furthermore, he seems to have had some prior knowledge of the form the expression of the principle should take. Actually, this was the theory's natural candidate.     

The relationship between the effect of endotoxin on inducible enzymes and biosynthetic activity in rat liver

Résumé Étude du mécanisme d'action de la cortisone. L'induction de tryptophane oxygénase hépatique peut être complètement abolie par l'injection d'endotoxine à un moment où la synthèse hormonale de l'ARN total n'est apparemment pas modifiée.     

Tuning up mind's pattern to nature's own idea: Eddington's early twenties case for variational derivatives

This paper sets out to show how Eddington's early twenties case for variational derivatives significantly bears witness to a steady and consistent shift in focus from a resolute striving for objectivity towards “selective subjectivism” and structuralism. While framing his so-called “Hamiltonian derivatives” along the lines of previously available variational methods allowing to derive gravitational field equations from an action principle, Eddington assigned them a theoretical function of his own devising in The Mathematical Theory of Relativity (1923). I make clear that two stages should be marked out in Eddington's train of thought if the meaning of such variational derivatives is to be adequately assessed. As far as they were originally intended to embody the mind's collusion with nature by linking atomicity of matter with atomicity of action, variational derivatives were at first assigned a dual role requiring of them not only to express mind's craving for permanence but also to tune up mind's privileged pattern to “Nature's own idea”. Whereas at a later stage, as affine field theory would provide a framework for world-building, such “Hamiltonian differentiation” would grow out of tune through gauge-invariance and, by disregarding how mathematical theory might precisely come into contact with actual world, would be turned into a mere heuristic device for structural knowledge.