Abstract: The work of the author is reviewed in terms of "keystone molecules" that serve as figurative points of support to understand the interactions of smaller molecules within biological macromolecules. The review emphasizes lessons learned in carboxylation of biotin, reactions of cyclic phosphates, the uses of acyl phosphate monoesters, and the mechanism of decarboxylation of thiamin-derived intermediates.
Key words: CIC medal, biotin, ATP, mechanisms, cyclic phosphates, thiamin, acyl phosphates, catalysis.
Resume : Ce rapport resume les travaux de l'auteur en fonction de molecules "cles de voute" qui servent d'une facon figurative de support pour comprendre les interactions de molecules plus petites dans les macromolecules biologiques. Cette revue met en relief les lecons tirees de la carboxylation de la biotine, des reactions des phosphates cycliques, des utilisations des monoesters des phosphates d'acyle et du mecanisme de decarboxylation des intermediaires derives de la thiamine.
Mots cles : medaille de l'ICC, biotine, ATP, mecanismes, phosphates cycliques, thiamine, phosphates d'acyle, catalyse.
[Traduit par la Redaction]
I was delighted to be designated the 2006 recipient of the CIC Medal; the Institute has been a central part of my scientific life. I gave the medal address as part of the Canadian Chemistry Conference in June 2006. This paper summarizes much of the talk and makes some clarifications while omitting some sections that do not follow an intelligible script. I organized the presentation around specific organic molecules that relate to mechanisms in biological chemistry. My objectives as a scientist result from approaching complex problems with the tools afforded by finding the right molecule to answer a question or target a larger system. I chose the phrase "molecular keystones" to describe species that are the basis of conceptual developments and built the talk around each of these as a section. The term "molecular keystone" has also been used to describe a structural role for a small molecule within a larger species (1).
In general, we chose molecular keystones as the simplest synthetic molecule containing the reacting functionality of a more complex biomolecule. This includes molecules designed to mimic biological interactions on a small scale and those that formed a basis for extended mechanism-based molecular design.
My interest in doing this work was the result of a perspective that goes back to my earliest days as a university student. I began doing organic chemistry research in my second undergraduate year at Columbia University in New York. Gilbert Stork hired me to work in his research group on projects that were odds and ends--preparing materials for others to use in their complex syntheses as well as changing the oil in the vacuum pumps. I was chosen for this from the many students taking introductory organic chemistry midway through the course. My teaching assistant was an undergraduate who had been with Stork and was leaving for graduate studies at mid-year. He designated me as his replacement. Of course, at the time I had no idea who Gilbert Stork was or how fortunate I was. The 3 years I spent in...