|Jean-Pierre Changeux at the 2009 meeting, Darwin: 200 years, at Collège de France. Image credit: Collège de France.
Neuroscientist Jean-Pierre Changeux at the Collège de France and the Institut Pasteur in Paris begins his recent “Reflections” article in The Journal of Biological Chemistry with a thought about theory in biology. “The identification of common conceptual rules further hinges on the considerable structural and functional diversity of the biological objects,” he writes.
In light of this, his “Reflections” article is a contemplation of allosteric interaction and its effects on the molecular chemistry of proteins “going from bacterial regulatory enzymes up to the nervous system and, tentatively, the higher functions of the brain.”
Changeux’s interest in theory and its role in biology stems from his days as a college student, during which he was exposed to evolutionary biology by inspirational professor Jean Bathellier.
The influence of his early research experiences resonates throughout the article. Changeux writes that Bathellier’s teachings and ideas “deeply influenced my scientific career to the extent that until now, as we shall see, my thinking has been framed within the Darwinian evolutionary paradigm.”
Changeux recalls an observation during the early 1960s with the bacterial enzyme L-threonine deaminase, the first enzyme of the isoleucine biosynthesis pathway. He notes, “the sensitivity of enzyme preparations to the feedback inhibitor L-isoleucine changed with time of storage, purification, heating, exposure to reagents for –SH groups, resulting in a loss of response to L-isoleucine without significant decline of enzymatic activity.”
He continues: “Interestingly, the loss of L-isoleucine feedback inhibition was also accompanied by the abolition of the ‘bimolecular’ kinetics of the enzyme towards its substrate.”
On the basis of these observations, Changeux theorized possible models for the antagonism between L-isoleucine and L-threonine, favoring one in which the substrate and regulatory effector bind topographically distinct sites referred to as allosteric interaction.
In 1965, along with fellow researchers Jacques Monod and Jeffries Wyman, Changeux proposed a concerted model that established a link between the structural organization of regulatory proteins into oligomers and their cooperative properties in signal transduction. This model now is known as the Monod-Wyman-Changeux model.
Changeux writes in his article about two major outcomes of this theory: a “paradigmatic shift from the cybernetics of biological systems to the molecular mechanism of signal transduction” and catalysis of “empirical research on regulatory proteins using the broad diversity of biophysical methods available.”
Changeux soon tried to extend the MWC model to acetylcholine esterase, or AChE, fulfilling a desire to bridge allostery and neuroscience. Then, after isolating the nicotinic receptor nAChR in 1970 and showing its allosteric properties in subsequent years, many other members of what soon became a family of pentameric receptors in the brain were identified including GABAA, GABAC, glycine, 5-HT3 receptors and others.
Allosteric modulation shed new light on neuropharmacology and resulted in discovery of new drugs and drug applications as well. “Without a doubt,” Changeux writes, “the concept of allosteric modulation has created a major landmark in the strategies of drug design for ligand-gated ion channels but also (G-protein–coupled receptors), resulting in the successful development of new classes of drugs used in the clinic.” Some of these drugs include Gleevec (allosteric inhibitor of Abl tyrosine kinase), Cinacalcet (allosteric activator of calcium-sensing receptor) and Maraviroc (allosteric inhibitor of chemokine receptor 5).
Changeux’s deep interest in the “chemistry of higher organisms” motivated him to further connect molecules with cognition. “Nicotine,” he writes, “exerts reinforcing effects through its action on brain (nAChRs) together with the laying down of long-term traces in the brain.” Experiments in mice provided in vivo data on the role of nAChRs in the mediation of nicotine’s biochemical rewarding effects. Varying allosteric properties in oligomers offered “conformational targets for long-term smoking cessation therapies.”
Changeux ends his “Reflections” article philosophically: “It appears legitimate to say that the future understanding of the mind-brain relationships and the relevant mental processes is likely to rest upon the biochemical world of the allosteric transitions (that) mediate interneuronal communications through multiple levels of organisation spanning the human brain.”
Zachary R. Conley (firstname.lastname@example.org
) is a freelance science writer based in the Kansas City area.