From feedback inhibition to allostery: the enduring example of aspartate transcarbamoylase

Abstract

Aspartate transcarbamoylase (ATCase) of Escherichia coli, the first enzyme of the pyrimidine biosynthetic pathway, is inhibited by CTP and UTP, the nucleotide end-products of the pathway. First discovered by Yates and Pardee in 1956 [Yates R & Pardee AB (1956) J Biol Chem 221, 743-756; Yates RA & Pardee AB (1956) J Biol Chem 221, 757-770], these interactions establish feedback inhibition in vivo, a key means of metabolic regulation by which end-product production by the pathway is adjusted to end-product usage in macromolecule synthesis. Activation of the enzyme by the purine nucleotide ATP may also have regulatory significance. ATCase and threonine deaminase of E. coli were the first enzymes to be characterized with regard to their allosteric properties, namely, sigmoidal saturation with regard to substrates, reflecting cooperative ligand binding at the active site, and inhibition and activation by nucleotides of very different chemical structure from the substrates. In the case of ATCase, the nucleotides bind at regulatory sites located on protein subunits different from those bearing the active sites. The early characterization of ATCase proved useful in the 1965 conceptualization of the allosteric transition by Monod, Wyman, and Changeux [Monod J et al. (1965) J Mol Biol 12, 88-118], and the protein in subsequent years has proved useful in the experimental analysis of the interactions of sites and of conformational changes in allosteric proteins. This is an account of the early years of work on ATCase, up to 1965.