Allostery (regulation of enzyme activity by ligands) and co-operativity are site-site interaction effects based on long range signal transmission within proteins. Aspartate transcarbamylases (ATCases) are a particularly well suited system to study these mechanisms since they present a wide range of molecular architectures and regulatory responses to ligands. The ATCase from E. coli, which catalyzes the first step of the de novo biosynthesis of pyrimidines, is one of the best-studied co-operative and allosteric enzymes. It shows co-operativity towards the substrate aspartate and its catalytic activity is inhibited by pyrimidine nucleotides ( CTP and UTP) and activated by ATP. This enzyme consists of two trimeric catalytic subunits which are held together by their interactions with three dimeric regulatory subunits which bind the nucleotide effectors. This quaternary structure is typical of class B microbial ATCases. ATCases from several hyperthermophilic microorganisms are class B ATCases too and they are co-operative and subject to allosteric regulation. The comparative study of the the ATCases from the archaeon Pyrococcus abyssi (optimal growth temperature 96°C) and of the mesophilic E. coli ATCase allows to study at molecular level the mechanisms of catalysis and allosteric regulation at high temperature and to investigate the strategy of ATCase thermostabilisation. This involves investigating the role of specific molecular interactions and secondary or ternary structural elements in these processes by the kinetic analysis of wild type and mutant P. abyssi and E. coli ATCases and by the determination of their 3-D structures.