It has been shown previously that the functional state of UDP-glucuronosyltransferase (GT) is determined in part by the lipid environment. Evidence obtained in the last grant period suggests that GT is an oligomer regulated by protein- protein interactions, which are modulated in turn by the lipids at the annulus. Moreover, it appears that the organization of protein-protein interactions as well as the distribution of lipids in untreated microsomes, which constrain the maximal activity of GT, is not the thermodynamically most stable state of microsomes. This metastable organization and associated constraint on the activity of microsomal enzymes seem to be general properties of microsomal enzymes in that two other enzymes studied behave like GT. This study establishes the validity of the above ideas via detailed studies of GT, glucose-6-Pase, and acylCoA ligase in microsomes and in pure, reconstituted systems. If current studies establish that pure GT is an oligomer the conditions under which it dissociates will be determined to establish the factors that account for constaint and organization in intact microsomes. Independent of these results ongoing studies are being conducted on the influence of the lipid environment on the functional state and stability of GT. This research is fundamental to our understanding of the organization and function of membrane proteins as well as the role of lipids in modulating the behavior of these proteins. Progress in this area will have an impact on basic cellular biology, biochemistry and pathobiology.***//
