ENZYME ORGANIZATION IN DNA PRECURSOR BIOSYNTHESIS

This chapter discusses the process by which DNA precursors are synthesized and delivered to replication sites and consider the possibility of physical or functional linkage between enzymes of deoxyribonucleoside 5‘-triphosphate (dNTP)’ synthesis and those directly involved in the replication. DNA replication has been shown in both prokaryotic and eukaryotic systems to involve the cooperative function of numerous proteins associated at replication forks. Many metabolic pathways involve multifunctional enzymes or tightly associated multienzyme complexes. Examples of the former are the fattyacyl- CoA synthetase enzyme in vertebrate cells and the eukaryotic “CAD protein” and UMP synthetase, which catalyze the first three and last two reactions, respectively, of the six steps in de novo pyrimidine-nucleotide synthesis. Examples of tightly but non-covalently bound aggregates include the well-known pyruvate and α-ketoglutarate dehydrogenase complexes of mitochondria. The potential biological advantages of enzyme association are fairly obvious and might include: maintenance of locally high metabolite concentrations without the need for physical compartmentation within a membrane; protection of the solvation capacity of cell water, because average concentrations of most metabolites are kept low, even though local concentrations may be much higher; efficiency of regulation of both enzyme synthesis and metabolic fluxes; and relative rapidity with which a metabolic process can respond to changes in the intracellular environment. © 1993 Academic Press Inc.