The new metabolism: molecular genetics in the analysis of metabolic regulation

Genetics is a powerful tool for analyzing metabolic regulation in bacteria, permitting definitive identification of key regulatory enzymes, and assignment of cause and effect relationships between molecular mechanisms that control activity of regulatory enzymes and flow of metabolites through the pathways of intermediary metabolism. In homeothermic vertebrates, however, traditional genetic analysis of metabolic regulation is difficult or impossible. Despite an enormous amount of factual information about metabolic pathways in vertebrates, our understanding of regulatory mechanisms is based largely on correlations between regulation of the activity of a purified enzyme by an effector and variations in the intracellular concentration of that effector under conditions that modulate flow of metabolites through the relevant metabolic pathway. Newly developed molecular genetic and gene transfer methods can now be used to study metabolic regulation in vertebrates. Some of these methods will be described in short reviews of the mechanisms by which diet, hormones, and tissue-type regulate transcription of the genes for L-type pyruvate kinase and phosphoenolpyruvate carboxykinase. Application of these techniques to analyses of structure/function in intact cells and animals will be illustrated with recent work on the receptor for low density lipoproteins and cyclic AMP-dependent protein kinases.