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The classic view in biochemistry is that metabolic pathways are regulated through allosteric regulation of the first enzyme in the pathway. Allosteric regulation is the induction by another molecule of a conformational change in an enzyme that alters the enzyme's activity Downstream enzymes in metabolic pathways that are not subject to allosteric regulation traditionally have been branded as "boring." But such "boring" enzymes are often crucial checkpoints in metabolic pathways, their activity being regulated through transcriptional or posttranslational mechanisms (1). This type of regulation requires the presence of proteins that can sense changes in metabolite levels. On page 332 of this issue, Moore et al. (2) provide compelling evidence in the model plant Arabidopsis that the not-so-boring enzyme, hexokinase, falls into this category and, furthermore, is itself a metabolite sensor. Hexokinase not only catalyzes the ATP-dependent phosphorylation of glucose but also senses glucose levels and the phosphorylation status of glucose, transmitting this information to the nucleus through a signal transduction pathway. By analyzing an Arabidopsis mutant that lacks hexokinase activity, the authors were able to separate the catalytic and glucose-- sensing properties of this enzyme.
Most higher organisms make multiple isoforms of hexokinase (3). For example, unicellular yeast produce hexokinases PI and PH, and glucokinase. Mammalian genomes encode two classes of hexokinase: the first comprises a low-affinity glucokinase; the second contains three high-affinity hexokinases I, II, and III that form dimers (3). Arabidopsis has six hexokinase genes. Amino acid residues for binding both glucore and ATP have been pinpointed in the crystal structure of hexokinase (4). The isoforms of this hexokinase interact not only with each other to form dimers, but also with other proteins and with cellular membranes (see the figure). In...