S ugar sensing clearly plays an important role in plant cell metabolism and the expression of many genes, including several involved in photosynthesis and carbo- hydrate metabolism, is affected by sugars. Un- ravelling the molecular mechanisms of plant sugar sensing is of fundamental importance to understanding plant metabolism and might have biotechnological applications, for exam- ple, in manipulating partitioning of carbon between different storage products (starch, proteins, oils) in crop seeds and tubers. At pres- ent, however, our understanding of this pro- cess is far from complete, and it is worth reviewing the much greater (although incom- plete) body of work on sugar sensing in fungi. Sugar sensing and glucose repression in fungi In Saccharomyces cerevisiae, genes required for growth on carbon sources other than glu- cose are repressed by the presence of glucose in the medium, and can be derepressed when it is removed. This is the phenomenon of glu- cose repression (also known as catabolite repression), which requires a mechanism for sensing the availability of glucose 1 . In spite of intensive study, the intracellular signals that mediate repression and derepression of genes in response to glucose in yeast remain un- known. Possible routes through which glu- cose could be sensed and a signal transduced are shown in Fig. 1. The signal for relief from catabolite repression in eubacteria is cyclic AMP, which also increases in response to glu- cose in S. cerevisiae and can regulate the expression of a few glucose-sensitive genes. However, a variety of evidence indicates that cyclic AMP is not a key component of the pathway controlling repression and derepres- sion of most glucose-regulated genes in this organism 1 . The idea that glucose-6-phosphate might be a signal appears to have originated with experiments that demonstrated that 2- deoxyglucose or glucosamine could mimic the effect of glucose in gene repression 2 . Because these hexose sugars were not metabolized at significant rates beyond the hexose phosphate stage, this suggested that the signal for glucose repression was either the hexose itself or the hexose phosphate formed from it. A flaw in this approach is that sugars that are rapidly phosphorylated by hexokinase, but for which the hexose phosphate is metabolized slowly or not at all, cause depletion of cellu- lar ATP. The hexose phosphate builds up to high levels in the cell, trapping phosphate and preventing rephosphorylation of ADP to ATP. In our experience 3 , incubation of yeast with the concentrations of 2-deoxyglucose used in these studies 2 results in a 95% decrease in cellular ATP. We therefore regard ‘non- metabolizable’ sugars, such as 2-deoxyglu- cose, to be toxic compounds that reduce ATP to levels where normal cellular function might be seriously impaired. Interestingly, although Holzer’s group 2 favoured the idea that changes in hexose or hexose phosphate were the key signal, they also discussed changes in ATP levels as an alternative possibility. The idea that the signal molecules were glucose and/or glucose-6-phosphate sug- gested that the enzyme hexokinase might be the sensor protein. The hexokinase hypothesis gained credence in the yeast-research com- munity when mutations (hex1) found to cause partially constitutive expression of glucose- repressed genes were mapped to the gene HXK2, encoding the major hexokinase iso- form PII (Ref. 4). Initial work with hxk2 alleles suggested that the glucose repression and hexo- kinase functions could be dissociated, and this led to the proposal that hexokinase PII had a glucose-sensing function independent of its enzymic activity 5 . However, this did not stand up to further investigation and there is, in fact, a good correlation between the overall hexo- kinase activity of different mutants and their ability to exhibit glucose repression 6,7 . These results suggest that hexokinase PII has a role in producing the signal molecule(s) but does not support the idea that it has a sensing role per se. The glucose repression phenotype of hxk2 mutants might merely be because the slow rate of glucose phosphorylation restricts overall glucose metabolism and ATP produc- tion when the major hexokinase isoform is missing or defective. 117 trends in plant science perspectives March 1999, Vol. 4, No. 3 1360 - 1385/99/$ – see front matter © 1999 Elsevier Science. All rights reserved. PII: S1360-1385(99)01377-1 Is hexokinase really a sugar sensor in plants? Nigel G. Halford, Patrick C. Purcell and D. Grahame Hardie The molecular mechanisms by which plant cells sense sugar levels are not understood, but current models (adapted from models for sugar sensing in yeast) favour hexokinase as the primary sugar sensor. However, the hypothesis that yeast hexokinase has a signalling function has not been supported by more recent studies and the idea that hexokinase is involved in sugar sensing in plants has yet to be proven. Fig. 1. Sugar sensing in a yeast cell. Although the intracellular signals involved in sugar sensing in yeast remain elusive, it is clear that hexoses, of which glucose is the most effec- tive, are perceived and that a functional sucrose nonfermenting-1 (SNF1) complex (con- taining the products of the SNF1 and SNF4 genes, and one of the products of the SIP1, SIP2 or GAL83 genes) is required. Glucose Glucose-6- phosphate Ethanol Transporter and/or receptor? Glucose Signal SNF1 Complex Downstream effects Direct effects on metabolism Protein phosphorylation Indirect effects on metabolism Regulation of gene expression Hexokinase Changes in AMP and/or ATP? Signal Nucleus Cytoplasm Cell wall