EFFECTS OF HEXOSE ANALOGUES ON FUNGI: MECHANISMS OF INGIBITION AND OF RESISTANCE

Abstract

I. SUMMARYAlthough the effects of a number of sugar analogues are discussed in this review, most attention is devoted to 2‐deoxy‐D‐glucose (deGlc) and L‐sorbose. The growth of fungi is not uniformly inhibited by sugar analogues since some species or strains can metabolize sugars which severely inhibit others. Sugar analogues usually cause inhibitions by being used in metabolism in place of glucose. Both deGlc and sorbose are metabolized by several species but, in general, only a small fraction of the analogue is utilized.The uptake and phosphorylation of readily metabolized sugars are inhibited by deGlc. Inhibitions by sugar analogues occur on media containing non‐carbohydrate sources of carbon, so inhibition of sugar uptake is unlikely to be a major component of the growth inhibition which occurs on sugar‐containing media. Hexokinase phosphorylates deGlc, and its 6‐phosphate inhibits the activity of especially phosphohexose isomerase and glucose 6‐phosphate dehydrogenase. Apart from an involvement in synthesis of more complex sugars, formation of deGlc‐6P is the usual limit of metabolism of this sugar analogue. Accumulation of the phosphate ester leads to a considerable drain on phosphate pools and ATP levels decline drastically. Indeed, deGlc rapidly initiates degradation of purine nucleotides which can proceed at least to the level of hypoxanthine. In Saccharomyces cerevisiae, deGlc can be condensed to dideoxytrehalose and, in most fungi, polysaccharide synthesis is affected. Preformed wall material is eroded and synthesis of new wall components is prevented by sequestering of uridine and guanosine nucleotides through reaction with deGlc. Interference with the structure of the wall greatly reduces osmotic stability, and cell lysis is the major cause of inhibition of growth by deGlc in yeasts and filamentous fungi alike.L‐Sorbose is not phosphorylated, and the biochemical basis of the inhibitions caused by this analogue is obscure. Some enzymes involved in polysaccharide synthesis are sensitive to inhibition by sorbose, and a characteristic of growth on this sugar is formation of an abnormally thick cell wall. Filamentous fungi grown on solid medium containing sorbose assume an abnormal growth form in which cells are much shortened and branching frequency is increased. There are indications that sorbose, perhaps by interfering with cell wall structure, affects hyphal morphogenesis and that this effect may be magnified into a macroscopic change in the characteristics of the colony during growth on solid medium by secondary environmental effects.Mutants, resistant to deGlc, have alterations in either transport, hexokinase or phosphatase functions, thus emphasizing the important of accumulation of deGlc‐6P in the inhibitions caused by this analogue. Generalization is less easy about mutants resistant to sorbose. The majority are defective in transport, but others show defects in phosphoglucomutase and polysaccharide synthases and there are some correlations with morphological changes which underline the involvement of the sugar in the observed alterations in cell walls. Many aspects of early carbohydrate metabolism need investigation and, for such studies, the sugar analogues have much to offer. However, there is also particular scope for their use in studies of hyphal morphogenesis, especially in relation to the connection between wall construction and morphology. Counterparts of the abnormal hyphal growth forms caused by sugar analogues can be found in normal hyphal cells which contribute to the tissues of complex fungal structures such as the basidiomycete carpophore. Experimental induction of these cell forms in vegetative culture by the sugar analogues shows promise for study of events which contribute to the morphogenesis of these fungal structures.