Candida albicans

Inositol is considered a growth factor in yeast cells and it plays an important role in Candida as
an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored
glycolipid on the cell surface of Candida which is involved in the pathogenicity of this opportunistic
fungus and which binds to and stimulates human macrophages. In addition, inositol plays an
essential role in the phosphatidylinositol signal transduction pathway, which controls many cell
cycle events. Here, high-affinity myo-inositol uptake in Candida albicans has been characterized,
with an apparent Km value of 240±15 mM, which appears to be active and energy-dependent
as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). Candida
myo-inositol transport was sodium-independent but proton-coupled with an apparent Km value of
11?0±1?1 nM for H+, equal pH 7?96±0?05, suggesting that the C. albicans myo-inositol–H+
transporter is fully activated at physiological pH. C. albicans inositol transport was not affected by
cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol
transport. Furthermore, myo-inositol transport showed high substrate specificity for inositol and
was not significantly affected by hexose or pentose sugars as competitors, despite their structural
similarity. Transport kinetics in the presence of eight different inositol isomers as competitors
revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of myo-inositol and the
transporter protein play a critical role for substrate recognition and binding. It is concluded that
C. albicans myo-inositol–H+ transport differs kinetically and pharmacologically from the human
sodium-dependent myo-inositol transport system and constitutes an attractive target for delivery of
cytotoxic inositol analogues in this pathogenic fungus.


The yeast Candida albicans is one of the most commonly
encountered human pathogens and is a normal component
of the human endogenous microflora. As an important
nosocomial and opportunistic fungus, C. albicans can cause
a wide variety of infections ranging from mucosal infections
in generally healthy persons to life-threatening
systemic infections in individuals with impaired immune
defence, cancer therapy, antibiotic treatment, diabetes or
burn victims. Furthermore, the development of drug
resistance and the limitations and severe side effects of
drug treatment pose an increasing problem with regard to
C. albicans infections (Vanden Bossche et al., 1998; Pfaller
et al., 1998; Cowen et al., 2002).
Inositol is considered a growth factor in yeast cells and
necessary for their optimum growth (Nikawa et al., 1982,
1991), despite the ability of some yeasts, including Saccharomyces
cerevisiae, to also synthesize myo-inositol de novo
at the expense of glycolysis. Inositol plays an important
role in Candida as an essential precursor for phospholipomannan,
a family of glycophosphatidylinositol (GPI)-
anchored glycolipids on the cell surface of Candida that
is involved in the pathogenicity of this fungus and which
binds to and stimulates human macrophages (Trinel et al.,
1999). Thus, phospholipomannan is considered a virulence
factor in Candida and has been shown to possess immunomodulatory
properties such as TNF-a induction (Jouault
et al., 1994). GPI-membrane anchors are of particular
significance in lower eukaryotes and parasitic protozoa
(McConville & Ferguson, 1993), and about 60 GPIanchored
membrane proteins were estimated in yeast from
the Saccharomyces cerevisiae genome project (Su¨tterlin et al.,
1997). Moreover, inhibition of GPI-anchor biosynthesis was
shown to be lethal in Saccharomyces cerevisiae (Leidich et al.,
1994). In addition to its role as an essential precursor for
GPI-membrane anchors, inositol plays a central role also
in the phosphatidylinositol signal transduction pathway,
which controls many cell cycle events in eukaryotic cells.
Hence, myo-inositol transport in C. albicans appears to
be an attractive drug target to interfere with important
Abbreviations: FCCP, carbonylcyanide-4-(trifluoromethoxy) phenylhydrazone;
GPI, glycophosphatidylinositol.