Inositol synthesis and catabolism inCryptococcus neoformans

Molina, Yanira; Ramos, Susan E.; Douglass, Thomas G.; Klig, Lisa S.

doi:10.1002/(sici)1097-0061(199911)15:15<1657::aid-yea493>3.0.co;2-3

Cited by 21 publications

(19 citation statements)

References 35 publications

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“…Our results showed that INO1 expression was not regulated by the availability of extracellular inositol; instead, it was upregulated by the nutrient limitation condition. Such an outcome is consistent with earlier studies in C. neoformans, which suggest that expression of Cryptococcus Ino1 and cellular phosphatidylinositol (PI) levels are not regulated by inositol (38,62), but these results differ from what has been observed in S. cerevisiae (10) and Candida glabrata (8). In S. cerevisiae, Ino1 expression is highly regulated by inositol concentrations.…”

Section: Discussionsupporting

confidence: 88%

“…It has been suggested that the high rate of cryptococcal meningitis may be related to the high inositol levels found in mammalian brains (38). The inositol concentration in human cerebrospinal fluid (CSF) is around 22 mg/liter, compared to an average 2.8 mg/liter in plasma, which makes the human brain the location with the most abundant free inositol (17,(55)(56)(57)(58).…”

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confidence: 99%

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Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

Wang

Liu²,

Delmas³

et al. 2011

Eukaryot Cell

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Cryptococcus neoformans is an AIDS-associated human fungal pathogen and the most common cause of fungal meningitis, with a mortality rate over 40% in AIDS patients. Significant advances have been achieved in understanding its disease mechanisms. Yet the underlying mechanism of a high frequency of cryptococcal meningitis remains unclear. The existence of high inositol concentrations in brain and our earlier discovery of a large inositol transporter (ITR) gene family in C. neoformans led us to investigate the potential role of inositol in Cryptococcus-host interactions. In this study, we focus on functional analyses of two major ITR genes to understand their role in virulence of C. neoformans. Our results show that ITR1A and ITR3C are the only two ITR genes among 10 candidates that can complement the growth defect of a Saccharomyces cerevisiae strain lacking inositol transporters. Both S. cerevisiae strains heterologously expressing ITR1A or ITR3C showed high inositol uptake activity, an indication that they are major inositol transporters. Significantly, itr1a itr3c double mutants showed significant virulence attenuation in murine infection models. Mutating both ITR1A and ITR3C in an ino1 mutant background activates the expression of several remaining ITR candidates and does not show more severe virulence attenuation, suggesting that both inositol uptake and biosynthetic pathways are important for inositol acquisition. Overall, our study provides evidence that host inositol and fungal inositol transporters are important for Cryptococcus pathogenicity.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

Wang

Liu²,

Delmas³

et al. 2011

Eukaryot Cell

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“…The specific activity of the recombinant MIOX4 (Table I) was approximately 11 times greater than MIOX purified from the yeast Cryptococcus neoformans (Molina et al, 1999) and 38 times more than the activity purified from oat seedlings (Koller et al, 1976). This variation in specific activity could be because of differences in the methods of purification, differences in the properties of the enzymes (the molecular mass reported for the oat MIOX is 62 kD), or the poor stability of the oat enzyme preparation (Koller et al, 1976).…”

Section: Discussionmentioning

confidence: 96%

“…This enzyme is of considerable interest physiologically because it catalyzes the first step of MI catabolism in plants (Loewus and Murthy, 2000), some yeast species (Molina et al, 1999), and also in the kidney and lens of several animals (Arner et al, 2001). The identity of MIOX4 was confirmed by expressing the candidate ORF in bacteria.…”

Section: Cloning and Characterization Of An Orf Encoding A Miox From mentioning

confidence: 99%

myo-Inositol Oxygenase Offers a Possible Entry Point into Plant Ascorbate Biosynthesis

et al. 2004

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Two biosynthetic pathways for ascorbate (l-ascorbic acid [AsA]; vitamin C) in plants are presently known, the mannose/ l-galactose pathway and an l-GalUA pathway. Here, we present molecular and biochemical evidence for a possible biosynthetic route using myo-inositol (MI) as the initial substrate. A MI oxygenase (MIOX) gene was identified in chromosome 4 (miox4) of Arabidopsis ecotype Columbia, and its enzymatic activity was confirmed in bacterially expressed recombinant protein. Miox4 was primarily expressed in flowers and leaves of wild-type Arabidopsis plants, tissues with a high concentration of AsA. Ascorbate levels increased 2-to 3-fold in homozygous Arabidopsis lines overexpressing the miox4 open reading frame, thus suggesting the role of MI in AsA biosynthesis and the potential for using this gene for the agronomic and nutritional enhancement of crops.l-Ascorbic acid (AsA) is the major antioxidant in plant cells. Since AsA was first isolated, there have been numerous reports on its role regulating redox potential during photosynthesis, environmentinduced oxidative stress (ozone, UV, high light, SO 2 , etc), and wound-and pathogen-induced oxidative processes. In both plants and animals, AsA is important as a cofactor for numerous key enzymes such as hydroxylases and dioxygenases, some of which are involved in the biosynthesis of phytohormones and secondary metabolites or in the hydroxylation of specific peptidyl-prolyl and peptidyl-lisyl residues (Loewus and Loewus, 1987;Smirnoff et al., 2001;Arrigoni and De Tullio, 2002). Current data indicate that AsA is a major substrate for synthesis of l-tartaric, l-threonic, l-glyceric, and l-oxalic acids used for calcium regulation via calcium oxalate formation (Loewus, 1999). There is emerging evidence that AsA is involved in photoprotection, metal and xenobiotic detoxification, the cell cycle, cell wall growth, and cell expansion (Smirnoff, 2000;Smirnoff and Wheeler, 2000;Franceschi and Tarlyn, 2002). Interestingly, a recent study indicates that leaf AsA content can also modulate the expression of genes involved in plant defense and regulate genes that control development through hormone signaling (Pastori et al., 2003). The antioxidant property of AsA also is one of its major functions in humans (Homo sapiens), who are unable to synthesize their own vitamin C. Because AsA can neither be produced nor stored in the body, the vitamin must be acquired regularly from dietary sources, primarily from plants rich in AsA. Because ascorbate levels in plants vary widely, the ability to increase the level of this vitamin in crops would increase their nutritive value, shelf life, and ability to withstand oxidative stress during the growing season.AsA biosynthetic pathways differ between animals and plants (Fig. 1). In animals, d-Glc is converted to AsA via d-glucuronate, l-gulonate, and l-gulono-1,4-lactone (l-GulL), which is then oxidized to AsA. In plants, AsA biosynthesis proceeds via GDP-Man, GDP-l-Gal, l-Gal-1-phosphate, l-Gal, and l-GalL (Wheeler et al., 1998). Althoug...

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“…In addition, some soil bacteria such as Pseudomonas and Klebsiella spp. and the pathogenic fungus Cryptococcus neoformans (Molina et al, 1999) can utilize myo-inositol as a major carbon source, thus taking advantage of the abundance of inositols in soil and plant materials.…”

Section: Discussionmentioning

confidence: 99%

High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology

Jian

Seyfang

2003

Microbiology

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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 K m value of 240±15 μM, 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 K m 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.

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Inositol synthesis and catabolism inCryptococcus neoformans

Cited by 21 publications

References 35 publications

Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

myo-Inositol Oxygenase Offers a Possible Entry Point into Plant Ascorbate Biosynthesis

High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology

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