The gene for cobalamin-independent methionine synthase is essential in Candida albicans: A potential antifungal target

Suliman, Huda S.; Appling, Dean R.; Robertus, Jon D.

doi:10.1016/j.abb.2007.09.003

Cited by 41 publications

(40 citation statements)

References 29 publications

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“…The absence of MetH enzymatic activity might trigger two deleterious effects for fungal cell metabolism, which could explain why a deletant cannot be isolated. First, its elimination may result in a toxic accumulation of homocysteine (78,79), and second, its absence might provoke a shortage of folate, since it cannot be recycled from methyl-tetrahydrofolate (80) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

et al. 2016

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e Fungal infections are of major relevance due to the increased numbers of immunocompromised patients, frequently delayed diagnosis, and limited therapeutics. To date, the growth and nutritional requirements of fungi during infection, which are relevant for invasion of the host, are poorly understood. This is particularly true for invasive pulmonary aspergillosis, as so far, sources of (macro)elements that are exploited during infection have been identified to only a limited extent. Here, we have investigated sulfur (S) utilization by the human-pathogenic mold Aspergillus fumigatus during invasive growth. Our data reveal that inorganic S compounds or taurine is unlikely to serve as an S source during invasive pulmonary aspergillosis since a sulfate transporter mutant strain and a sulfite reductase mutant strain are fully virulent. In contrast, the S-containing amino acid cysteine is limiting for fungal growth, as proven by the reduced virulence of a cysteine auxotroph. Moreover, phenotypic characterization of this strain further revealed the robustness of the subordinate glutathione redox system. Interestingly, we demonstrate that methionine synthase is essential for A. fumigatus virulence, defining the biosynthetic route of this proteinogenic amino acid as a potential antifungal target. In conclusion, we provide novel insights into the nutritional requirements of A. fumigatus during pathogenesis, a prerequisite to understanding and fighting infection.

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Section: Resultsmentioning

confidence: 99%

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

et al. 2016

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“…Expressions of the bZIP transcription factor metR (22) and S-adenosylhomocysteinase (sahA) were also upregulated (P value of Ͻ0.00015 to 0.001), as were those of glycine dehydrogenase (GDH) (P Ͻ 0.0056) and serine hydroxymethyltransferase (SHMT) (P Ͻ 0.0001) (see Table S3 in the supplemental material). GDH and SHMT act in concert with the folate cycle to transfer methyl groups to Hcy for methionine biosynthesis (37). Interestingly, the A. fumigatus ⌬metR strain showed significantly increased sensitivity to gliotoxin (P Ͻ 0.05) compared to the wild type (ATCC 46645) (see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, of special significance, the abundance of the cobalamin-independent methionine synthase MetH/D (AFUA_4G07360) was significantly increased (1.9-to 2.2-fold), and that of MTHFR/MtrA was significantly increased (1.8-fold), in response to gliotoxin exposure. Both of these enzymes are essential for methionine biosynthesis (37,38) and for the operation of the methyl/methionine cycle, which affects SAM biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

“…MetH has also been shown to be a target of the transcriptional activator yap1 in A. fumigatus, and expression of this protein is induced in the presence of oxidative stress (50). In fungi, the production of methionine from Hcy is catalyzed by MetH/D, and in Candida albicans, this enzyme has been shown to be essential for cell viability (37). Indeed, Hcy induces the upregulation of A. nidulans methionine synthase (51), in addition to the positive regulation of MTHFR/MtrA expression (38).…”

Section: Integrated Systems In Aspergillus Fumigatusmentioning

confidence: 99%

“…As shown here, significantly elevated SAH levels are also uniquely observed in this strain in response to gliotoxin exposure. Methionine produced from Hcy can either be used in protein synthesis or, alternatively, enter the methionine cycle, whereby it is S-adenylated to form SAM (37). SAM is a ubiquitous cellular methyl donor and is utilized by methyltransferases for DNA, protein, and metabolite methylation reactions (46).…”

Section: Integrated Systems In Aspergillus Fumigatusmentioning

confidence: 99%

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Interplay between Gliotoxin Resistance, Secretion, and the Methyl/Methionine Cycle in Aspergillus fumigatus

et al. 2015

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Mechanistic studies on gliotoxin biosynthesis and self-protection in Aspergillus fumigatus, both of which require the gliotoxin oxidoreductase GliT, have revealed a rich landscape of highly novel biochemistries, yet key aspects of this complex molecular architecture remain obscure. Here we show that an A. fumigatus ⌬gliA strain is completely deficient in gliotoxin secretion but still retains the ability to efflux bisdethiobis(methylthio)gliotoxin (BmGT). This correlates with a significant increase in sensitivity to exogenous gliotoxin because gliotoxin trapped inside the cell leads to (i) activation of the gli cluster, as disabling gli cluster activation, via gliZ deletion, attenuates the sensitivity of an A. fumigatus ⌬gliT strain to gliotoxin, thus implicating cluster activation as a factor in gliotoxin sensitivity, and (ii) increased methylation activity due to excess substrate (dithiol gliotoxin) for the gliotoxin bis-thiomethyltransferase GtmA. Intracellular dithiol gliotoxin is oxidized by GliT and subsequently effluxed by GliA. In the absence of GliA, gliotoxin persists in the cell and is converted to BmGT, with levels significantly higher than those in the wild type. Similarly, in the ⌬gliT strain, gliotoxin oxidation is impeded, and methylation occurs unchecked, leading to significant S-adenosylmethionine (SAM) depletion and S-adenosylhomocysteine (SAH) overproduction. This in turn significantly contributes to the observed hypersensitivity of gliT-deficient A. fumigatus to gliotoxin. Our observations reveal a key role for GliT in preventing dysregulation of the methyl/methionine cycle to control intracellular SAM and SAH homeostasis during gliotoxin biosynthesis and exposure. Moreover, we reveal attenuated GliT abundance in the A. fumigatus ⌬gliK strain, but not the ⌬gliG strain, following exposure to gliotoxin, correlating with relative sensitivities. Overall, we illuminate new systems interactions that have evolved in gliotoxin-producing, compared to gliotoxin-naive, fungi to facilitate their cellular presence. Biosynthesis, self-protection mechanisms, and functionality of gliotoxin and related epidithiodiketopiperazine (ETP) molecular species, such as chaetocin and acetylaranotin, are attracting ever-increasing attention as a consequence of findings from highthroughput genome sequencing projects, application of gene deletion technologies, and mass spectrometric analytical methodologies (1-5). Indeed, existing paradigms of gliotoxin (Fig. 1) as a toxin and the perspective of the disulfide bridge-containing (oxidized) form as the final, or only, product are undergoing significant reconsideration (6-11).Self-protection against disulfide-containing metabolites appears to be essential in both fungi and bacteria. It has been demonstrated that the gliotoxin oxidoreductase GliT (12), encoded within the gli cluster, protects Aspergillus fumigatus against exogenous gliotoxin and is essential for gliotoxin biosynthesis (12, 13). A similar mechanism for self-protection against holomycin in Streptomyces clavulige...

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A proteomic evaluation of Pyrenophora tritici‐repentis, causal agent of tan spot of wheat, reveals major differences between virulent and avirulent isolates

et al. 2009

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Pyrenophora tritici-repentis causes tan spot, an important foliar disease of wheat. The fungus produces multiple host-specific toxins, including Ptr ToxB, a chlorosis-inducing protein encoded by the ToxB gene. A homolog of ToxB is also found in avirulent isolates of the fungus. In order to improve understanding of the role of this homolog and evaluate the general pathogenic ability of P. tritici-repentis, we compared the proteomes of avirulent race 4 and virulent race 5 isolates of the pathogen. Western blotting analysis revealed the presence of Ptr ToxB in spore germination and culture fluids of race 5 but not race 4. A comprehensive proteome-level comparison by 2-DE indicated 133 differentially abundant proteins in the secretome (29 proteins) and mycelium (104 proteins) of races 4 and 5, of which 63 were identified by MS/MS. A number of the proteins found to be up-regulated in race 5 have been implicated in microbial virulence in other pathosystems, and included the secreted enzymes alpha-mannosidase and exo-beta-1,3-glucanase, heat-shock and BiP proteins, and various metabolic enzymes. These proteome-level differences suggest a reduced general pathogenic ability in race 4 of P. tritici-repentis, irrespective of toxin production. Such differences may reflect an adaptation to a saprophytic habit.

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The gene for cobalamin-independent methionine synthase is essential in Candida albicans: A potential antifungal target

Cited by 41 publications

References 29 publications

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

Interplay between Gliotoxin Resistance, Secretion, and the Methyl/Methionine Cycle in Aspergillus fumigatus

A proteomic evaluation of Pyrenophora tritici‐repentis, causal agent of tan spot of wheat, reveals major differences between virulent and avirulent isolates

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