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ICL and MS gene expression and mutant virulence phenotypes during interactions with host organisms 

ICL and MS gene expression and mutant virulence phenotypes during interactions with host organisms 

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The glyoxylate cycle is an anaplerotic pathway of the tricarboxylic acid (TCA) cycle that allows growth on C(2) compounds by bypassing the CO(2)-generating steps of the TCA cycle. The unique enzymes of this route are isocitrate lyase (ICL) and malate synthase (MS). ICL cleaves isocitrate to glyoxylate and succinate, and MS converts glyoxylate and a...

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The metabolic pathway of the glyoxylate cycle has been investigated in peroxisomes isolated from senescent pumpkin (Cucurbitn sp.) cotyledons. P-oxidation activity, as well as activities of glyoxylate cycle enzymes isocitrate lyase (EC 4.1.3.1), malate synthase (EC 4.1.3.2), malate dehydrogenase (EC 1.1.1.37) and citrate synthase (EC 4.1.3.7) were...

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... A review of the individual genes revealed that each of the three MAGs possesses at least two genes that encode for a potential alcohol dehydrogenase (ADH). Additionally, Castellaniella (Bin_20) is known to utilize acetyl-CoA from acetate, ethanol, or pyruvate via the glyoxylate cycle [60][61][62][63][64]. The incubation period for these three strains in the presence of ethanol was likely insufficient for the strains to multiply sufficiently to allow for the detection of these proteins. ...
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... The two key glyoxylate cycle enzymes, malate synthase and isocitrate lyase, completely facilitate this transition. Because of this change in the route, C. albicans may grow in phagocytic cells-such as neutrophils and macrophages-that are devoid of all nutrients (Dunn et al. 2009). The glyoxylate cycle is necessary for both the virulence and survival of Candida when it is taken up by neutrophils and macrophages (Lorenz and Fink 2001). ...
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... Overall, the detailed analysis of the docking interactions provides valuable insights into the mechanism of action of dihydroergotamine as a potential inhibitor of isocitrate lyase. By targeting this enzyme, dihydroergotamine may offer a promising approach for developing new antibiotics to address bacterial infections 67 . ...
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... The glyoxylate cycle, a variation in the TCA cycle, enables organisms to convert acetyl-CoA into anaplerotic compounds using isocitrate lyase (ICL), which bypasses decarboxylation to produce glyoxylate and succinate. This process is mainly found in plants and some microorganisms that include intracellular bacteria and fungi [1]. The glyoxylate cycle helps in the intracellular survival and pathogenesis of important pathogens, for instance Mycobacterium tuberculosis, Salmonella typhimurium, Pseudomonas aeruginosa, Yersinia pestis, Candida albicans, Paracoccidioides brasiliensis, and Penicillium marneffei [1,2]. ...
... This process is mainly found in plants and some microorganisms that include intracellular bacteria and fungi [1]. The glyoxylate cycle helps in the intracellular survival and pathogenesis of important pathogens, for instance Mycobacterium tuberculosis, Salmonella typhimurium, Pseudomonas aeruginosa, Yersinia pestis, Candida albicans, Paracoccidioides brasiliensis, and Penicillium marneffei [1,2]. ...
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Thymoquinone (TQ), a bioactive compound from black cumin (Nigella sativa), has demonstrated a broad range of therapeutic effects. The aim of this study is to evaluate the antifungal efficacy of TQ by targeting key virulence factors in Candida albicans, specifically focusing on isocitrate lyase (ICL) activity, biofilm formation, and gene expression. This study explored TQ’s impact on ICL, a decisive enzyme in the glyoxylate cycle, along with its effect on hyphal formation, biofilm development, and the virulent gene expression of C. albicans through in silico and in vitro studies. Molecular docking revealed a binding energy of −6.4 kcal/mol between TQ and ICL, indicating moderate affinity. The stability of the ICL-TQ complex was validated through 50 ns molecular dynamics simulations, showing the root mean square deviation (RMSD) values of 0.35 nm for ICL and 0.38 nm for the complex. In vitro studies further validated these findings, showing a dose-dependent inhibition of ICL activity. TQ at 2 µg/mL reduced enzyme activity by 57%, and at 4 µg/mL, by 91.4%. Additionally, TQ disrupted the yeast-to-hyphae switch, a key virulence factor, with 1 and 2 µg/mL doses significantly inhibiting hyphal formation. The biofilm formation was similarly affected, with a 58% reduction at 2 µg/mL and an 83% reduction at 4 µg/mL. TQ also downregulated the ALS1 and HWP1 genes that are associated with adhesion and biofilm development, demonstrating its broad-spectrum antifungal activity. These findings suggest that TQ is a promising candidate for antifungal therapies, targeting multiple virulence factors in C. albicans and potentially overcoming biofilm-associated drug resistance. Future research should focus on in vivo validation, optimization for clinical applications, and expanding its spectrum against other drug-resistant fungal species.
... led to the identification of methylisocitrate lyase as the closest homologue. The corresponding enzyme has been shown to be unable to catalyse the same reaction (Dunn et al., 2009). For Candidatus F. meridionalis, no significant hit for the icl sequence could be found. ...
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... Glyoxylate shunt is a bypass of the TCA cycle and plays an important role in fungal and bacterial pathogenesis (47,48). The glyoxylate shunt bypasses the two decarbox ylation steps of the TCA cycle, which are catalyzed by isocitrate dehydrogenase and α-ketoglutarate dehydrogenase; thus, bacteria can utilize two-carbon compounds as solo carbon sources (49). Isocitrate lyase and malate synthase are the two key character istic enzymes in the glyoxylate shunt (50). ...
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... For example, the dysregulation of enzymes involved in this pathway, such as isocitrate lyase (ICL) and malate synthase (MS), has been shown to promote tumor growth and metastasis in certain types of cancer. These enzymes are involved in the conversion of glyoxylate and dicarboxylate compounds into intermediates of the tricarboxylic acid (TCA) cycle, which plays a crucial role in cellular energy production [41]. ...
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... For example, the human genome appears to have lost a large number of genes associated with carbohydrate metabolism, amino acid metabolism, and membrane biogenesis, including those for isocitrate lyase (ICL) and malate synthase, enzymes of the glyoxylate cycle. Glyoxylate is a highly reactive aldehyde and glyoxylate cycles have been demonstrated in nearly every other branch of life outside of mammals [46,47]. Because of malate synthase loss, human cells must rely on other enzymes to neutralize glyoxylate: (alanine-glyoxylate aminotransferase (AGT) in the peroxisome or glyoxylate reductase (GRHPR) in the cytosol). ...
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... These included thiI (tRNA uracil 4-sulfurtransferase), glcB (malate synthase), metB (cystathionine gammasynthase), and bioI (pimeloyl-ACP synthase), which are associated with thiamine biosynthesis, glyoxylate cycle, methionine biosynthesis, and biotin metabolism, respectively. Specifically, glcB serves as the unique enzyme in the glyoxylate cycle, converting glyoxylate, and acetyl-CoA into malate [74]. It has been observed that glcB is more susceptible to loss within cohabitants [75]. ...
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