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<p>Fungal infections pose a significant threat to human health in spite of the huge literature available on the fungal biology, infection mechanisms and antifungal drug discovery. Mitochondria primarily known as the power house of the cell is now receiving attention for its critical role in fungal virulence and drug tolerance. Hence, mitochondrial proteins are ideal targets of antifungal interventions. Domain specific post-transcriptional modifications of the first base at the wobble position in the tRNA(CAU) determines the decoding of AUA codon as Isoleucine. The modification of wobble cytidine are catalyzed by tRNA(Ile) lysidine synthetase (TilS) and 2-agmatinylcytidine synthetase (TiaS) in an ATP-dependent manner in bacteria and archaea respectively. These ATP dependent enzymes are absent in mammals making them unique drug targets. During a genome wide survey of tRNA modification enzymes in fungal genomes, a tRNA(Ile) lysidine synthetase with possible mitochondrial localization was identified in few fungal pathogens. Comparison of the codon usage frequency and tRNA content of the completed mitochondrial genomes of fungal pathogens provide clear evidences for the predominant use of AUA and AUU for Ile. Phylogenetic analysis clearly demonstrates evolutionary relatedness of fungal TilS to plant and bacterial TilS. Among the fungal priority pathogens list released by the World health Organization, <i>Candida albicans</i> stands in the critical pathogens list. Therefore, a detailed investigation on the 3-D structural model of <i>Ca</i>TilS is presented. Possible ATP competitive inhibitors are also suggested based on the molecular docking analysis of the homology model.</p>

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In silico dissection of an unwonted decoding system for AUA codon in fungal pathogens

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Venkatraman Subramanian Gowri

摘要

Fungal infections pose a significant threat to human health in spite of the huge literature available on the fungal biology, infection mechanisms and antifungal drug discovery. Mitochondria primarily known as the power house of the cell is now receiving attention for its critical role in fungal virulence and drug tolerance. Hence, mitochondrial proteins are ideal targets of antifungal interventions. Domain specific post-transcriptional modifications of the first base at the wobble position in the tRNA(CAU) determines the decoding of AUA codon as Isoleucine. The modification of wobble cytidine are catalyzed by tRNA(Ile) lysidine synthetase (TilS) and 2-agmatinylcytidine synthetase (TiaS) in an ATP-dependent manner in bacteria and archaea respectively. These ATP dependent enzymes are absent in mammals making them unique drug targets. During a genome wide survey of tRNA modification enzymes in fungal genomes, a tRNA(Ile) lysidine synthetase with possible mitochondrial localization was identified in few fungal pathogens. Comparison of the codon usage frequency and tRNA content of the completed mitochondrial genomes of fungal pathogens provide clear evidences for the predominant use of AUA and AUU for Ile. Phylogenetic analysis clearly demonstrates evolutionary relatedness of fungal TilS to plant and bacterial TilS. Among the fungal priority pathogens list released by the World health Organization, Candida albicans stands in the critical pathogens list. Therefore, a detailed investigation on the 3-D structural model of CaTilS is presented. Possible ATP competitive inhibitors are also suggested based on the molecular docking analysis of the homology model.