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myo‐Inositol Metabolism: Inositol Catabolism and Coordination with Synthesis in the Yeast Cryptococcus neoformans.

Regulation of inositol metabolism is critical for the growth and viability of many organisms. In mammals, inositol catabolism occurs primarily in the kidneys. The kidneys also synthesize and transport inositol from external sources. Cryptococcus neoformans is an encapsulated opportunistic fungal pathogen of humans that can synthesize, transport and catabolize inositol. This yeast is atypical in that through the action of myo‐inositol oxygenase (MIOX) it can thrive in medium containing inositol as a sole carbon source. The activity of MIOX in C. neoformans has been shown to be regulated in response to environmental inositol. MIOX incorporates molecular oxygen into inositol to generate glucuronic acid leading to either energy production or precursors for the polysaccharide capsule. MIOX is the first committed step in the catabolism of inositol. Several eukaryote genomes contain MIOX genes (mammals, fish, insects, plants and fungi). Optimal alignment of expressed MIOX proteins from several organisms coupled with predicted exposed amino acids indicates three groups of amino acids that possibly form active sites. There are three sequences annotated as MIOX (MIOX1, MIOX2, MIOX3) in the C. neoformans genome. MIOX1 gene is 64% identical to MIOX2 and 63% identical to MIOX3. The MIOX 2 and MIOX3 genes are 80% identical. MIOX1 gene has been experimentally confirmed. Transcripts with nearly 100% identity to MIOX2 have been isolated. mRNA secondary structures have been predicted for the three sequences and suggest possible differences in degradation rates. Open reading frames, introns/exons and stop codons were identified for each sequence. MIOX1 and MIOX3 sequences contain UASino and a TATA box. The role of UASino in the regulation of inositol catabolism, and coordination of inositol synthesis with catabolism, could provide key insights to the inositol metabolic pathway.