Emerging roles of inositol pyrophosphates as key modulators of fungal pathogenicity

Inositol pyrophosphates (PP-IPs) are energy-rich small molecules that are omnipresent in eukaryotic cells, from yeast to mammals, playing central roles in overall cellular homeostasis as a diverse and multifaceted class of intracellular messengers. Recent studies of the metabolic pathways and physiological roles of PP-IPs in the human pathogenic fungus Cryptococcus neoformans have revealed that the PP-IP(5) (IP(7)) is a key metabolite essential for fungal metabolic adaptation to the host environment, immune recognition, and pathogenicity. This suggests the PP-IP biosynthesis pathway, comprising phospholipase C1 (Plc1) and a series of sequentially acting inositol polyphosphate kinases (IPKs), as a new virulence-related signaling pathway in C. neoformans. Given that fungal species have a reduced array of the kinases required for the synthesis of PP-IPs and that the homology between human and fungal IPKs is restricted to a few catalytically important residues, identification of IPK inhibitors specifically targeting the kinases of pathogenic fungi has emerged as a desirable and achievable strategy for antifungal drug development.