[6][11][8][12] By directly binding membrane PtdIns(3)P,[13] the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes.

[27][28] Concordantly, mice with selective Pikfyve gene disruption in skeletal muscle, the tissue mainly responsible for the decrease of postprandial blood sugar, exhibit systemic insulin resistance; glucose intolerance; hyperinsulinemia; and increased adiposity, i.e. symptoms, typical for human prediabetes.

Under sustained activation of glutamate receptors PIKfyve binds to and facilitates the lysosomal degradation of Cav1.2, voltage-dependent calcium channel type 1.2, thereby protecting the neurons from excitotoxicity.

Single copy genes, encoding similarly-structured FYVE-domain–containing phosphoinositide kinases exist in most genomes from yeast to man.

[24][41][42][43] Thus, in evolution, the FYVE-domain-containing phosphoinositide kinases retain several aspects of the structural organization, enzyme activity and protein interactions from budding yeast.

In higher eukaryotes, the enzymes acquire one additional domain, a role in the production of PtdIns5P, a new set of interacting proteins and become essential in embryonic development.