The presence of both a sensory PAS domain and a canonical serine/threonine kinase domain posit a role for PAS kinase in metabolic regulation (see for a summary of PAS kinase regulation and function). The regulation of PAS kinase in response to cellular status has been documented in both mammalian beta-cells and yeast, with the unifying theme of activation under conditions that induce respiration (high glucose in pancreatic beta cells and nonfermentative carbon sources in yeast). However, the precise role of PAS kinase as a metabolic sensor awaits the identification of a biological ligand (either a small molecule or protein) that binds to the PAS domain and activates the enzyme. This identification is a formidable task since the PAS domain/ligand interaction is most likely transient, as no protein or small molecule ligands have been discovered despite repeated attempts at biochemical purification (unpublished). Additionally, PAS kinase activation may require auto- or transphosphorylation and key PAS kinase residues have been shown to be phosphorylated, however the in vivo
relevance of phosphorylation remains unknown [15
]. The presence of a regulating ligand does not preclude phosphorylation as a mechanism to stabilize the activated state.
PAS kinase inhibition may prove to be a valid therapeutic target in the defense against the metabolic syndrome since PAS kinase-deficient mice are protected against weight gain, liver triglyceride accumulation and insulin resistance when fed a high-fat diet [13
]. Intriguingly, these mice display no phenotype when fed a normal chow diet. The molecular mechanisms behind these phenotypes, specifically the identification of PAS kinase substrates and interacting partners, will provide valuable insight into PAS kinase function.
PAS kinase regulates glucose homeostasis in yeast primarily through the phosphorylation of Ugp1 [9
]. Ugp1 is the cellular source of UDP-glucose, an essential carrier of glucose. Phosphorylation of Ugp1 directs the flow of glucose towards the biosynthesis of structural carbohydrates at the expense of glycogen [7
]. Although the phosphorylation site (Ser11) is not conserved in mammalian cells, both yeast and mammalian glycogen synthase proteins are putative PAS kinase substrates [9
]. Many proteins and pathways are well conserved from yeast to man. Thus, the pathways regulated by PAS kinase in yeast may be similar to the mammalian pathways even if the actual phosphorylated substrates may vary. Although bona fide
PAS kinase substrates are scarce, the recent identification of PAS kinase-activating stimuli [8
] and in vitro
yeast and mammalian PAS kinase substrates [9
] should greatly aid in elucidating its regulation and function.