Phosphatidylinositol-3-kinases structure

Helliwell, S.B. Wagner, P. Kunz, J. Deuter-Reinhard, M. Henriquez, R. Hall, M.N. TORI and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol. Biol. Cell, 5, 105-118 (1994)... 

Figure 1. Structure of phosphatidylinositol. Phosphatidylinositol (Ptdins) constitutes about 10% of the total phospholipids in eukaryotic cells and is the precursor of the other phosphoinositides (polyphosphoinositides) through sequential phosphorylations by specific kinases. As indicated, its inositol head group can be phosphorylated at three positions (D-3, D-4 and D-5) by specific kinases in vivo. The cleavage by phosphoinositide-specific phospholipase C (PLC), which has as its preferred substrate PtdIns(4,5)P2, is also shown. PI3K, phosphoinositide 3-kinase. PI-K II and III, phosphatidylinositol kinase types II and III. PIP-K I, phosphatidylinositol monophosphate kinase type I. PIP-K II, phosphatidylinositol monophosphate kinase type II.

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Agullo, G. et al.. Relationship between flavonoid structure and inhibition of phosphatidylinositol-3 kinase a comparison with tyrosine kinase and protein kinase C inhibition, Biochem. Pharmacol., 53, 1649, 1997. 

Fykse EM, Li C, and Stidhof TC (1995) Phosphorylation of rabphilin-3A by Ca2+/calmodulin-and cAMP-dependent protein kinases in vitro. J Neurosci 15 2385-95 Gales C, Van Durm JJ, Schaak S et al (2006) Probing the activation-promoted structural rearrangements in preassembled receptor-G protein complexes. Nat Stmct Mol Biol 13 778-86 Gamper N, Reznikov V, Yamada Y et al (2004) Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J Neurosci 24 10980-92... 

Xue, H.W., Pical, C., Brearley, C., Elge, S., and Muller-Rober, B., 1999, A plant 126-kDa phosphatidylinositol 4-kinase with a novel repeat structure. Cloning and functional expression in baculovirus-infected insect cells. J. Biol. Chem. 274 5738-5745. 

The number and breadth of reports of synthetic studies relating to phos-phatidylinositols and related structures has increased markedly as the following selection demonstrates. A series of unnatural phosphatidylinositols (41) with C2 to C18 fatty acids replacing the natural C20 fatty acid at the sn-2 position have been prepared and subjected to phosphorylation conditions with phos-phatidylinositol 3-kinase. The results show that phosphorylation can be achieved in molecules carrying small fatty acid side chains Cg shows reactivity comparable to that of the natural substrate. l-D-l-(sn-3-Phosphatidyl)-myo-inositol (42) has been prepared in excellent yield by the direct phosphatidylation of l-D-2,3,4,5,6-penta-0-benzyl-myo-inositol with sn-3-phosphatidic acid and subsequent deprotection (Scheme 6) The method has the advantage of producing products of unequivocal structure and stereochemical purity and being... 

PIKfyve is a mammalian class III phosphatidylinositol phosphate kinase which synthesizes phosphatidylinositol 3,5-bisphosphate. The physiological role of this pathway is not yet clear. The PI3K inhibitor PI-103 (85) also inhibits PIKfyve. A structural analog, YM201636 (86), was shown to be... 

---