InterPro: IPR000403 Phosphatidylinositol 3-/4-kinase, catalytic

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [1]:

• Serine/threonine-protein kinases
• Tyrosine-protein kinases
• Dual specific protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)

Protein kinase function has been evolutionarily conserved from Escherichia coli to human [2]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [3]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [4], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [5].

Phosphatidylinositol 3-kinase (PI3-kinase) (EC:2.7.1.137) [6] is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The three products of PI3-kinase - PI-3-P, PI-3,4-P(2) and PI-3,4,5-P(3) function as secondary messengers in cell signalling. Phosphatidylinositol 4-kinase (PI4-kinase) (EC:2.7.1.67) [7] is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1'4'5'-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases [8].

The PI3- and PI4-kinases share a well conserved domain at their C-terminal section; this domain seems to be distantly related to the catalytic domain of protein kinases [9, 10]. The catalytic domain of PI3K has the typical bilobal structure that is seen in other ATP-dependent kinases, with a small N-terminal lobe and a large C-terminal lobe. The core of this domain is the most conserved region of the PI3Ks. The ATP cofactor binds in the crevice formed by the N-and C-terminal lobes, a loop between two strands provides a hydrophobic pocket for binding of the adenine moiety, and a lysine residue interacts with the alpha-phosphate. In contrast to protein kinases, the PI3K loop which interacts with the phosphates of the ATP and is known as the glycine-rich or P-loop, contains no glycine residues. Instead, contact with the ATP -phosphate is maintained through the side chain of a conserved serine residue.