Kinetic mechanism of AKT/PKB enzyme family.

Article Details


Zhang X, Zhang S, Yamane H, Wahl R, Ali A, Lofgren JA, Kendall RL

Kinetic mechanism of AKT/PKB enzyme family.

J Biol Chem. 2006 May 19;281(20):13949-56. Epub 2006 Mar 15.

PubMed ID
16540465 [ View in PubMed

AKT/PKB is a phosphoinositide-dependent serine/threonine protein kinase that plays a critical role in the signal transduction of receptors. It also serves as an oncogene in the tumorigenesis of cancer cells when aberrantly activated by genetic lesions of the PTEN tumor suppressor, phosphatidylinositol 3-kinase, and receptor tyrosine kinase overexpression. Here we have characterized and compared kinetic mechanisms of the three AKT isoforms. Initial velocity studies revealed that all AKT isozymes follow the sequential kinetic mechanism by which an enzyme-substrate ternary complex forms before the product release. The empirically derived kinetic parameters are apparently different among the isoforms. AKT2 showed the highest Km value for ATP, and AKT3 showed the highest kcat value. The patterns of product inhibition of AKT1, AKT2, and AKT3 by ADP were all consistent with an ordered substrate addition mechanism with ATP binding to the enzymes prior to the peptide substrate. Further analysis of steady state kinetics of AKT1 in the presence of dead-end inhibitors supported the finding and suggested that the AKT family of kinases catalyzes reactions via an Ordered Bi Bi sequential mechanism with ATP binding to the enzyme prior to peptide substrate and ADP being released after the phosphopeptide product. These results suggest that ATP is an initiating factor for the catalysis of AKT enzymes and may play a role in the regulation AKT enzyme activity in cells.

DrugBank Data that Cites this Article

NameUniProt ID
RAC-alpha serine/threonine-protein kinaseP31749Details
RAC-beta serine/threonine-protein kinaseP31751Details