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Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 FEBS+Open+Bio 2018 ; 8 (4): 606-13 Nephropedia Template TP
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Kinetics and inhibition studies of the L205R mutant of cAMP?dependent protein kinase involved in Cushing s syndrome #MMPMID29632813
Luzi NM; Lyons CE; Peterson DL; Ellis KC
FEBS Open Bio 2018[Apr]; 8 (4): 606-13 PMID29632813show ga
Overproduction of cortisol by the hypothalamus?pituitary?adrenal hormone system results in the clinical disorder known as Cushing's syndrome. Genomics studies have identified a key mutation (L205R) in the ??isoform of the catalytic subunit of cAMP?dependent protein kinase (PKAC?) in adrenal adenomas of patients with adrenocorticotropic hormone?independent Cushing's syndrome. Here, we conducted kinetics and inhibition studies on the L205R?PKAC? mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12?fold and 4.5?fold, respectively. We have also determined the IC50 and Ki for the peptide substrate?competitive inhibitor PKI(5?24) and the ATP?competitive inhibitor H89. The L205R mutation had no effect on the potency of H89, but causes a > 250?fold loss in potency for PKI(5?24). Collectively, these data provide insights for the development of L205R?PKAC? inhibitors as potential therapeutics.