Kinetics and inhibition studies of the L205R mutant of cAMP-dependent protein kinase involved in Cushing's syndrome.
FEBS Open Bio
; 8(4): 606-613, 2018 04.
Article
em En
| MEDLINE
| ID: mdl-29632813
ABSTRACT
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 α-isoform of the catalytic subunit of cAMP-dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone-independent Cushing's syndrome. Here, we conducted kinetics and inhibition studies on the L205R-PKACα 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 IC 50 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-PKACα inhibitors as potential therapeutics.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
FEBS Open Bio
Ano de publicação:
2018
Tipo de documento:
Article