Structural insights into the function of steroidogenic cytochrome P450 17A1

Abstract

Cytochrome P450 17A1 (CYP17A1) operates at the core of human steroidogenesis, directing precursors into mineralocorticoids, glucocorticoids, or sex steroids. Although the 17α–hydroxylase and 17,20-lyase activities of this dual function enzyme have been investigated extensively, until recently no CYP17A1 structures were available to inform our understanding. Structures of CYP17A1 with a range of steroidal inhibitors and substrates are now available. This review relates functional knowledge of this enzyme to structural features defining the selective differentiation between its various substrates. While both hydroxylase and lyase substrates have similar orientations with respect to the heme, subtle differences in hydrogen bonding between CYP17A1 and the C3 substituent at the opposite end of ligands appear to correlate with differential substrate utilization and product formation. Complementary structural information from solution NMR supports cytochrome b5 allosteric modulation of the lyase reaction, implicating regions involved in ligand access to the otherwise buried active site.

Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency

“…Given the information from crystal structure of human CYP17A1 with abiraterone (nitrogen at 2.9 Å from the heme iron) ( Figure 8 ), this implies that PREG either does not have to get this close to the heme or can accesses it from a different angle and is hence relatively unimpaired by the methionine. Recent structures of the human CYP17A1 bound with different steroid substrates confirm this hypothesis and show that 17OH-PREG binds much closer to the heme iron than PROG or PREG ( Figure 7 and Figure 9 ) [ 23 , 24 ]. For the 17OH-PREG we observed the existence of poses with the hydroxyl positioned very close to the CH3 of the methionine, indicating the bulky methionine residue could be preventing the ligand from getting close enough to the heme ( Figure 7 d and Figure S2 ).…”

“…The validity of our docking protocol was supported by a set of additional CYP17A1 crystal structures containing all the ligands of interest (PDB codes: 4NKW, 4NKX, 4NKY, and 4NKZ) in very similar poses enabling hydrogen-bonding to a distal N202 residue for PROG/PREG but not for 17OH-PREG [ 23 ]. Based on these observations, we hypothesized that the methionine side-chain could prevent a closer proximity to the heme iron necessary for the substrates undergoing lyase reaction [ 23 , 24 ]. To check this, we performed an additional pair of simulations with 17OH-PREG docked into the wild-type and mutant binding sites.…”

“…Along with CYB5A, higher molecular ratios of POR and phosphorylation of CYP17A1 also influence 17,20 lyase activity [ 17 , 18 , 19 , 20 , 21 ]. Recently several X-ray crystal structures of solubilized human CYP17A1 have been reported, but the structural basis of 17α-hydroxylase and 17,20, lyase activities remains unknown [ 22 , 23 , 24 , 25 , 26 ]. Generally, the mutations that affect the steroid-binding domain of CYP17A1 or disturb the interaction with P450 oxidoreductase (POR) for electron transfer, cause combined 17α-hydroxylase and 17,20 lyase deficiency, and are those more frequently found in humans [ 4 , 25 ].…”

Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1

“…A completely processive reaction should not have differential sensitivities to a single inhibitor. Even in a dissociative mechanism, the question arises as to how a drug can occupy a single site on the enzyme and have different K i values for two reactions (42,43).…”

Стан Вуглеводного Обміну У Хворих Із Синдромом Полікістозних Яєчників

“…Ймовірно, механізми формування ГА при інсулінорезистентності є гетерогенними. Притаманна СПКЯ ГА може бути обумовлена над-лишковою концентрацією в сироватці крові інсу-ліну, який, як відомо, чинить стимулюючий вплив на активність цитохрому Р450с17 -ключового ферменту синтезу андрогенів наднирковими за-лозами та яєчниками [13]. Крім того, інсулін на рівні яєчників збільшує число рецепторів до ЛГ у гранульозних клітинах і потенціює їх стероїдоген-ну відповідь на гонадотропіни.…”