Abstract
Cytochromes P450 (CYP450s) promote the biosynthesis of steroid hormones with major impact on the onset of diseases such as breast and prostate cancers. By merging distinct functions into the same catalytic scaffold, steroidogenic CYP450s enhance complex chemical transformations with extreme efficiency and selectivity. Mammalian CYP450s and their redox partners are membrane-anchored proteins, dynamically associating to form functional machineries. Mounting evidence signifies that environmental factors are strictly intertwined with CYP450s catalysis. Atomic-level simulations have the potential to provide insights into the catalytic mechanism of steroidogenic CYP450s and on its regulation by environmental factors, furnishing information often inaccessible to experimental means. In this review, after an introduction of computational methods commonly employed to tackle these systems, we report the current knowledge on three steroidogenic CYP450s—CYP11A1, CYP17A1, and CYP19A1—endowed with multiple catalytic functions and critically involved in cancer onset. In particular, besides discussing their catalytic mechanisms, we highlight how the membrane environment contributes to (i) regulate ligand channeling through these enzymes, (ii) modulate their interactions with specific protein partners, (iii) mediate post-transcriptional regulation induced by phosphorylation. The results presented set the basis for developing novel therapeutic strategies aimed at fighting diseases originating from steroid metabolism dysfunction.
Highlights
Cytochromes P450 (CYP450s) catalyze a variety of reactions over a broad range of substrates, being among the most versatile enzymes in Nature
Molecular dynamics (MD) simulations have often been used to study CYP450s. This method allows the dynamic evolution of a system to be followed at near-physiological conditions, while its thermodynamic properties are calculated from averages over sufficiently long trajectories [12]
CYP450s are partly immersed in the hydrophobic framework of the membrane and assume a characteristic heme tilt angle oscillating between 30–89 degrees [2]
Summary
Cytochromes P450 (CYP450s) catalyze a variety of reactions over a broad range of substrates, being among the most versatile enzymes in Nature. Understanding the mechanism of steroidogenesis has several pathologies, such as polycystic ovary syndrome, hypertension, and of distinct cancer types (i.e., innumerable biological andHence, pharmacological implications andofissteroidogenesis rooted into unraveling their breast and prostate cancers). It ismolecules commonly accepted that the hydroxylation reaction protons, and electrons supplied from water and specific protein partners, respectively It is now is mediatedaccepted by Compound (Cpd I) via anreaction oxygenisrebound mechanism [5,6].I the commonly that theIhydroxylation mediated by Compound (Cpd I) viabesides an oxygen canonicalmechanism mono-oxygenation, CYP450s canthepromote variety of distinctCYP450s chemical rebound [5,6]. Unraveling the inner-working mechanism of this intricate and utmost important machinery has broad biological and pharmacological implications to tackle disorders linked to steroid metabolism dysfunction, setting the basis for novel inhibitory strategies against cancer (breast and prostate) disease
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