Journal Article

FZJ-2020-00306

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Post-Translational Regulation of CYP450s Metabolism As Revealed by All-Atoms Simulations of the Aromatase Enzyme

Ritacco, I. ; Spinello, A. ; Ippoliti, E.FZJ* ; Magistrato, A. (Corresponding author)

2019
American Chemical Society64160 Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jcim.9b00157

Abstract: Phosphorylation by kinases enzymes is a widespread regulatory mechanism able of rapidly altering the function of target proteins. Among these are cytochrome P450s (CYP450), a superfamily of enzymes performing the oxidation of endogenous and exogenous substrates thanks to the electron supply of a redox partner. In spite of its pivotal role, the molecular mechanism by which phosphorylation modulates CYP450s metabolism remains elusive. Here by performing microsecond-long all-atom molecular dynamics simulations, we disclose how phosphorylation regulates estrogen biosynthesis, catalyzed by the Human Aromatase (HA) enzyme. Namely, we unprecedentedly propose that HA phosphorylation at Y361 markedly stabilizes its adduct with the flavin mononucleotide domain of CYP450s reductase (CPR), the redox partner of microsomal CYP450s, and a variety of other proteins. With CPR present at physiological conditions in a limiting ratio with respect to its multiple oxidative partners, the enhanced stability of the CPR/HA adduct may favor HA in the competition with the other proteins requiring CPR’s electron supply, ultimately facilitating the electron transfer and estrogen biosynthesis. As a result, our work elucidates at atomic-level the post-translational regulation of CYP450s catalysis. Given the potential for rational clinical management of diseases associated with steroid metabolism disorders, unraveling this mechanism is of utmost importance, and raises the intriguing perspective of exploiting this knowledge to devise novel therapies.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. JARA - HPC (JARA-HPC)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
2. Post-Transcriptional regulation mechanism of Human Aromatase investigated by molecular simulations (jias5a_20190501) (jias5a_20190501)

Appears in the scientific report 2020

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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