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Impact of Phosphorylation at Various Sites on the Active Pocket of Human Ferrochelatase: Insights from Molecular Dynamics Simulations.
Guo, Mingshan; Lin, Yuhong; Obi, Chibuike David; Zhao, Peng; Dailey, Harry A; Medlock, Amy E; Shen, Yong.
Afiliación
  • Guo M; School of Chemistry, IGCME, Sun Yat-sen University, Guangzhou 510006, China.
  • Lin Y; School of Chemistry, IGCME, Sun Yat-sen University, Guangzhou 510006, China.
  • Obi CD; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Zhao P; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
  • Dailey HA; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Medlock AE; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Shen Y; Augusta University/University of Georgia Medical Partnership, Athens, GA 30602, USA.
Int J Mol Sci ; 25(12)2024 Jun 08.
Article en En | MEDLINE | ID: mdl-38928065
ABSTRACT
Ferrochelatase (FECH) is the terminal enzyme in human heme biosynthesis, catalyzing the insertion of ferrous iron into protoporphyrin IX (PPIX) to form protoheme IX (Heme). Phosphorylation increases the activity of FECH, and it has been confirmed that the activity of FECH phosphorylated at T116 increases. However, it remains unclear whether the T116 site and other potential phosphorylation modification sites collaboratively regulate the activity of FECH. In this study, we identified a new phosphorylation site, T218, and explored the allosteric effects of unphosphorylated (UP), PT116, PT218, and PT116 + PT218 states on FECH in the presence and absence of substrates (PPIX and Heme) using molecular dynamics (MD) simulations. Binding free energies were evaluated with the MM/PBSA method. Our findings indicate that the PT116 + PT218 state exhibits the lowest binding free energy with PPIX, suggesting the strongest binding affinity. Additionally, this state showed a higher binding free energy with Heme compared to UP, which facilitates Heme release. Moreover, employing multiple analysis methods, including free energy landscape (FEL), principal component analysis (PCA), dynamic cross-correlation matrix (DCCM), and hydrogen bond interaction analysis, we demonstrated that phosphorylation significantly affects the dynamic behavior and binding patterns of substrates to FECH. Insights from this study provide valuable theoretical guidance for treating conditions related to disrupted heme metabolism, such as various porphyrias and iron-related disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protoporfirinas / Dominio Catalítico / Simulación de Dinámica Molecular / Ferroquelatasa / Hemo Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protoporfirinas / Dominio Catalítico / Simulación de Dinámica Molecular / Ferroquelatasa / Hemo Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza