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Impact of Phosphorylation at Various Sites on the Active Pocket of Human Ferrochelatase: Insights from Molecular Dynamics Simulations.

التفاصيل البيبلوغرافية
العنوان: Impact of Phosphorylation at Various Sites on the Active Pocket of Human Ferrochelatase: Insights from Molecular Dynamics Simulations.
المؤلفون: 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.; Augusta University/University of Georgia Medical Partnership, Athens, GA 30602, USA., Shen Y; School of Chemistry, IGCME, Sun Yat-sen University, Guangzhou 510006, China.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2024 Jun 08; Vol. 25 (12). Date of Electronic Publication: 2024 Jun 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Ferrochelatase*/metabolism , Ferrochelatase*/chemistry , Molecular Dynamics Simulation* , Heme*/metabolism , Heme*/chemistry , Protoporphyrins*/chemistry , Protoporphyrins*/metabolism , Catalytic Domain*, Humans ; Phosphorylation ; Protein Binding ; Binding Sites ; Thermodynamics
مستخلص: 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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معلومات مُعتمدة: 2021A1515010068 People's Government of Guangdong Province; DK111653 United States NH NIH HHS; DK110858 United States NH NIH HHS
فهرسة مساهمة: Keywords: human ferrochelatase; molecular dynamics; phosphorylation
المشرفين على المادة: EC 4.99.1.1 (Ferrochelatase)
42VZT0U6YR (Heme)
0 (Protoporphyrins)
C2K325S808 (protoporphyrin IX)
تواريخ الأحداث: Date Created: 20240627 Date Completed: 20240627 Latest Revision: 20240629
رمز التحديث: 20240629
مُعرف محوري في PubMed: PMC11203519
DOI: 10.3390/ijms25126360
PMID: 38928065
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms25126360