Structural Insight into the Working Mechanism of the FAD Synthetase from the Human Pathogen <i>Streptococcus pneumoniae</i>: A Molecular Docking Simulation Study
Flavin adenine dinucleotide synthetases (FADSs) catalyze FAD biosynthesis through two consecutive catalytic reactions, riboflavin (RF) phosphorylation and flavin mononucleotide (FMN) adenylylation. Bacterial FADSs have RF kinase (RFK) and FMN adenylyltransferase (FMNAT) domains, whereas the two doma...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3121 |
| Summary: | Flavin adenine dinucleotide synthetases (FADSs) catalyze FAD biosynthesis through two consecutive catalytic reactions, riboflavin (RF) phosphorylation and flavin mononucleotide (FMN) adenylylation. Bacterial FADSs have RF kinase (RFK) and FMN adenylyltransferase (FMNAT) domains, whereas the two domains are separated into two independent enzymes in human FADSs. Bacterial FADSs have attracted considerable attention as drug targets due to the fact that they differ from human FADSs in structure and domain combinations. In this study, we analyzed the putative FADS structure from the human pathogen <i>Streptococcus pneumoniae</i> (<i>Sp</i>FADS) determined by Kim et al., including conformational changes of key loops in the RFK domain upon substrate binding. Structural analysis and comparisons with a homologous FADS structure revealed that <i>Sp</i>FADS corresponds to a hybrid between open and closed conformations of the key loops. Surface analysis of <i>Sp</i>FADS further revealed its unique biophysical properties for substrate attraction. In addition, our molecular docking simulations predicted possible substrate-binding modes at the active sites of the RFK and FMNAT domains. Our results provide a structural basis to understand the catalytic mechanism of <i>Sp</i>FADS and develop novel <i>Sp</i>FADS inhibitors. |
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| ISSN: | 1661-6596 1422-0067 |