Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization
Abstract In oxygen-deprived conditions, cells respond by activating adaptive mechanisms to bolster their survival and protect tissue integrity. A key player in this process is the HIF-1α signaling cascade, meticulously regulated by Prolyl Hydroxylase Domain 2 (PHD2), which orchestrates cellular resp...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-83730-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544722008506368 |
|---|---|
| author | Jainabbi Irshad Ahmed Patel Jagadeesha Poyya Apeksha Padakannaya Namrata Manjunath Kurdekar Ajay Sathayanarayan Khandagale Chandrashekhar Gajanan Joshi Santosh R. Kanade Kapaettu Satyamoorthy |
| author_facet | Jainabbi Irshad Ahmed Patel Jagadeesha Poyya Apeksha Padakannaya Namrata Manjunath Kurdekar Ajay Sathayanarayan Khandagale Chandrashekhar Gajanan Joshi Santosh R. Kanade Kapaettu Satyamoorthy |
| author_sort | Jainabbi Irshad Ahmed Patel |
| collection | DOAJ |
| description | Abstract In oxygen-deprived conditions, cells respond by activating adaptive mechanisms to bolster their survival and protect tissue integrity. A key player in this process is the HIF-1α signaling cascade, meticulously regulated by Prolyl Hydroxylase Domain 2 (PHD2), which orchestrates cellular responses to varying oxygen levels. The primary aim of this investigation is to utilize gut siderophores as inhibitors of PHD2 in ischemic conditions. This study also helps in understanding the structural mechanisms by which gut microbiota regulate HIF-1α via PHD2 inhibition through the secretion of siderophores. We explore potential PHD2 inhibitors through in-silico approaches, specifically molecular docking, binding pose metadynamics, molecular dynamics simulations, and free energy calculations. We evaluated siderophores secreted by gut microbiota as candidate inhibitors for PHD2. Docking studies revealed that Salmochelin SX exhibits the highest binding affinity to PHD2 (− 9.527 kcal/mol), interacting with key residues such as ASP254, TYR310, ASP315, and ARG322. Despite its high affinity, binding pose metadynamics indicated instability for Salmochelin SX, whereas Staphyloferrin A demonstrated superior stability. Molecular dynamics simulations confirmed stable ligand interactions with PHD2, highlighting HIS313 and ASP315 as critical for inhibition. Principal Component Analysis (PCA) and Free Energy Landscape (FEL) analyses underscored conformational changes and binding stability, suggesting that these interactions may stabilize PHD2’s active site and have potential therapeutic implications. Additionally, the study reveals how gut microbiota prevent gut dysbiosis through the stabilization of HIF-1α signaling by secreting siderophores. |
| format | Article |
| id | doaj-art-2337761933e94dbb913d11337fe37c25 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-2337761933e94dbb913d11337fe37c252025-01-12T12:17:39ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-83730-8Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilizationJainabbi Irshad Ahmed Patel0Jagadeesha Poyya1Apeksha Padakannaya2Namrata Manjunath Kurdekar3Ajay Sathayanarayan Khandagale4Chandrashekhar Gajanan Joshi5Santosh R. Kanade6Kapaettu Satyamoorthy7SDM Research Institute for Biomedical Sciences, Shri Dharmasthala Manjunatheshwara UniversitySDM Research Institute for Biomedical Sciences, Shri Dharmasthala Manjunatheshwara UniversitySDM Research Institute for Biomedical Sciences, Shri Dharmasthala Manjunatheshwara UniversitySDM Research Institute for Biomedical Sciences, Shri Dharmasthala Manjunatheshwara UniversitySDM Research Institute for Biomedical Sciences, Shri Dharmasthala Manjunatheshwara UniversityDepartment of Biochemistry, Mangalore UniversityDepartment of Plant Sciences, School of Life Sciences, University of HyderabadShri Dharmasthala Manjunatheshwara (SDM) UniversityAbstract In oxygen-deprived conditions, cells respond by activating adaptive mechanisms to bolster their survival and protect tissue integrity. A key player in this process is the HIF-1α signaling cascade, meticulously regulated by Prolyl Hydroxylase Domain 2 (PHD2), which orchestrates cellular responses to varying oxygen levels. The primary aim of this investigation is to utilize gut siderophores as inhibitors of PHD2 in ischemic conditions. This study also helps in understanding the structural mechanisms by which gut microbiota regulate HIF-1α via PHD2 inhibition through the secretion of siderophores. We explore potential PHD2 inhibitors through in-silico approaches, specifically molecular docking, binding pose metadynamics, molecular dynamics simulations, and free energy calculations. We evaluated siderophores secreted by gut microbiota as candidate inhibitors for PHD2. Docking studies revealed that Salmochelin SX exhibits the highest binding affinity to PHD2 (− 9.527 kcal/mol), interacting with key residues such as ASP254, TYR310, ASP315, and ARG322. Despite its high affinity, binding pose metadynamics indicated instability for Salmochelin SX, whereas Staphyloferrin A demonstrated superior stability. Molecular dynamics simulations confirmed stable ligand interactions with PHD2, highlighting HIS313 and ASP315 as critical for inhibition. Principal Component Analysis (PCA) and Free Energy Landscape (FEL) analyses underscored conformational changes and binding stability, suggesting that these interactions may stabilize PHD2’s active site and have potential therapeutic implications. Additionally, the study reveals how gut microbiota prevent gut dysbiosis through the stabilization of HIF-1α signaling by secreting siderophores.https://doi.org/10.1038/s41598-024-83730-8IschemiaHypoxiaHIF-1α signalingGut microbiotaSiderophores |
| spellingShingle | Jainabbi Irshad Ahmed Patel Jagadeesha Poyya Apeksha Padakannaya Namrata Manjunath Kurdekar Ajay Sathayanarayan Khandagale Chandrashekhar Gajanan Joshi Santosh R. Kanade Kapaettu Satyamoorthy Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization Scientific Reports Ischemia Hypoxia HIF-1α signaling Gut microbiota Siderophores |
| title | Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization |
| title_full | Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization |
| title_fullStr | Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization |
| title_full_unstemmed | Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization |
| title_short | Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization |
| title_sort | mechanistic insights into gut microbe derived siderophores and phd2 interactions with implications for hif 1α stabilization |
| topic | Ischemia Hypoxia HIF-1α signaling Gut microbiota Siderophores |
| url | https://doi.org/10.1038/s41598-024-83730-8 |
| work_keys_str_mv | AT jainabbiirshadahmedpatel mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT jagadeeshapoyya mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT apekshapadakannaya mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT namratamanjunathkurdekar mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT ajaysathayanarayankhandagale mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT chandrashekhargajananjoshi mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT santoshrkanade mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization AT kapaettusatyamoorthy mechanisticinsightsintogutmicrobederivedsiderophoresandphd2interactionswithimplicationsforhif1astabilization |