ArticleProceedings of the National Academy of Sciences of the United States of America2014
Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 69 citations in OpenAlex.
- Protist oxygen-sensing and the role of prolyl hydroxylase-regulation of E3(SCF) ubiquitin ligases.Biochimica et biophysica acta. General subjects · 2026Review
- Collagen IV biosynthesis: Intracellular choreography of post-translational modifications.Matrix biology : journal of the International Society for Matrix Biology · 2025Review
- Unusual O-H Activation-Initiated C-C Bond Cleavage Reaction by a Nonheme Fe Enzyme in Antifungal Nucleoside Biosynthesis.Journal of the American Chemical Society · 2025Article
- Transposons and accessory genes drive adaptation in a clonally evolving fungal pathogen.Nature communications · 2025Article
- Article
- Gas Tunnel Engineering of Prolyl Hydroxylase Reprograms Hypoxia Signaling in Cells.Angewandte Chemie (International ed. in English) · 2024Article
- Understanding the significance of oxygen tension on the biology of Plasmodium falciparum blood stages: From the human body to the laboratory.PLoS pathogens · 2024Review
- Gas tunnel engineering of prolyl hydroxylase reprograms hypoxia signaling in cells.bioRxiv : the preprint server for biology · 2024Article
- The Structural and Molecular Mechanisms ofMolecules (Basel, Switzerland) · 2024Review
- Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.Proteins · 2023Article
- Factor inhibiting HIF can catalyze two asparaginyl hydroxylations in VNVN motifs of ankyrin fold proteins.The Journal of biological chemistry · 2022Article
- Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes.Nucleic acids research · 2022Article
- The origin and distribution of the main oxygen sensing mechanism across metazoans.Frontiers in physiology · 2022Article
- Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions.Cellular and molecular life sciences : CMLS · 2021Review
- Biochemical and biophysical analyses of hypoxia sensing prolyl hydroxylases fromThe Journal of biological chemistry · 2020Article
- Carbon-fluorine bond cleavage mediated by metalloenzymes.Chemical Society reviews · 2020Review
- Biochemical pathways to α-ketoglutarate, a multi-faceted metabolite.World journal of microbiology & biotechnology · 2020Review
- The putative bacterial oxygen sensor Pseudomonas prolyl hydroxylase (PPHD) suppresses antibiotic resistance and pathogenicity inThe Journal of biological chemistry · 2020Article
- Replication ofFrontiers in cellular and infection microbiology · 2020Article
- Studies on the selectivity of proline hydroxylases reveal new substrates including bicycles.Bioorganic chemistry · 2020Article
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Authors and funding
20 authors at 2 institutions in 2 countries.
Funding
Abstract
The roles of 2-oxoglutarate (2OG)-dependent prolyl-hydroxylases in eukaryotes include collagen stabilization, hypoxia sensing, and translational regulation. The hypoxia-inducible factor (HIF) sensing system is conserved in animals, but not in other organisms. However, bioinformatics imply that 2OG-dependent prolyl-hydroxylases (PHDs) homologous to those acting as sensing components for the HIF system in animals occur in prokaryotes. We report cellular, biochemical, and crystallographic analyses revealing that Pseudomonas prolyl-hydroxylase domain containing protein (PPHD) contain a 2OG oxygenase related in structure and function to the animal PHDs. A Pseudomonas aeruginosa PPHD knockout mutant displays impaired growth in the presence of iron chelators and increased production of the virulence factor pyocyanin. We identify elongation factor Tu (EF-Tu) as a PPHD substrate, which undergoes prolyl-4-hydroxylation on its switch I loop. A crystal structure of PPHD reveals striking similarity to human PHD2 and a Chlamydomonas reinhardtii prolyl-4-hydroxylase. A crystal structure of PPHD complexed with intact EF-Tu reveals that major conformational changes occur in both PPHD and EF-Tu, including a >20-Å movement of the EF-Tu switch I loop. Comparison of the PPHD structures with those of HIF and collagen PHDs reveals conservation in substrate recognition despite diverse biological roles and origins. The observed changes will be useful in designing new types of 2OG oxygenase inhibitors based on various conformational states, rather than active site iron chelators, which make up most reported 2OG oxygenase inhibitors. Structurally informed phylogenetic analyses suggest that the role of prolyl-hydroxylation in human hypoxia sensing has ancient origins.
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