ArticleProceedings of the National Academy of Sciences of the United States of America2024
PHD2 enzyme is an intracellular manganese sensor that initiates the homeostatic response against elevated manganese.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Manganese: biology, physiology and role in disease.Cell discovery · 2026Review
- Overlaps in mammalian iron and manganese homeostasis: recent advances.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- The Dual Nature of Metals: Essential Nutrients and Environmental Contaminants.International journal of molecular sciences · 2026Review
- Neuron-specific modulation of SLC30A10 identifies dopaminergic and glutamatergic neurons as targets of manganese-induced motor disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Removal of Toxic Metabolites-Chelation: Manganese Disorders.Journal of inherited metabolic disease · 2025Review
- Molecular mechanisms of SLC30A10-mediated manganese transport.Nature communications · 2025Article
- Elevated brain manganese induces motor disease by upregulating the kynurenine pathway of tryptophan metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Metal Ion Signaling in Biomedicine.Chemical reviews · 2025Review
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7 authors.
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Abstract
Intracellular sensors detect changes in levels of essential metals to initiate homeostatic responses. But, a mammalian manganese (Mn) sensor is unknown, representing a major gap in understanding of Mn homeostasis. Using human-relevant models, we recently reported that: 1) the primary homeostatic response to elevated Mn is upregulation of hypoxia-inducible factors (HIFs), which increases expression of the Mn efflux transporter SLC30A10; and 2) elevated Mn blocks the prolyl hydroxylation of HIFs by prolyl hydroxylase domain (PHD) enzymes, which otherwise targets HIFs for degradation. Thus, the mammalian mechanism for sensing elevated Mn likely relates to PHD inhibition. Moreover, 1) Mn substitutes for a catalytic iron (Fe) in PHD structures; and 2) exchangeable cellular levels of Fe and Mn are comparable. Therefore, we hypothesized that elevated Mn directly inhibits PHD by replacing its catalytic Fe. In vitro assays using catalytically active PHD2, the primary PHD isoform, revealed that Mn inhibited, and Fe supplementation rescued, PHD2 activity. However, a mutation in PHD2 (D315E) that selectively reduced Mn binding without substantially impacting Fe binding or enzymatic activity resulted in complete insensitivity of PHD2 to Mn in vitro. Additionally, hepatic cells expressing full-length PHD2
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