Chelation

Overview

Chelation is a biochemical and pharmacological process in which small-molecule chelating agents—such as organic compounds, natural metallophores, or synthetic ligands like dimethylglyoxime (DMG)—bind to metal ions with high affinity to sequester, redistribute, or remove metallic elements from biological systems.^[1] Chelating agents function by surrounding and complexing metal cations through multiple coordinate bonds, thereby reducing the bioavailability and toxicity of toxic metals or redistributing essential metals to maintain physiological homeostasis.^[2]  For example, dimethylglyoxime is a nickel-specific chelator that exhibits selective binding to nickel and copper ions but not iron, zinc, or selenium, and has demonstrated therapeutic potential in inhibiting amyloid-beta peptide aggregation in Alzheimer’s disease by preventing nickel-enhanced aggregation.^[3] Chelation-based interventions operate across multiple biological contexts, from nutritional immunity mechanisms where host proteins like calprotectin sequester bacterial nutrients through metal chelation, to soil remediation applications where glomalin produced by arbuscular mycorrhizal fungi chelates heavy metals to stabilize contaminated environments, representing promising therapeutic strategies for managing metal dyshomeostasis and metal-associated pathologies.^[4] [5]

Chelation as Metallome-Targeted Interventions (MTIs)

Chelation represents a sophisticated category of metallome-targeted interventions (MTIs) that employs chelating agents—small molecules or natural compounds with high-affinity metal binding properties—to sequester, redistribute, or remove metal ions from biological systems.^[6] Chelation can function therapeutically through multiple mechanisms: reducing bioavailability of toxic metals (e.g., iron or copper sequestration to limit oxidative stress), redistributing metals to normalize dyshomeostasis, or removing accumulated metals in toxic metal overload conditions.^[7]  Natural metallophores, termed chalkophores, represent biologically-derived chelating compounds that regulate copper bioavailability within microbial communities.^[8] The effectiveness of chelation as an MTI depends critically on chemical selectivity for target metals, cellular accessibility, and coordination with other cellular metal homeostatic mechanisms.^[9] 

FAQs

Why is chelation important in the microbiome?

Chelation fundamentally regulates microbial metal homeostasis and nutrient availability in the microbiome. Natural metallophores produced by microorganisms chelate essential metals like copper and iron, controlling their bioavailability.^[10] [Additionally, host proteins employ chelation as “nutritional immunity“—sequestering metals to limit pathogenic bacterial growth. ^[11] Dysbiosis-associated alterations in metal chelation capacity affect microbial community composition.^[12]

What metals can chelating agents bind?

Chelating agents demonstrate variable metal selectivity depending on their chemical structure and binding ligands. ^[13] Common targets include iron, copper, zinc, nickel, manganese, and cadmium. Specific chelators like DMG selectively target particular metals—DMG preferentially binds nickel and copper ^[15] while broader-spectrum chelators like EDTA coordinate multiple divalent transition metals across diverse biological contexts.^[16]

What is mismetallation and how does chelation prevent it?

Mismetallation occurs when incorrect metal cofactors incorporate into metalloenzymes, causing loss of function or toxicity.^[17] Chelation prevents mismetallation by maintaining proper metal homeostasis—sequestering excess or toxic metals while ensuring correct metals are available for metallation.^[18] Reductive chelation of copper leads to cysteine oxidation, preventing inappropriate copper-protein interactions and preserving enzyme function.^[19]

How does chelation relate to nutritional immunity?

Nutritional immunity is the host’s strategy of sequestering essential metals through chelation to restrict pathogenic microbial growth . ^[20] Host-defense proteins like calprotectin employ high-affinity metal-binding properties to chelate iron, zinc, and manganese in infected tissue microenvironments.^[21]  This chelation-based metal sequestration fundamentally limits bacterial virulence and survival, representing a critical innate immune mechanism. ^[22]

What is the difference between chelation and sequestration?

Chelation specifically involves chemical binding through coordinate bonds between a ligand and a metal ion, forming a stable complex.^[23] Sequestration is a broader term encompassing any process that removes a substance from circulation or reduces its bioavailability, which may include chelation but also physical compartmentalization, precipitation, or absorption.^[24]  Both mechanisms reduce toxic metal effects but operate through distinct molecular processes. ^[25]

Are there risks associated with chelation therapy?

While chelation can therapeutically remove toxic metals, excessive or inappropriate chelation risks depleting essential metals necessary for metalloenzyme function and physiological processes.^[26]  Long-term chelation therapy requires careful monitoring to maintain metal homeostasis .^[27] Additionally, some proposed chelation therapies lack clinical evidence supporting efficacy, as demonstrated in controversial Alzheimer’s disease copper-chelation approaches.^[28]

Research Feed

Update History

References

1. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
2. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
3. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
4. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
5. The role of glomalin in mitigation of multiple soil degradation problems.. A. Singh, Xiai Zhu et al.. (Critical Reviews in Environmental Science and Technology. 2020.)
6. The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.. Simon C. Drew.. (Frontiers in Neuroscience. 2017.)
7. The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.. Simon C. Drew.. (Frontiers in Neuroscience. 2017.)
8. Chalkophores.. Grace E. Kenney, Amy C. Rosenzweig.. (Annual Review of Biochemistry. 2018.)
9. The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.. Simon C. Drew.. (Frontiers in Neuroscience. 2017.)
10. Chalkophores.. Grace E. Kenney, Amy C. Rosenzweig.. (Annual Review of Biochemistry. 2018.)
11. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
12. Influence of the Soil Microbiome on the Availability of Metals.. A. N., S. Sheeba, J. Prabhaharan, S. V. Kannan, R. Amutha, B. Sivasankari et al.. (Geomicrobiology Journal. Aug. 2024.)
13. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
14. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
15. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
16. Comments for Mertens et al. (2018), Glyphosate, a chelating agent—relevant for ecological risk assessment?.. J. Swarthout, M. Bleeke et al.. (Environmental Science and Pollution Research. 2018.)
17. Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface.. Daiana A. Capdevila, Jiefei Wang et al.. (Journal of Biological Chemistry. 2016.)
18. BR-Bodies Facilitate Adaptive Responses and Survival During Copper Stress in Caulobacter crescentus.. Christie Passos, Dylan T. Tomares et al.. (bioRxiv, Mar. 2025.)
19. BR-Bodies Facilitate Adaptive Responses and Survival During Copper Stress in Caulobacter crescentus.. Christie Passos, Dylan T. Tomares et al.. (bioRxiv, Mar. 2025.)
20. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
21. Transition Metal Sequestration by the Host-Defense Protein Calprotectin.. Emily M. Zygiel, Elizabeth M. Nolan.. (Annual Review of Biochemistry. 2018.)
22. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
23. The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation.. Benoit SL, Maier RJ.. (Sci Rep. 2021;11:6622.)
24. Effects of exogenous sulfur on alleviating cadmium stress in tartary buckwheat.. Yang Lu, Qi-fu Wang et al.. (Scientific Reports. 2019.)
25. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration.. Valeria M. Reyes Ruiz, Jeffrey A. Freiberg et al.. (mBio. 2024.)
26. The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.. Simon C. Drew.. (Frontiers in Neuroscience. 2017.)
27. Aluminum and its potential contribution to Alzheimer's disease (AD).. S. Bhattacharjee, Yuhai Zhao et al.. (Frontiers in Aging Neuroscience. 2014.)
28. The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.. Simon C. Drew.. (Frontiers in Neuroscience. 2017.)