Compositions and methods for facilitating heme-iron export from cells
The invention provides a high affinity heme-binding agent, which can be provided in the form of a pharmaceutical composition that includes, optionally, a pharmaceutically acceptable carrier. The heme-binding agent can be used in a method of facilitating heme-iron export from a cell. The method comprises contacting a cell with a high affinity heme-binding agent. Also provided is a method of treating a disorder associated with excess iron in cells in a subject. The method comprises administering to the subject an effective amount of the composition of the invention. The subject is typically a mammal, most typically a human or veterinary subject.
1. A method of facilitating heme-iron export from a cell comprising contacting the cell with a heme-binding agent, wherein the heme-binding agent is hemopexin, a synthetic heme binder, a bacterial hemophore or a bacterial heme-binding protein, and wherein the heme-iron is exported from the cell.
2. The method of claim 1 , wherein the cell is a developing red blood cell.
3. The method of claim 1 , wherein the heme-binding agent is hemopexin.
4. The method of claim 1 , wherein the heme-binding agent is selected from the group consisting of: heme-binding protein 23 (HBP23); adrenal inner zone antigen (IZA1); rhodnius heme-binding protein (RHBP); NADPH-dependent methemoglobin reductase; histidine-rich protein 2 (HRP-2); damage resistance protein 1 (Dap1p); HupA, HpbA, ShuT, PhuS and HemS.
5. The method of claim 1 , wherein the heme-binding agent comprises a heme-binding site having two histidines that are 43-52 amino acids apart and hydrophobic amino acids lining a heme binding pocket.
6. The method of claim 1 , wherein the heme-binding agent has binds heme with a Kd of up to 1 nM.
7. The method of claim 1 , wherein the bacterial heme-binding protein comprises S. dysenteriae heme shuttle protein ShuT.
8. A method of treating a disorder associated with excess iron in cells in a subject comprising administering to the subject an effective amount of a heme-binding agent, wherein the heme-binding agent is hemopexin, a synthetic heme binder, a bacterial hemophore or a bacterial heme-binding protein, and wherein the disorder is treated.
9. The method of claim 8 , wherein the disorder is anemia.
10. The method of claim 9 , wherein the anemia is associated with inflammation, myelodysplasia or ineffective erythropoiesis.
11. The method of claim 8 , wherein the disorder is an iron overload disorder.
12. The method of claim 11 , wherein the disorder is hemochromatosis.
13. The method of claim 8 , wherein the administering is intravenous or subcutaneous.
14. The method of claim 8 , wherein the administering is oral.
15. The method of claim 8 , wherein the heme-binding agent is hemopexin.
16. The method of claim 8 , wherein the heme-binding agent is selected from the group consisting of: heme-binding protein 23 (HBP23); adrenal inner zone antigen (IZA1); rhodnius heme-binding protein (RHBP); NADPH-dependent methemoglobin reductase; histidine-rich protein 2 (HRP-2); damage resistance protein 1 (Dap1p); HupA, HpbA, ShuT, PhuS and HemS.
17. The method of claim 8 , wherein the heme-binding agent comprises a heme-binding site having two histidines that are 43-52 amino acids apart and hydrophobic amino acids lining a heme binding pocket.
18. The method of claim 8 , wherein the heme-binding agent binds heme with a Kd of up to 1 nM.
19. The method of claim 8 , wherein the heme-binding agent binds heme with a Kd of up to 1 μM.
20. The method of claim 8 , wherein the heme-binding agent is provided in polypeptide form.