1. Goldie DaCosta & Brit Gillard
Human Heme Oxygenase
Goldie DaCosta & Brit Gillard

2. Overview
Structure
Function
Inhibition
Therapeutics

3. Overview of isoforms Enzyme involved in heme catabolism
Two isoforms = HO-1 and HO-2
HO-1 is the common form
Km for HO-2 is 3x greater than Km for HO-1
Different activating stimuli

4. Primary structure HO-1 80% similarity HO-2 90% similarity
Human HO-1 vs HO-2 58% similarity
Conserved 24 residue sequence = heme binding pocket
HO-1:
HO-2:

5. 23 hydrophobic C-terminal amino acids
Primary structure
HO-1
HMOX1 (chromosome 22)
32 kDa
288 residues
HO-2
HMOX2 (chromosome 16)
36 kDa
316 amino acids HO ER
23 hydrophobic C-terminal amino acids

6. Secondary Structure α-helices

7. tertiary structure

8. function Rate-limiting step of heme degradation
Most active in the spleen
Senescent RBCs isolated and destroyed
Cleaves heme and releases CO, Fe, and biliverdin
Most efficient heme degrading enzyme
High levels of heme are toxic

9. Function 1 2

12. protoporphyrin ix
Image from:
Image from:

13. INHIBITORS
Yoshinaga, T., Sassa. S., and A. Kappas. (1982). Biochem. J. 257,

14. INHIBITORS Co Sn Zn Co Sn Zn

15. Clinical Implications
Genetic HO -1 deficiency and disease pathology
Inhibited growth phenotype
Endothelial damage
Hemolytic anemia
Iron deposits seen in kidneys and liver

16. HO -1 Inhibitor in neonatal jaundice
Causes
Treatment
Phototherapy
Prevention
Potential Use of Sn - PIPX

17. HO – 1: a therapeutic Funnel
Otterbein, L., Soares, M. et. Al. (2003)

18. Transplant organs can prevent host rejection via HO-1 expression

19. Works cited
Drummond, G. and A. Kappas. “Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc. Natl. Acad. Sci – USA 10 (1981): 6466 – Huber, Warren, and Brittni Scruggs and Wayne Backers. “C-Terminal Membrane Spanning Region of Human Heme Oxygenase-1 Mediates a Time-Dependent Complex Formation with Cytochrome P450 Reductase.” Biochemistry (2009): Print. Maines, Mahin D. “The Heme Oxygenase System: A Regulator of Second Messenger Gases.” Annual Review of Pharmacology and Toxicology. (1997) 37: Print. Morse, D. and Augustine M. K. Choi. “Heme Oxygenase -1: The ‘Emerging Molecule’ Has Arrived. Cell Mol. Biol. 27 (2002) , 8 – 16. Otterbein, L, Soares, M., et. Al. Heme Oxygenase – 1: unleashing the protective properties of heme”. TRENDS in Immunology (2003), 24, 449 – 455. Print. Sassa, S. “Why Heme Needs to be Degraded to Iron, Biliverdin Ixalpha, and Carbon Monoxide?” Antixodiants & Redox Signaling. 6.5 (2004): Print. Ryter, S., Alam, J., et. Al. “Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications”. Physiol Rev 24 (2006): Print Unno, Masaki, Toshitaka Matsui, and Masao Ikeda-Saito. “Structure and Catalytic Mechanism of Heme Oxygenase.” Natural Product Reports 24 (2007): 553. Web. 20 Nov Yi, L. “Characterization of the Redox Switches in Human Heme Oxygenase-2 and a Human Heme-Responsive Potassium Channel.” 2010 : n. pag. Print.