Structural highlights
Disease
HMOX1_HUMAN Defects in HMOX1 are the cause of heme oxygenase 1 deficiency (HMOX1D) [MIM:614034. A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.[1]
Function
HMOX1_HUMAN Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Development of inhibitors specific for heme oxygenases (HOs) should aid our understanding of the HO system and facilitate future therapeutic applications. The crystal structure of human HO-1 complexed with 1-(adamantan-1-yl)-2-(1 H-imidazol-1-yl)ethanone ( 3) was determined. This inhibitor binds to the HO-1 distal pocket such that the imidazolyl moiety coordinates with heme iron while the adamantyl group is stabilized by a hydrophobic binding pocket. Distal helix flexibility, coupled with shifts in proximal residues and heme, acts to expand the distal pocket, thus accommodating the bulky inhibitor without displacing heme. Inhibitor binding effectively displaces the catalytically critical distal water ligand. Comparison with the binding of 2-[2-(4-chlorophenyl)ethyl]-2-[1 H-imidazol-1-yl)methyl]-1,3-dioxolane ( 2) revealed a common binding mode, despite differing chemical structures beyond the imidazolyl moiety. The inhibitor binding pocket is flexible, yet contains well-defined subpockets to accommodate appropriate functional groups. On the basis of these structural insights, we rationalize binding features to optimize inhibitor design.
X-ray Crystal Structure of Human Heme Oxygenase-1 in Complex with 1-(Adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone: A Common Binding Mode for Imidazole-Based Heme Oxygenase-1 Inhibitors.,Rahman MN, Vlahakis JZ, Szarek WA, Nakatsu K, Jia Z J Med Chem. 2008 Sep 18. PMID:18798608[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999 Jan;103(1):129-35. PMID:9884342 doi:10.1172/JCI4165
- ↑ Rahman MN, Vlahakis JZ, Szarek WA, Nakatsu K, Jia Z. X-ray Crystal Structure of Human Heme Oxygenase-1 in Complex with 1-(Adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone: A Common Binding Mode for Imidazole-Based Heme Oxygenase-1 Inhibitors. J Med Chem. 2008 Sep 18. PMID:18798608 doi:10.1021/jm800505m
