Crystallographic studies of heme oxygenase complexed with an unstable reaction intermediate, verdoheme

Unno, Masaki; Matsui, Toshitaka; Ikeda‐Saito, Masao

doi:10.1016/j.jinorgbio.2012.04.012

Cited by 19 publications

(10 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HO-1 mRNA expression is increased significantly by the presence of haem as well as a variety of other proinflammatory signal molecules 51. HO proteins degrade haem into carbon monoxide, biliverdin and Fe 2+ 52. The biliverdin is converted to bilirubin (an antioxidant known to be neurotoxic in preterm neonates) by biliverdin reductase,53 54 while the iron is bound by Ft and sequestered.…”

Section: Iron Homeostasis In Normal Brainmentioning

confidence: 99%

Brain iron overload following intracranial haemorrhage

et al. 2016

View full text Add to dashboard Cite

Intracranial haemorrhages, including intracerebral haemorrhage (ICH), intraventricular haemorrhage (IVH) and subarachnoid haemorrhage (SAH), are leading causes of morbidity and mortality worldwide. In addition, haemorrhage contributes to tissue damage in traumatic brain injury (TBI). To date, efforts to treat the long-term consequences of cerebral haemorrhage have been unsatisfactory. Incident rates and mortality have not showed significant improvement in recent years. In terms of secondary damage following haemorrhage, it is becoming increasingly apparent that blood components are of integral importance, with haemoglobin-derived iron playing a major role. However, the damage caused by iron is complex and varied, and therefore, increased investigation into the mechanisms by which iron causes brain injury is required. As ICH, IVH, SAH and TBI are related, this review will discuss the role of iron in each, so that similarities in injury pathologies can be more easily identified. It summarises important components of normal brain iron homeostasis and analyses the existing evidence on iron-related brain injury mechanisms. It further discusses treatment options of particular promise.

show abstract

Section: Iron Homeostasis In Normal Brainmentioning

confidence: 99%

Brain iron overload following intracranial haemorrhage

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In the first step heme is oxidized to hydroxyheme, and in the second step verdoheme is formed and CO is released. The third step results in biliverdin and Fe 2+ [77]. The last step is rate limiting but is also the least characterized [78].…”

Section: Ho-1mentioning

confidence: 99%

The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging

Thomsen

Etzerodt

Svendsen

et al. 2013

Oxidative Medicine and Cellular Longevity

148

View full text Add to dashboard Cite

The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.

show abstract

“…4). The last step in a standard HO reaction involves protonation and reduction of the iron in the ferric-biliverdin complex, which does not have significant spectroscopic features to produce free ferrous iron and biliverdin (which absorbs at the 640-680 nm range) (Liu and Ortiz de Montellano 2000;Unno et al 2012;Wilks and Heinzl 2014). The formation of the broad band at 660 nm by the HupZ reaction suggests therefore that this enzyme is able to carry on and liberate the iron.…”

Section: Discussionmentioning

confidence: 99%

“…The most common pathway, however, relies on oxidative cleavage of the porphyrin ring by enzymes known as heme oxygenases (HOs) (Wilks and Heinzl 2014;Wilks and Ikeda-Saito 2014). When supplied with oxygen and electron donors, canonical HOs (e.g., HO-1 in eukaryotes) break down heme through three sequential mono-oxygenation steps (Unno et al 2012). In the first step, heme is reduced to the ferrous form and rapidly binds oxygen.…”

Section: Introductionmentioning

confidence: 99%

In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus

et al. 2016

View full text Add to dashboard Cite

In Group A streptococcus (GAS), the metallorepressor MtsR regulates iron homeostasis. Here we describe a new MtsR-repressed gene, which we named hupZ (heme utilization protein). A recombinant HupZ protein was purified bound to heme from Escherichia coli grown in the presence of 5-aminolevulinic acid and iron. HupZ specifically binds heme with stoichiometry of 1:1. The addition of NADPH to heme-bound HupZ (in the presence of cytochrome P450 reductase, NADPH-regeneration system and catalase) triggered progressive decrease of the HupZ Soret band and the appearance of an absorption peak at 660 nm that was resistance to hydrolytic conditions. No spectral changes were observed when ferredoxin and ferredoxin reductase were used as redox partners. Differential spectroscopy with myoglobin or with the ferrous chelator, ferrozine, confirmed that carbon monoxide and free iron are produced during the reaction. ApoHupZ was crystallized as a homodimer with a split β-barrel conformation in each monomer comprising six β strands and three α helices. This structure resembles the split β-barrel domain shared by the members of a recently described family of heme degrading enzymes. However, HupZ is smaller and lacks key residues found in the proteins of the latter group. Phylogenetic analysis places HupZ on a clade separated from those for previously described heme oxygenases. In summary, we have identified a new GAS enzyme-containing split β-barrel and capable of heme biotransformation in vitro; to the best of our knowledge, this is the first enzyme among Streptococcus species with such activity.

show abstract

Crystallographic studies of heme oxygenase complexed with an unstable reaction intermediate, verdoheme

Cited by 19 publications

References 76 publications

Brain iron overload following intracranial haemorrhage

Brain iron overload following intracranial haemorrhage

The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging

In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus

Contact Info

Product

Resources

About