View source for Hemerythrin

{{short description|InterPro Family}}
{{Infobox protein family
|Name = Hemerythrin-like family
|image=Hemerythrin Monomer (1HMO).png|caption=Singly oxygenated hemerythrin protein. {{PDB|1HMO}}
| PROSITE = PDOC00476
|Pfam=PF01814 |Symbol=Hemerythrin 
|InterPro=IPR035938
|CATH=1HMO
|image_size=240|SCOP=2HMZ 
}}

[[Image:HemerythrinTri.jpg|thumb|right|Trimeric Hemerythrin Protein Complex ({{PDB|1HMO}})]]
'''Hemerythrin''' (also spelled '''haemerythrin'''; {{langx|grc|αἷμα|haîma|blood}}, {{langx|grc|ἐρυθρός|erythrós|red}}) is an [[oligomer]]ic [[protein]] responsible for [[oxygen]] (O<sub>2</sub>) transport in the [[marine invertebrate]] [[Phylum (biology)|phyla]] of [[priapulid]]s, [[brachiopod]]s, and in the [[annelid]] worm clades ''[[Magelona]]'' and [[Sipuncula]]. '''Myohemerythrin''' is a [[monomer]]ic O<sub>2</sub>-binding protein found in the muscles of marine invertebrates. Hemerythrin and myohemerythrin are essentially colorless when deoxygenated, but turn a violet-pink in the oxygenated state.

Hemerythrin does not, as the name might suggest, contain a [[heme]]. The names of the blood oxygen transporters [[hemoglobin]], [[hemocyanin]], and hemerythrin do not refer to the heme group (only found in globins). Instead, these names are derived from the Greek word for blood. Hemerythrin may also contribute to [[Innate immune system|innate immunity]] and anterior [[Regeneration (biology)|tissue regeneration]] in certain worms.<ref>{{cite journal | author=Coates, C.J., Decker, H. | title=Immunological properties of oxygen transport proteins: hemoglobin, hemocyanin and hemerythrin | journal=Cell. Mol. Life Sci. | year=2017 | volume=74 | issue=2 | pages=293–317 | pmid=27518203 | doi=10.1007/s00018-016-2326-7 | pmc=5219038}}</ref>

==O<sub>2</sub> binding mechanism==
The mechanism of dioxygen binding is unusual. Most O<sub>2</sub> carriers operate via formation of [[dioxygen complex]]es, but hemerythrin holds the O<sub>2</sub> as a [[hydroperoxide]] (HO<sub>2</sub>, or -OOH<sup>−</sup>). The site that binds O<sub>2</sub> consists of a pair of iron centres. The iron atoms are bound to the protein through the carboxylate side chains of a [[glutamate]] and [[aspartate]]s as well as through five [[histidine]] residues. Hemerythrin and myohemerythrin are often described according to oxidation and ligation states of the iron center:

{| class=wikitable
|Fe<sup>2+</sup>—OH—Fe<sup>2+</sup>
|deoxy (reduced)
|-
|Fe<sup>2+</sup>—OH—Fe<sup>3+</sup>
|semi-met
|-
|Fe<sup>3+</sup>—O—Fe<sup>3+</sup>—OOH<sup>−</sup>
|oxy (oxidized)
|-
|Fe<sup>3+</sup>—OH—Fe<sup>3+</sup>— (any other ligand)
|met (oxidized)
|}

The uptake of O<sub>2</sub> by hemerythrin is accompanied by two-electron oxidation of the di[[ferrous]] centre to produce a [[hydroperoxide]] (OOH<sup>−</sup>) complex. The binding of O<sub>2</sub> is roughly described in this diagram:

:[[File:O2+hemerythrin.svg|thumb|center|440px|class=skin-invert-image|Active site of hemerythrin before and after oxygenation.]]

Deoxyhemerythrin contains two high-spin ferrous ions bridged by [[hydroxyl]] group ('''A'''). One iron is hexacoordinate and another is pentacoordinate. A [[hydroxyl]] group serves as a [[bridging ligand]] but also functions as a proton donor to the O<sub>2</sub> substrate.  This proton-transfer result in the formation of a single oxygen atom (μ-oxo) bridge in oxy- and methemerythrin. O<sub>2</sub> binds to the pentacoordinate Fe<sup>2+</sup> centre at the vacant coordination site ('''B'''). Then electrons are transferred from the ferrous ions to generate the binuclear ferric (Fe<sup>3+</sup>,Fe<sup>3+</sup>) centre with bound peroxide ('''C''').<ref>D. M. Kurtz, Jr. "Dioxygen-binding Proteins" in Comprehensive Coordination Chemistry II 2003, Volume 8, Pages 229–260. {{doi|10.1016/B0-08-043748-6/08171-8}}</ref><ref>{{cite journal | last1 = Friesner | first1 = R. A. | last2 = Baik | first2 = M.-H. | last3 = Gherman | first3 = B. F. | last4 = Guallar | first4 = V. | last5 = Wirstam | first5 = M. | last6 = Murphy | first6 = R. B. | last7 = Lippard | first7 = S. J. | year = 2003 | title = How iron-containing proteins control dioxygen chemistry: a detailed atomic level description via accurate quantum chemical and mixed quantum mechanics/molecular mechanics calculations | journal = Coord. Chem. Rev. | volume = 238–239 | pages = 267–290 | doi = 10.1016/S0010-8545(02)00284-9 }}</ref>

==Quaternary structure and cooperativity==
[[File:Hemerythrin Homooctamer (1HMO).png|thumb|Hemerythrin homooctamer with a single monomer highlighted in yellow. {{PDB|1HMO}}]]
Hemerythrin typically exists as a homooctamer or heterooctamer composed of α- and β-type subunits of 13–14 [[Dalton (unit)|kDa]] each, although some species have dimeric, trimeric and tetrameric hemerythrins. Each subunit has a four-α-helix fold binding a binuclear iron centre. Because of its size hemerythrin is usually found in cells or "corpuscles" in the blood rather than free floating.

Unlike hemoglobin, most hemerythrins lack [[cooperative binding]] to oxygen, making it roughly 1/4 as efficient as hemoglobin. In some [[brachiopods]] though, hemerythrin shows cooperative binding of O<sub>2</sub>. Cooperative binding is achieved by interactions between subunits: the oxygenation of one subunit increases the affinity of a second unit for oxygen.

Hemerythrin affinity for [[carbon monoxide]] (CO) is actually lower than its affinity for O<sub>2</sub>, unlike hemoglobin which has a very high affinity for CO. Hemerythrin's low affinity for CO poisoning reflects the role of hydrogen-bonding in the binding of O<sub>2</sub>, a pathway mode that is incompatible with CO complexes which usually do not engage in hydrogen bonding.

==Hemerythrin/HHE cation-binding domain==
The hemerythrin/HHE cation-binding [[protein domain|domain]] occurs as a duplicated domain in hemerythrins, myohemerythrins and related proteins. This domain binds [[iron]] in hemerythrin, but can bind other metals in related proteins, such as [[cadmium]] in the ''[[Nereis diversicolor]]'' hemerythrin. It is also found in the NorA protein from ''[[Cupriavidus necator]]'', this protein is a regulator of response to [[nitric oxide]], which suggests a different set-up for its metal [[ligands]]. A protein from ''[[Cryptococcus neoformans]]'' (Filobasidiella neoformans) that contains haemerythrin/HHE cation-binding domains is also involved in nitric oxide response.<ref name="pmid17661046">{{cite journal |vauthors=Chow ED, Liu OW, O'Brien S, Madhani HD | title = Exploration of whole-genome responses of the human AIDS-associated yeast pathogen Cryptococcus neoformans var grubii: nitric oxide stress and body temperature | journal = Curr. Genet. | volume = 52 | issue = 3–4 | pages = 137–48 |date=September 2007 | pmid = 17661046 | doi = 10.1007/s00294-007-0147-9 | s2cid = 10212964 }}</ref> A ''[[Staphylococcus aureus]]'' protein containing this domain, iron-sulfur cluster repair protein ScdA, has been noted to be important when the [[organism]] switches to living in environments with low oxygen concentrations; perhaps this protein acts as an oxygen store or scavenger.<ref name="pmid18203837">{{cite journal |vauthors=Overton TW, Justino MC, Li Y, Baptista JM, Melo AM, Cole JA, etal | title=Widespread Distribution in Pathogenic Bacteria of Di-Iron Proteins That Repair Oxidative and Nitrosative Damage to Iron-Sulfur Centers | journal=J Bacteriol | year= 2008 | volume= 190 | issue= 6 | pages= 2004–13 | pmid=18203837 | doi=10.1128/JB.01733-07 | pmc=2258886   }}</ref>

Hemerythrin/HHE (H-HxxxE-HxxxH-HxxxxD) proteins found in bacteria are implicated in signal transduction and [[chemotaxis]]. More distantly related ones include H-HxxxE-H-HxxxE proteins (including the [[E3 ligase]]) and animal [[F-box protein]]s (H-HExxE-H-HxxxE).<ref>{{cite journal |last1=Alvarez-Carreño |first1=Claudia |last2=Alva |first2=Vikram |last3=Becerra |first3=Arturo |last4=Lazcano |first4=Antonio |title=Structure, function and evolution of the hemerythrin-like domain superfamily: Hemerythrin-like Domain Superfamily |journal=Protein Science |date=April 2018 |volume=27 |issue=4 |pages=848–860 |doi=10.1002/pro.3374|pmid=29330894 |pmc=5866928 |doi-access=free }}</ref>

==References==
<references/>

==Further reading==<!--some rather dated and not of historic interest-->
* {{cite journal | author=Karlsen, O.A., Ramsevik, L., Bruseth, L.J., Larsen, Ø., Brenner, A., Berven, F.S., Jensen, H.B. and Lillehaug, J.R. | title=Characterization of a prokaryotic haemerythrin from the methanotrophic bacterium ''Methylococcus capsulatus'' (Bath) | journal=FEBS J. | year=2005 | volume=272 | pages=2428–2440 | pmid=15885093 | doi=10.1111/j.1742-4658.2005.04663.x | issue=10| s2cid=11002682 }}
* {{cite journal | author=Stenkamp, R.E. | title=Dioxygen and hemerythrin | journal=Chem. Rev. | year=1994 | volume=94 | pages=715–726 | doi=10.1021/cr00027a008 | issue=3}}

==External links==
* [https://www.rcsb.org/structure/1HMD 1HMD] - [[Protein Data Bank|PDB]] structure of deoxyhemerythrin ''Themiste dyscrita'' (sipunculid worm)
* [https://www.rcsb.org/structure/1HMO 1HMO] – PDB structure of oxyhemerythrin from ''Themiste dyscrita''
* [https://www.rcsb.org/structure/2MHR 2MHR] – PDB structure of azido-met myohemerythrin from ''Themiste zostericola'' (sipunculid worm)
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR002063 IPR002063] – [http://www.ebi.ac.uk/interpro/ InterPro] entry for hemerythrin

{{Iron-binding proteins}}
{{InterPro content|IPR012312}}

[[Category:Protein domains]]
[[Category:Metalloproteins]]
[[Category:Iron compounds]]
[[Category:Respiratory pigments]]