Editing Hemoglobin (section)

==Structure of heme==
[[File:Heme B.svg|thumb|[[Heme]] b group]]

Hemoglobin has a [[quaternary structure]] characteristic of many multi-subunit globular proteins.<ref name="Van Kessel-2002">{{cite book |last1=Van Kessel |first1=Hans |title=Nelson Chemistry 12 |date=2002 |publisher=Thomson |location=Toronto |isbn=978-0-17-625986-0 |page=122 |chapter=Proteins – Natural Polyamides}}</ref> Most of the amino acids in hemoglobin form [[alpha helix|alpha helices]], and these helices are connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, which then causes each polypeptide chain to fold into a specific shape.<ref>[https://www.umass.edu/molvis/tutorials/hemoglobin/index.htm "Hemoglobin Tutorial."] {{Webarchive|url=https://web.archive.org/web/20091126133327/https://www.umass.edu/molvis/tutorials/hemoglobin/index.htm |date=2009-11-26}} University of Massachusetts Amherst. Web. 23 Oct. 2009.</ref> Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.<ref name="Van Kessel-2002"/>

In most vertebrates, the hemoglobin [[molecule]] is an assembly of four [[globular protein]] subunits. Each subunit is composed of a protein chain tightly associated with a non-protein [[prosthetic group|prosthetic]] [[heme]] group. Each protein chain arranges into a set of [[alpha helix|alpha-helix]] structural segments connected together in a [[globin fold]] arrangement. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as [[myoglobin]].<ref name="Steinberg-2001">{{cite book
|last1=Steinberg |first1=MH
|year=2001
|title=Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management
|publisher=Cambridge University Press
|isbn=978-0-521-63266-9
|page=95
|url=https://books.google.com/books?id=ISBN0521632668
|access-date=2016-02-18
|url-status=live
|archive-url=https://web.archive.org/web/20161117110812/https://books.google.com/books?vid=ISBN0521632668
|archive-date=2016-11-17
}}</ref><ref name="Hardison-1996">{{cite journal
|last1=Hardison |first1=RC
|title=A brief history of hemoglobins: plant, animal, protist, and bacteria
|periodical=Proc Natl Acad Sci USA
|year=1996
|volume=93
|issue=12
|pages=5675–79
|bibcode=1996PNAS...93.5675H
|pmid=8650150
|doi=10.1073/pnas.93.12.5675
|doi-access=free
|pmc=39118
}}</ref> This folding pattern contains a pocket that strongly binds the heme group.{{citation needed|date=November 2023}}

A heme group consists of an iron (Fe) [[ion]] held in a [[heterocyclic compound|heterocyclic]] ring, known as a [[porphyrin]]. This porphyrin ring consists of four [[pyrrole]] molecules cyclically linked together (by [[methine]] bridges) with the iron ion bound in the center.<ref>[https://www.chm.bris.ac.uk/motm/hemoglobin/hemoglobjm.htm "Hemoglobin."] {{Webarchive|url=https://web.archive.org/web/20091113153809/https://www.chm.bris.ac.uk/motm/hemoglobin/hemoglobjm.htm |date=2009-11-13}} School of Chemistry – Bristol University – UK. Web. 12 Oct. 2009.</ref> The iron ion, which is the site of oxygen binding, coordinates with the four [[nitrogen]] atoms in the center of the ring, which all lie in one plane. The heme is bound strongly (covalently) to the globular protein via the N atoms of the [[imidazole]] ring of F8 [[histidine]] residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a [[coordinate covalent bond]],<ref>[https://wikipremed.com/interdisciplinary_course.php?code=0213000100000000 WikiPremed > Coordination Chemistry] {{Webarchive|url=https://web.archive.org/web/20090823044401/https://wikipremed.com/interdisciplinary_course.php?code=0213000100000000 |date=2009-08-23}}. Retrieved July 2, 2009</ref> completing the octahedral group of six ligands. This reversible bonding with oxygen is why hemoglobin is so useful for transporting oxygen around the body.<ref>{{cite web |author=Basic Biology |date=2015 |title=Blood cells |url=https://basicbiology.net/micro/cells/blood |access-date=2020-03-27 |url-status=live |archive-url=https://web.archive.org/web/20210718032539/https://basicbiology.net/micro/cells/blood |archive-date=2021-07-18}}</ref> Oxygen binds in an "end-on bent" geometry where one oxygen atom binds to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted [[octahedron]].

Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions but is bound to the amine groups of the protein chains attached to the heme groups.

The iron ion may be either in the [[ferrous|ferrous Fe<sup>2+</sup>]] or in the [[iron(III)|ferric Fe<sup>3+</sup>]] state, but ferrihemoglobin ([[methemoglobin]]) (Fe<sup>3+</sup>) cannot bind oxygen.<ref>{{cite journal |vauthors=Linberg R, Conover CD, Shum KL, Shorr RG |title=Hemoglobin based oxygen carriers: how much methemoglobin is too much? |journal=Artif Cells Blood Substit Immobil Biotechnol |volume=26 |issue=2 |pages=133–48 |year=1998 |pmid=9564432 |doi=10.3109/10731199809119772 |doi-access=free}}</ref> In binding, oxygen temporarily and reversibly oxidizes (Fe<sup>2+</sup>) to (Fe<sup>3+</sup>) while oxygen temporarily turns into the [[superoxide]] ion, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe<sup>3+</sup> is protonated, the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme [[cytochrome b5 reductase|methemoglobin reductase]] will be able to eventually reactivate methemoglobin by reducing the iron center.

In adult humans, the most common hemoglobin type is a [[tetrameric protein|tetramer]] (which contains four subunit proteins) called ''hemoglobin A'', consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α<sub>2</sub>β<sub>2</sub>. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000&nbsp;[[dalton (unit)|daltons]],<ref>[https://www.worthington-biochem.com/HB/cat.html Hemoglobin] {{Webarchive|url=https://web.archive.org/web/20170315070213/https://www.worthington-biochem.com/HB/cat.html |date=2017-03-15}}. Worthington-biochem.com. Retrieved 2013-09-05.</ref> for a total [[molecular weight]] of the tetramer of about 64,000&nbsp;daltons (64,458 g/mol).<ref name="Van Beekvelt-2001">{{cite journal |vauthors=Van Beekvelt MC, Colier WN, Wevers RA, Van Engelen BG |title=Performance of near-infrared spectroscopy in measuring local O2 consumption and blood flow in skeletal muscle |journal=J Appl Physiol |volume=90 |issue=2 |pages=511–19 |year=2001 |pmid=11160049 |doi=10.1152/jappl.2001.90.2.511 |s2cid=15468862}}</ref> Thus, 1 g/dL=0.1551&nbsp;mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.{{citation needed|date=November 2023}}

In human infants, the [[fetal hemoglobin]] molecule is made up of 2 α chains and 2 γ chains. The γ chains are gradually replaced by β chains as the infant grows.<ref name="HemoglobinMedicineNet">[https://www.medicinenet.com/hemoglobin/article.htm "Hemoglobin."] {{Webarchive|url=https://web.archive.org/web/20120124064054/https://www.medicinenet.com/hemoglobin/article.htm |date=2012-01-24}} MedicineNet. Web. 12 Oct. 2009.</ref>

The four [[polypeptide chains]] are bound to each other by [[salt bridge (protein)|salt bridges]], [[hydrogen bond]]s, and the [[hydrophobic effect]].

===Oxygen saturation===
In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).<ref>[https://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Heiner/hemoglobin.html "Hemoglobin Home."] {{Webarchive|url=https://web.archive.org/web/20091201035525/https://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Heiner/hemoglobin.html |date=2009-12-01}} Biology @ Davidson. Web. 12 Oct. 2009.</ref>

====Oxyhemoglobin====
''Oxyhemoglobin'' is formed during [[respiration (physiology)|physiological respiration]] when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the [[pulmonary capillaries]] adjacent to the [[pulmonary alveolus|alveoli]] of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of [[adenosine triphosphate|ATP]] by the process of [[oxidative phosphorylation]]. It does not, however, help to counteract a decrease in blood pH. [[Ventilation (physiology)|Ventilation]], or breathing, may reverse this condition by removal of [[carbon dioxide]], thus causing a shift up in pH.<ref name="altitude.org">{{cite web |publisher=altitude.org |title=Hemoglobin saturation graph |url=https://www.altitude.org/hemoglobin_saturation.php |access-date=2010-07-06 |url-status=dead |archive-url=https://web.archive.org/web/20100831024941/https://www.altitude.org/hemoglobin_saturation.php |archive-date=2010-08-31}}</ref>

Hemoglobin exists in two forms, a ''taut (tense) form'' (T) and a ''relaxed form'' (R). Various factors such as low pH, high CO<sub>2</sub> and high [[2,3 BPG]] at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO<sub>2</sub>, or low 2,3 BPG favors the relaxed form, which can better bind oxygen.<ref name="King-2012">{{cite web |author=King, Michael W |title=The Medical Biochemistry Page – Hemoglobin |url=https://themedicalbiochemistrypage.org/hemoglobin-myoglobin.php#hemoglobin |access-date=2012-03-20 |url-status=live |archive-url=https://web.archive.org/web/20120304095702/https://themedicalbiochemistrypage.org/hemoglobin-myoglobin.php#hemoglobin |archive-date=2012-03-04}}</ref> The partial pressure of the system also affects O<sub>2</sub> affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues), the (low affinity, T) tense state is favoured.<ref>Voet, D. (2008) ''Fundamentals of Biochemistry'', 3rd. ed., Fig. 07_06, John Wiley & Sons. {{ISBN|0470129301}}</ref> Additionally, the binding of oxygen to the iron(II) heme pulls the iron into the plane of the porphyrin ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (thus, oxygen binding is cooperative).{{citation needed|date=November 2023}}

Classically, the iron in oxyhemoglobin is seen as existing in the iron(II) oxidation state. However, the complex of oxygen with heme iron is [[diamagnetic]], whereas both oxygen and high-spin iron(II) are [[paramagnetic]]. Experimental evidence strongly suggests heme iron is in the iron(III) oxidation state in oxyhemoglobin, with the oxygen existing as [[superoxide anion]] (O<sub>2</sub><sup>•−</sup>) or in a covalent charge-transfer complex.<ref name="Shikama-2006">{{cite journal |vauthors=Shikama K |title=Nature of the FeO2 bonding in myoglobin and hemoglobin: A new molecular paradigm |journal=Prog Biophys Mol Biol |volume=91 |issue=1–2 |pages=83–162 |year=2006 |pmid=16005052 |doi=10.1016/j.pbiomolbio.2005.04.001 |doi-access=free}}</ref>

====Deoxygenated hemoglobin====
Deoxygenated hemoglobin (deoxyhemoglobin) is the form of hemoglobin without the bound oxygen. The [[absorption spectrum|absorption spectra]] of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660&nbsp;nm [[wavelength]] than deoxyhemoglobin, while at 940&nbsp;nm its absorption is slightly higher. This difference is used for the measurement of the amount of oxygen in a patient's blood by an instrument called a [[pulse oximeter]]. This difference also accounts for the presentation of [[cyanosis]], the blue to purplish color that tissues develop during [[hypoxia (medical)|hypoxia]].<ref>{{cite book |last1=Ahrens |last2=Kimberley |first2=Basham |title=Essentials of Oxygenation: Implication for Clinical Practice |year=1993 |publisher=Jones & Bartlett Learning |page=194 |isbn=978-0-86720-332-5}}</ref>

Deoxygenated hemoglobin is [[paramagnetic]]; it is weakly attracted to [[magnetic field]]s.<ref>
{{cite journal
|year=1993
|last1=Ogawa |first1=S
|title=Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model
|journal=Biophysical Journal
|volume=64
|issue=3
|pages=803–12
|last2=Menon |first2=R. S.
|last3=Tank |first3=D. W.
|last4=Kim |first4=S. G.
|last5=Merkle |first5=H
|last6=Ellermann |first6=J. M.
|last7=Ugurbil |first7=K
|bibcode=1993BpJ....64..803O
|pmid=8386018
|doi=10.1016/S0006-3495(93)81441-3
|pmc=1262394
}}</ref><ref name="Bren-2015"/> In contrast, oxygenated hemoglobin exhibits [[diamagnetism]], a weak repulsion from a magnetic field.<ref name="Bren-2015">{{cite journal |vauthors=Bren KL, Eisenberg R, Gray HB |title=Discovery of the magnetic behavior of hemoglobin: A beginning of bioinorganic chemistry |journal=Proc Natl Acad Sci U S A |year=2015 |volume=112 |issue=43 |pages=13123–27 |bibcode=2015PNAS..11213123B |pmid=26508205 |doi=10.1073/pnas.1515704112 |doi-access=free |pmc=4629386}}</ref>