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Hemoglobin

Hemoglobin (American English) or haemoglobin (British English)


(Greek αἷμα (haîma, “blood”) + -in) + -o- + globulin (from Latin
hemoglobin
globus (“ball, sphere”) + -in) (/ˈhiːməˌɡloʊbɪn, ˈhɛ-, (heterotetramer, (αβ)2)
-moʊ-/[1][2][3]), abbreviated Hb or Hgb, is the iron-containing
oxygen-transport metalloprotein in the red blood cells (erythrocytes)
of almost all vertebrates[4] (the exception being the fish family
Channichthyidae[5]) as well as the tissues of some invertebrates.
Hemoglobin in blood carries oxygen from the lungs or gills to the rest
of the body (i.e. the tissues). There it releases the oxygen to permit
aerobic respiration to provide energy to power the functions of the
organism in the process called metabolism. A healthy individual has
12 to 20 grams of hemoglobin in every 100 ml of blood.

In mammals, the protein makes up about 96% of the red blood cells'
dry content (by weight), and around 35% of the total content
(including water).[6] Hemoglobin has an oxygen-binding capacity of Structure of human haemoglobin. α
1.34 mL O2 per gram,[7] which increases the total blood oxygen and β subunits are in red and blue,
capacity seventy-fold compared to dissolved oxygen in blood. The respectively, and the iron-containing
mammalian hemoglobin molecule can bind (carry) up to four oxygen heme groups in green. From PDB:
molecules.[8] 1GZX (https://www.rcsb.org/structur
e/1GZX) Proteopedia Hemoglobin
Hemoglobin is involved in the transport of other gases: It carries some (http://www.proteopedia.org/wiki/ind
of the body's respiratory carbon dioxide (about 20–25% of the total[9])
ex.php/Hemoglobin)
as carbaminohemoglobin, in which CO2 is bound to the heme protein.
The molecule also carries the important regulatory molecule nitric Protein metalloprotein,
oxide bound to a globin protein thiol group, releasing it at the same type globulin
time as oxygen.[10] Function oxygen-transport

Hemoglobin is also found outside red blood cells and their progenitor Cofactor(s) heme (4)
lines. Other cells that contain hemoglobin include the A9 Subunit Gene Chromosomal
dopaminergic neurons in the substantia nigra, macrophages, alveolar name locus
cells, lungs, retinal pigment epithelium, hepatocytes, mesangial cells
Hb-α1 HBA1 Chr. 16 p13.3 (http
in the kidney, endometrial cells, cervical cells and vaginal epithelial
cells.[11] In these tissues, hemoglobin has a non-oxygen-carrying s://www.ncbi.nlm.ni
function as an antioxidant and a regulator of iron metabolism.[12] h.gov/Omim/getma
Excessive glucose in one's blood can attach to hemoglobin and raise p.cgi?chromosome
the level of hemoglobin A1c.[13] =16p13.3)
Hb-α2 HBA2 Chr. 16 p13.3 (http
Hemoglobin and hemoglobin-like molecules are also found in many
s://www.ncbi.nlm.ni
invertebrates, fungi, and plants.[14] In these organisms, hemoglobins
h.gov/Omim/getma
may carry oxygen, or they may act to transport and regulate other
p.cgi?chromosome
small molecules and ions such as carbon dioxide, nitric oxide,
hydrogen sulfide and sulfide. A variant of the molecule, called =16p13.3)
leghemoglobin, is used to scavenge oxygen away from anaerobic Hb-β HBB Chr. 11 p15.5 (http
systems, such as the nitrogen-fixing nodules of leguminous plants, lest s://www.ncbi.nlm.ni
the oxygen poison (deactivate) the system. h.gov/Omim/getma
Hemoglobinemia is a medical condition in which there is an excess of p.cgi?chromosome
hemoglobin in the blood plasma. This is an effect of intravascular =11p15.5)
hemolysis, in which hemoglobin separates from red blood cells, a
form of anemia.

Contents
Research history
Genetics
Synthesis
Structure of heme
Oxygen saturation
Oxyhemoglobin
Deoxygenated hemoglobin
Evolution of vertebrate hemoglobin
Iron's oxidation state in oxyhemoglobin
Cooperativity
Binding for ligands other than oxygen
Competitive
Allosteric
Types in humans
Degradation in vertebrate animals
Role in disease
Diagnostic uses
Athletic tracking and self tracking uses
Analogues in non-vertebrate organisms
Other oxygen-binding proteins
Presence in nonerythroid cells
In history, art and music
See also
References
Further reading
External links

Research history
In 1825 J. F. Engelhart discovered that the ratio of iron to protein is identical in the hemoglobins of several
species.[16][17] From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n ×
16000 (n = number of iron atoms per hemoglobin, now known to be 4), the first determination of a protein's
molecular mass. This "hasty conclusion" drew a lot of ridicule at the time
from scientists who could not believe that any molecule could be that big.
Gilbert Smithson Adair confirmed Engelhart's results in 1925 by measuring
the osmotic pressure of hemoglobin solutions.[18]

The oxygen-carrying property of hemoglobin was discovered by Hünefeld in


1840.[19] In 1851, German physiologist Otto Funke published a series of
articles in which he described growing hemoglobin crystals by successively
diluting red blood cells with a solvent such as pure water, alcohol or ether,
followed by slow evaporation of the solvent from the resulting protein
solution.[20][21] Hemoglobin's reversible oxygenation was described a few
years later by Felix Hoppe-Seyler.[22] Max Perutz won the Nobel
Prize for chemistry for his
In 1959, Max Perutz determined the molecular structure of hemoglobin by X- work determining the
ray crystallography.[23][24] This work resulted in his sharing with John molecular structure of
Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures hemoglobin and
of globular proteins. myoglobin[15]

The role of hemoglobin in the blood was elucidated by French physiologist


Claude Bernard. The name hemoglobin is derived from the words heme and globin, reflecting the fact that
each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains
one iron atom, that can bind one oxygen molecule through [ion]-induced dipole forces. The most common
type of hemoglobin in mammals contains four such subunits.

Genetics
Hemoglobin consists of protein subunits (the "globin" molecules), and these proteins, in turn, are folded chains
of a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide
created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid
sequence that determines the protein's chemical properties and function.

There is more than one hemoglobin gene: in humans, hemoglobin A (the main form of hemoglobin present) is
coded for by the genes, HBA1, HBA2, and HBB.[25] The amino acid sequences of the globin proteins in
hemoglobins usually differ between species. These differences grow with evolutionary distance between
species. For example, the most common hemoglobin sequences in humans, bonobos and chimpanzees are
completely identical, without even single amino acid difference in either the alpha or the beta globin protein
chains.[26][27][28] Whereas the human and gorilla hemoglobin differ in one amino acid in both alpha and beta
chains, these differences grow larger between less closely related species.

Even within a species, variants of hemoglobin exist, although one sequence is usually "most common" in each
species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants.[29][30]
Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin,
however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known
hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood
at the molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of
normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All
these diseases produce anemia.[31]

Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example,
hemoglobin has been found to adapt in different ways to high altitudes. Organisms living at high elevations
experience lower partial pressures of oxygen compared to those at sea level. This presents a challenge to the
organisms that inhabit such environments because hemoglobin, which normally binds oxygen at high partial
pressures of oxygen, must be able to bind oxygen when
it is present at a lower pressure. Different organisms have
adapted to such a challenge. For example, recent studies
have suggested genetic variants in deer mice that help
explain how deer mice that live in the mountains are able
to survive in the thin air that accompanies high altitudes. Protein alignment of human hemoglobin proteins,
A researcher from the University of Nebraska-Lincoln alpha, beta, and delta subunits respectively. The
found mutations in four different genes that can account alignments were created using Uniprot's alignment
for differences between deer mice that live in lowland tool available online.
prairies versus the mountains. After examining wild mice
captured from both highlands and lowlands, it was found
that: the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying
capacity of their hemoglobin". "The genetic difference enables highland mice to make more efficient use of
their oxygen", since less is available at higher altitudes, such as those in the mountains.[32] Mammoth
hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling
mammoths to migrate to higher latitudes during the Pleistocene.[33] This was also found in hummingbirds that
inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet
Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the
hemoglobin gene of multiple species living at high elevations (Oreotrochilus, A. castelnaudii, C. violifer, P.
gigas, and A. viridicuada) have caused the protein to have less of an affinity for inositol hexaphosphate (IHP),
a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind
oxygen in lower partial pressures.[34]

Birds' unique circulatory lungs also promote efficient use of oxygen at low partial pressures of O2 . These two
adaptations reinforce each other and account for birds' remarkable high-altitude performance.

Hemoglobin adaptation extends to humans, as well. There is a higher offspring survival rate among Tibetan
women with high oxygen saturation genotypes residing at 4,000 m.[35] Natural selection seems to be the main
force working on this gene because the mortality rate of offspring is significantly lower for women with higher
hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low
hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear,
selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them
to better sustain crucial metabolic processes.

Synthesis
Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps
in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized
by ribosomes in the cytosol.[36] Production of Hb continues in the cell throughout its early development from
the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red
blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual
ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the
vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and
name).[37]

Structure of heme
Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.[38] Most of the
amino acids in hemoglobin form 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.[39]
Hemoglobin's quaternary structure comes from its four subunits in
roughly a tetrahedral arrangement.[38]

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 heme group. Each
protein chain arranges into a set of 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.[40][41] This folding pattern
contains a pocket that strongly binds the heme group.

A heme group consists of an iron (Fe) ion held in a heterocyclic ring,


known as a porphyrin. This porphyrin ring consists of four pyrrole Heme b group
molecules cyclically linked together (by methine bridges) with the
iron ion bound in the center.[42] 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 iron 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,[43] completing the octahedral group of six ligands. This
reversible bonding with oxygen is why hemoglobin is so useful for transporting oxygen around the body.[44]
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 Fe2+ or in the ferric Fe3+ state, but ferrihemoglobin (methemoglobin)
(Fe3+) cannot bind oxygen.[45] In binding, oxygen temporarily and reversibly oxidizes (Fe2+) to (Fe3+) 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 Fe3+ is protonated, the hemoglobin iron will remain oxidized and incapable of
binding oxygen. In such cases, the enzyme methemoglobin reductase will be able to eventually reactivate
methemoglobin by reducing the iron center.

In adult humans, the most common hemoglobin type is a 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 α2 β2 . The subunits are structurally similar and about the
same size. Each subunit has a molecular weight of about 16,000 daltons,[46] for a total molecular weight of the
tetramer of about 64,000 daltons (64,458 g/mol).[47] Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the
most intensively studied of the hemoglobin molecules.

In human infants, the hemoglobin molecule is made up of 2 α chains and 2 γ chains. The gamma chains are
gradually replaced by β chains as the infant grows.[48]

The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic
effect.

Oxygen saturation
In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen
molecules (deoxyhemoglobin).[49]

Oxyhemoglobin

Oxyhemoglobin is formed during 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 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 ATP by the process of oxidative phosphorylation. It does not,
however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by
removal of carbon dioxide, thus causing a shift up in pH.[50]

Hemoglobin exists in two forms, a taut (tense) form (T) and a relaxed form (R). Various factors such as low
pH, high CO2 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 CO2 , or low 2,3 BPG favors the relaxed form,
which can better bind oxygen.[51] The partial pressure of the system also affects O2 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.[52] 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).

Deoxygenated hemoglobin

Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of
oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the
660 nm wavelength than deoxyhemoglobin, while at 940 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.[53]

Deoxygenated hemoglobin is paramagnetic; it is weakly attracted to magnetic fields.[54][55] In contrast,


oxygenated hemoglobin exhibits diamagnetism, a weak repulsion from a magnetic field.[55]

Evolution of vertebrate hemoglobin


Scientists agree that the event that separated myoglobin from hemoglobin occurred after lampreys diverged
from jawed vertebrates.[56] This separation of myoglobin and hemoglobin allowed for the different functions
of the two molecules to arise and develop: myoglobin has more to do with oxygen storage while hemoglobin
is tasked with oxygen transport.[57] The α- and β-like globin genes encode the individual subunits of the
protein.[25] The predecessors of these genes arose through another duplication event also after the gnathosome
common ancestor derived from jawless fish, approximately 450–500 million years ago.[56] The development
of α and β genes created the potential for hemoglobin to be composed of multiple subunits, a physical
composition central to hemoglobin's ability to transport oxygen. Having multiple subunits contributes to
hemoglobin's ability to bind oxygen cooperatively as well as be regulated allosterically.[57] Subsequently, the α
gene also underwent a duplication event to form the HBA1 and HBA2 genes.[58] These further duplications
and divergences have created a diverse range of α- and β-like globin genes that are regulated so that certain
forms occur at different stages of development.[57]

Most ice fish of the family Channichthyidae have lost their hemoglobin genes as an adaptation to cold water.[5]
Iron's oxidation state in oxyhemoglobin
Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O2 ), by
experimental measurement, is diamagnetic (no net unpaired electrons), yet the lowest-energy (ground-state)
electron configurations in both oxygen and iron are paramagnetic (suggesting at least one unpaired electron in
the complex). The lowest-energy form of oxygen, and the lowest energy forms of the relevant oxidation states
of iron, are these:

Triplet oxygen, the lowest-energy molecular oxygen species, has two unpaired electrons in
antibonding π* molecular orbitals.
Iron(II) tends to exist in a high-spin 3d6 configuration with four unpaired electrons.
Iron(III) (3d5) has an odd number of electrons, and thus must have one or more unpaired
electrons, in any energy state.

All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g.,
a higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must
exist, in order to explain the observed diamagnetism and no unpaired electrons.

The two logical possibilities to produce diamagnetic (no net spin) Hb-O2 are:

1. Low-spin Fe2+ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic.
However, the singlet form of oxygen is the higher-energy form of the molecule.
2. Low-spin Fe3+ binds to O2•− (the superoxide ion) and the two unpaired electrons couple
antiferromagnetically, giving observed diamagnetic properties. Here, the iron has been
oxidized (has lost one electron), and the oxygen has been reduced (has gained one electron).

Another possible model in which low-spin Fe4+ binds to peroxide, O2 2−, can be ruled out by itself, because
the iron is paramagnetic (although the peroxide ion is diamagnetic). Here, the iron has been oxidized by two
electrons, and the oxygen reduced by two electrons.

Direct experimental data:

X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2.
Infrared vibrational frequencies of the O-O bond suggests a bond length fitting with superoxide
(a bond order of about 1.6, with superoxide being 1.5).
X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between
deoxyhemoglobin and oxyhemoglobin, as for all the methemoglobin species, strongly suggests
an actual local charge closer to Fe3+ than Fe2+ .[59][60][61]

Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in the −1 state (as
superoxide .O2 −). The diamagnetism in this configuration arises from the single unpaired electron on
superoxide aligning antiferromagnetically with the single unpaired electron on iron (in a low-spin d5 state), to
give no net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin from
experiment.[62][63]

The second choice of the logical possibilities above for diamagnetic oxyhemoglobin being found correct by
experiment, is not surprising: singlet oxygen (possibility #1) is an unrealistically high energy state. Model 3
leads to unfavorable separation of charge (and does not agree with the magnetic data), although it could make
a minor contribution as a resonance form. Iron's shift to a higher oxidation state in Hb-O2 decreases the atom's
size, and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and
initiating the allosteric changes seen in the globulins.
Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should
exist in oxidation state II. This conclusion seemed likely, since the iron oxidation state III as methemoglobin,
when not accompanied by superoxide .O2 − to "hold" the oxidation electron, was known to render hemoglobin
incapable of binding normal triplet O2 as it occurs in the air. It was thus assumed that iron remained as Fe(II)
when oxygen gas was bound in the lungs. The iron chemistry in this previous classical model was elegant, but
the required presence of the diamagnetic, high-energy, singlet oxygen molecule was never explained. It was
classically argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of
strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's
electrons to pair into the low-spin configuration, which would be diamagnetic in Fe(II). This forced low-spin
pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in
size. Extraction of an additional electron from iron by oxygen is required to explain both iron's smaller size and
observed increased oxidation state, and oxygen's weaker bond.

The assignment of a whole-number oxidation state is a formalism, as the covalent bonds are not required to
have perfect bond orders involving whole electron transfer. Thus, all three models for paramagnetic Hb-O2
may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O2 . However,
the model of iron in Hb-O2 being Fe(III) is more correct than the classical idea that it remains Fe(II).

Cooperativity
When oxygen binds to the iron complex,
it causes the iron atom to move back
toward the center of the plane of the
porphyrin ring (see moving diagram). At
the same time, the imidazole side-chain
of the histidine residue interacting at the
other pole of the iron is pulled toward the
porphyrin ring. This interaction forces the
plane of the ring sideways toward the
outside of the tetramer, and also induces a
strain in the protein helix containing the
histidine as it moves nearer to the iron
atom. This strain is transmitted to the
remaining three monomers in the
tetramer, where it induces a similar
conformational change in the other heme
sites such that binding of oxygen to these A schematic visual model of oxygen-binding process, showing all
sites becomes easier. four monomers and hemes, and protein chains only as
diagrammatic coils, to facilitate visualization into the molecule.
As oxygen binds to one monomer of Oxygen is not shown in this model, but, for each of the iron atoms,
hemoglobin, the tetramer's conformation it binds to the iron (red sphere) in the flat heme. For example, in the
shifts from the T (tense) state to the R upper-left of the four hemes shown, oxygen binds at the left of the
(relaxed) state. This shift promotes the iron atom shown in the upper-left of diagram. This causes the iron
binding of oxygen to the remaining three atom to move backward into the heme that holds it (the iron moves
monomer's heme groups, thus saturating upward as it binds oxygen, in this illustration), tugging the histidine
the hemoglobin molecule with residue (modeled as a red pentagon on the right of the iron) closer,
[64] as it does. This, in turn, pulls on the protein chain holding the
oxygen.
histidine.
In the tetrameric form of normal adult
hemoglobin, the binding of oxygen is,
thus, a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen
saturation of the molecule, with the first molecules of oxygen bound influencing the shape of the binding sites
for the next ones, in a way favorable for binding. This positive cooperative binding is achieved through steric
conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein
in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated,
causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding
curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with
noncooperative binding.

The dynamic mechanism of the cooperativity in hemoglobin and its relation with low-frequency resonance has
been discussed.[65]

Binding for ligands other than oxygen


Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also
include competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide
(CO2 ) and nitric oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins to form
carbaminohemoglobin; this mechanism is thought to account for about 10% of carbon dioxide transport in
mammals. Nitric oxide can also be transported by hemoglobin; it is bound to specific thiol groups in the globin
protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin
releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist
oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.[66]

Competitive

The binding of oxygen is affected by molecules such as carbon monoxide (for example, from tobacco
smoking, exhaust gas, and incomplete combustion in furnaces). CO competes with oxygen at the heme
binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen,[67][68]
meaning that small amounts of CO dramatically reduce hemoglobin's ability to deliver oxygen to the target
tissue.[69] Since carbon monoxide is a colorless, odorless and tasteless gas, and poses a potentially fatal threat,
carbon monoxide detectors have become commercially available to warn of dangerous levels in residences.
When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin, which
may cause the skin of CO poisoning victims to appear pink in death, instead of white or blue. When inspired
air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to
0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by
CO.

In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN−), sulfur monoxide (SO),
and sulfide (S2−), including hydrogen sulfide (H2 S). All of these bind to iron in heme without changing its
oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

The iron atom in the heme group must initially be in the ferrous (Fe2+) oxidation state to support oxygen and
other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as
explained above). Initial oxidation to the ferric (Fe3+) state without oxygen converts hemoglobin into
"hemiglobin" or methemoglobin, which cannot bind oxygen. Hemoglobin in normal red blood cells is
protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small
fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the
more ancient nitric oxide dioxygenase function of globins.

Allosteric
Carbon dioxide occupies a different binding site on the hemoglobin. At tissues, where carbon dioxide
concentration is higher, carbon dioxide binds to allosteric site of hemoglobin, facilitating unloading of oxygen
from hemoglobin and ultimately its removal from the body after the oxygen has been released to tissues
undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Bohr
effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which
decomposes into bicarbonate and protons:

CO2 + H2O → H2CO3 → HCO3− + H+

Hence, blood with high carbon dioxide levels is also lower in


pH (more acidic). Hemoglobin can bind protons and carbon
dioxide, which causes a conformational change in the protein
and facilitates the release of oxygen. Protons bind at various
places on the protein, while carbon dioxide binds at the α-
amino group.[70] Carbon dioxide binds to hemoglobin and
forms carbaminohemoglobin.[71] This decrease in
hemoglobin's affinity for oxygen by the binding of carbon
dioxide and acid is known as the Bohr effect. The Bohr effect
favors the T state rather than the R state. (shifts the O2 -
saturation curve to the right). Conversely, when the carbon
dioxide levels in the blood decrease (i.e., in the lung
capillaries), carbon dioxide and protons are released from
The sigmoidal shape of hemoglobin's oxygen-
hemoglobin, increasing the oxygen affinity of the protein. A
dissociation curve results from cooperative
reduction in the total binding capacity of hemoglobin to
binding of oxygen to hemoglobin.
oxygen (i.e. shifting the curve down, not just to the right) due
to reduced pH is called the root effect. This is seen in bony
fish.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The
sigmoidal curve of hemoglobin makes it efficient in binding (taking up O2 in lungs), and efficient in unloading
(unloading O2 in tissues).[72]

In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is
increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of
lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport
molecule Z, is called a heterotropic allosteric effect. Hemoglobin in organisms at high altitudes has also
adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R
state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the
necessary metabolic processes when oxygen is present at low partial pressures.[73]

Animals other than humans use different molecules to bind to hemoglobin and change its O2 affinity under
unfavorable conditions. Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish
hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.[74] GTP
reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen
bond formed that further stabilizes the tense state.[75] Under hypoxic conditions, the concentration of both
ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.[76]

A variant hemoglobin, called fetal hemoglobin (HbF, α2 γ2 ), is found in the developing fetus, and binds
oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal
hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen
tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take
oxygen from maternal blood.
Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves oxygen delivery
in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue
in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated
hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure
and respiration. NO is not released in the cytoplasm of red blood cells but transported out of them by an anion
exchanger called AE1.[77]

Types in humans
Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic
mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin
variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other
variants cause no detectable pathology, and are thus considered non-pathological variants.[78][79]

In the embryo:

Gower 1 (ζ2ε2)
Gower 2 (α2ε2) (PDB: 1A9W (https://www.rcsb.org/structure/1A9W))
Hemoglobin Portland I (ζ2γ2)
Hemoglobin Portland II (ζ2β2).

In the fetus:

Hemoglobin F (α2γ2) (PDB: 1FDH (https://www.rcsb.org/structure/1FDH)).

After birth:

Hemoglobin A (adult hemoglobin) (α2β2) (PDB: 1BZ0 (https://www.rcsb.org/structure/1BZ0)) –


The most common with a normal amount over 95%
Hemoglobin A2 (α2δ2) – δ chain synthesis begins late in the third trimester and, in adults, it has
a normal range of 1.5–3.5%
Hemoglobin F (fetal hemoglobin) (α2γ2) – In adults Hemoglobin F is restricted to a limited
population of red cells called F-cells. However, the level of Hb F can be elevated in persons
with sickle-cell disease and beta-thalassemia.

Variant forms that cause disease:

Hemoglobin D-Punjab – (α2βD2) – A variant form of hemoglobin.


Hemoglobin H (β4) – A variant form of hemoglobin, formed by a tetramer of β chains, which may
be present in variants of α thalassemia.
Hemoglobin Barts (γ4) – A variant form of hemoglobin, formed by a tetramer of γ chains, which
may be present in variants of α thalassemia.
Hemoglobin S (α2βS2) – A variant form of hemoglobin found in people with sickle cell disease.
There is a variation in the β-chain gene, causing a change in the properties of hemoglobin,
which results in sickling of red blood cells.
Hemoglobin C (α2βC2) – Another variant due to a variation in the β-chain gene. This variant
causes a mild chronic hemolytic anemia.
Hemoglobin E (α2βE2) – Another variant due to a variation in the β-chain gene. This variant
causes a mild chronic hemolytic anemia.
Hemoglobin AS – A heterozygous form causing
sickle cell trait with one adult gene and one
sickle cell disease gene
Hemoglobin SC disease – A compound
heterozygous form with one sickle gene and
another encoding Hemoglobin C.
Hemoglobin Hopkins-2 - A variant form of
hemoglobin that is sometimes viewed in
combination with Hemoglobin S to produce
sickle cell disease.

Degradation in vertebrate animals


Gene expression of hemoglobin before and after
When red blood cells reach the end of their life due to birth. Also identifies the types of cells and organs
aging or defects, they are removed from the circulation in which the gene expression (data on Wood W.G.,
by the phagocytic activity of macrophages in the spleen (1976). Br. Med. Bull. 32, 282.)
or the liver or hemolyze within the circulation. Free
hemoglobin is then cleared from the circulation via the
hemoglobin transporter CD163, which is exclusively expressed on monocytes or macrophages. Within these
cells the hemoglobin molecule is broken up, and the iron gets recycled. This process also produces one
molecule of carbon monoxide for every molecule of heme degraded.[80] Heme degradation is one of the few
natural sources of carbon monoxide in the human body, and is responsible for the normal blood levels of
carbon monoxide even in people breathing pure air. The other major final product of heme degradation is
bilirubin. Increased levels of this chemical are detected in the blood if red blood cells are being destroyed more
rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the
blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the
kidneys, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as
hemosiderin or ferritin in tissues and transported in plasma by beta globulins as transferrins. When the
porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is
secreted into the intestines as bile. Intestines metabolise bilirubin into urobilinogen. Urobilinogen leaves the
body in faeces, in a pigment called stercobilin. Globulin is metabolised into amino acids that are then released
into circulation.

Role in disease
Hemoglobin deficiency can be caused either by a decreased amount of hemoglobin molecules, as in anemia, or
by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen.
Hemoglobinopathies (genetic defects resulting in abnormal structure of the hemoglobin molecule)[81] may
cause both. In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity. Hemoglobin
deficiency is, in general, strictly distinguished from hypoxemia, defined as decreased partial pressure of
oxygen in blood,[82][83][84][85] although both are causes of hypoxia (insufficient oxygen supply to tissues).

Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems,
chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO2 ,
causing an altered oxygen–hemoglobin dissociation curve. However, it can also be pathologically altered in,
e.g., carbon monoxide poisoning.
Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of
anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia
are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood
cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller
than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated
jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause kidney
failure.

Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and
thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely
as hemoglobin variants.

There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic
pathways of heme synthesis. King George III of the United Kingdom was probably the most famous
porphyria sufferer.

To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of
each β chain. The resulting molecule is often referred to as Hb A1c, a glycosylated hemoglobin. The binding
of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in
many proteins, and is not known to serve a useful purpose. However, as the concentration of glucose in the
blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually
runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the
Hb A1c percentage reflects a weighted average of blood glucose levels over the lifetime of red cells, which is
approximately 120 days.[86] The levels of glycosylated hemoglobin are therefore measured in order to monitor
the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results
in high levels of glycosylated hemoglobin in the red blood cells. The normal reference range is approximately
4.0–5.9%. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels
greater than 9% are associated with poor control of the glycosylated hemoglobin, and levels greater than 12%
are associated with very poor control. Diabetics who keep their glycosylated hemoglobin levels close to 7%
have a much better chance of avoiding the complications that may accompany diabetes (than those whose
levels are 8% or higher).[87] In addition, increased glycosylation of hemoglobin increases its affinity for
oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.[88]

Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called
polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis,
too much erythropoietin, or polycythemia vera.[89] High hemoglobin levels may also be caused by exposure to
high altitudes, smoking, dehydration (artificially by concentrating Hb), advanced lung disease and certain
tumors.[48]

A recent study done in Pondicherry, India, shows its importance in coronary artery disease.[90]

Diagnostic uses
Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part
of a complete blood count. For example, it is typically tested before or after blood donation. Results are
reported in g/L, g/dL or mol/L. 1 g/dL equals about 0.6206 mmol/L, although the latter units are not used as
often due to uncertainty regarding the polymeric state of the molecule.[91] This conversion factor, using the
single globin unit molecular weight of 16,000 Da, is more common for hemoglobin concentration in blood.
For MCHC (mean corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the
tetramer weight of 64,500 Da, is more common.[92] Normal levels are:

Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17 mmol/L)
Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to
9.37 mmol/L)
Children: 11 to 16 g/dL (110 to 160 g/L, or 6.83 to
9.93 mmol/L)
Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to
8.69 mmol/L) (9.5 to 15 usual value during
pregnancy)[93][94]

Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant


women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd
trimester.[95]

Dehydration or hyperhydration can greatly influence measured


hemoglobin levels. Albumin can indicate hydration status.

If the concentration is below normal, this is called anemia. Anemias


are classified by the size of red blood cells, the cells that contain A hemoglobin concentration
hemoglobin in vertebrates. The anemia is called "microcytic" if red measurement being administered
cells are small, "macrocytic" if they are large, and "normocytic" before a blood donation at the
otherwise. American Red Cross Boston Blood
Donation Center.
Hematocrit, the proportion of blood volume occupied by red blood
cells, is typically about three times the hemoglobin concentration
measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of
51%.[96]

Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on
hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method
called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.[97]

Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively
using NIRS.[98][99][100][101][102] NIRS can be used both on the head and on muscles. This technique is often
used for research in e.g. elite sports training, ergonomics, rehabilitation, patient monitoring, neonatal research,
functional brain monitoring, brain computer interface, urology (bladder contraction), neurology
(Neurovascular coupling) and more.

Long-term control of blood sugar concentration can be measured by the concentration of Hb A1c. Measuring it
directly would require many samples because blood sugar levels vary widely through the day. Hb A1c is the
product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in
more Hb A1c. Because the reaction is slow, the Hb A1c proportion represents glucose level in blood averaged
over the half-life of red blood cells, is typically 50–55 days. An Hb A1c proportion of 6.0% or less show good
long-term glucose control, while values above 7.0% are elevated. This test is especially useful for
diabetics.[103]

The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is
sensitive to magnetic fields since it is paramagnetic. Combined measurement with NIRS shows good
correlation with both the oxy- and deoxyhemoglobin signal compared to the BOLD signal.[104]

Athletic tracking and self tracking uses


Hemoglobin can be tracked noninvasively, to build an individual data set tracking the hemoconcentration and
hemodilution effects of daily activities for better understanding of sports performance and training. Athletes are
often concerned about endurance and intensity of exercise. The sensor uses light-emitting diodes that emit red
and infrared light through the tissue to a light detector, which then sends a signal to a processor to calculate the
absorption of light by the hemoglobin protein.[105] This sensor is similar to a pulse oximeter, which consists of
a small sensing device that clips to the finger.

Analogues in non-vertebrate organisms


A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant
kingdoms. Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose
known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins
contain globins and the heme moiety (iron in a flat porphyrin support), they are often called hemoglobins, even
if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the
distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these
organisms do not contain muscles. Or, they may have a recognizable separate circulatory system but not one
that deals with oxygen transport (for example, many insects and other arthropods). In all these groups,
heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as
oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO,
CO2 , sulfide compounds, and even O2 scavenging in environments that must be anaerobic.[106] They may
even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes
and peroxidases.

The structure of hemoglobins varies across species. Hemoglobin


occurs in all kingdoms of organisms, but not in all organisms.
Primitive species such as bacteria, protozoa, algae, and plants often
have single-globin hemoglobins. Many nematode worms, molluscs,
and crustaceans contain very large multisubunit molecules, much
larger than those in vertebrates. In particular, chimeric hemoglobins
found in fungi and giant annelids may contain both globin and other
types of proteins.[14] The giant tube worm Riftia pachyptila
showing red hemoglobin-containing
One of the most striking occurrences and uses of hemoglobin in plumes
organisms is in the giant tube worm (Riftia pachyptila, also called
Vestimentifera), which can reach 2.4 meters length and populates
ocean volcanic vents. Instead of a digestive tract, these worms contain a population of bacteria constituting half
the organism's weight. The bacteria oxidize H2 S from the vent with O2 from the water to produce energy to
make food from H2 O and CO2 . The worms' upper end is a deep-red fan-like structure ("plume"), which
extends into the water and absorbs H2 S and O2 for the bacteria, and CO2 for use as synthetic raw material
similar to photosynthetic plants. The structures are bright red due to their content of several extraordinarily
complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These
hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry
sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species
are.[107][108]

Other oxygen-binding proteins


Myoglobin
Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a
distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but
is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store
oxygen rather than transport it.

Hemocyanin
The second most common oxygen-transporting protein found in nature, it is found in the
blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme
groups and is blue in color when oxygenated.

Hemerythrin
Some marine invertebrates and a few species of annelid use this iron-containing non-heme
protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.

Chlorocruorin
Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly
different in structure. Appears green when deoxygenated and red when oxygenated.

Vanabins
Also known as vanadium chromagens, they are found in the blood of sea squirts. They were
once hypothesized to use the rare metal vanadium as an oxygen binding prosthetic group.
However, although they do contain vanadium by preference, they apparently bind little
oxygen, and thus have some other function, which has not been elucidated (sea squirts also
contain some hemoglobin). They may act as toxins.

Erythrocruorin
Found in many annelids, including earthworms, it is a giant free-floating blood protein
containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits
bound together into a single protein complex with a molecular mass greater than 3.5 million
daltons.

Pinnaglobin
Only seen in the mollusc Pinna nobilis. Brown manganese-based porphyrin protein.

Leghemoglobin
In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are
protected from oxygen by this iron heme containing oxygen-binding protein. The specific
enzyme protected is nitrogenase, which is unable to reduce nitrogen gas in the presence of
free oxygen.

Coboglobin
A synthetic cobalt-based porphyrin. Coboprotein would appear colorless when oxygenated,
but yellow when in veins.

Presence in nonerythroid cells


Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these
include the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and
hippocampus, and in all mature oligodendrocytes.[12] It has been suggested that brain hemoglobin in these
cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is
especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy
production".[12] It has been noted further that "A9 dopaminergic neurons may be at particular risk since in
addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of
hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine
and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals".[12] This may
explain the risk of these cells for degeneration in Parkinson's disease.[12] The hemoglobin-derived iron in these
cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia nigra), but
rather is due to neuromelanin.

Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron
metabolism in macrophages,[109] alveolar cells,[110] and mesangial cells in the kidney.[111]

In history, art and music


Historically, an association between the color of blood and rust occurs
in the association of the planet Mars, with the Roman god of war,
since the planet is an orange-red, which reminded the ancients of
blood. Although the color of the planet is due to iron compounds in
combination with oxygen in the Martian soil, it is a common
misconception that the iron in hemoglobin and its oxides gives blood
its red color. The color is actually due to the porphyrin moiety of Heart of Steel (Hemoglobin) (2005)
by Julian Voss-Andreae. The images
hemoglobin to which the iron is bound, not the iron itself,[112]
show the 5-foot (1.50 m) tall
although the ligation and redox state of the iron can influence the pi to
sculpture right after installation, after
pi* or n to pi* electronic transitions of the porphyrin and hence its
10 days, and after several months of
optical characteristics.
exposure to the elements.

Artist Julian Voss-Andreae created a sculpture called Heart of Steel


(Hemoglobin) in 2005, based on the protein's backbone. The
sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art
mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.[113][114]

Montreal artist Nicolas Baier created Lustre (Hémoglobine), a sculpture in stainless steel that shows the
structure of the hemoglobin molecule. It is displayed in the atrium of McGill University Health Centre's
research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres.[115][116]

See also

Hemoglobin variants: Chlorophyll


Complete Blood Count
Hb A1C Globin fold
Hemoglobin A2 Hemocyanin
Hemoglobin C Hemoglobinemia
Hemoglobin F Hemoglobinometer
Hemoprotein
Hemoglobin protein subunits Sickle-cell disease
(genes):
Vaska's complex – iridium organometallic complex
Alpha globin 1 notable for its ability to bind to O2 reversibly.
Beta globin
Delta globin

Hemoglobin compounds:

Carbaminohemoglobin (with carbon


dioxide, colored dark red)
Carboxyhemoglobin (with carbon
monoxide, colored cherry-red)
Oxyhemoglobin (with diatomic
oxygen, colored blood-red)

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Further reading
Campbell, MK (1999). Biochemistry (https://archive.org/details/biochemistry00camp) (third ed.).
Harcourt. ISBN 978-0030244261.
Eshaghian, S; Horwich, TB; Fonarow, GC (2006). "An unexpected inverse relationship
between HbA1c levels and mortality in patients with diabetes and advanced systolic heart
failure". Am Heart J. 151 (1): 91.e1–91.e6. doi:10.1016/j.ahj.2005.10.008 (https://doi.org/10.101
6%2Fj.ahj.2005.10.008). PMID 16368297 (https://pubmed.ncbi.nlm.nih.gov/16368297).
Ganong, WF (2003). Review of Medical Physiology (21st ed.). Lange. ISBN 978-0071402361.
Hager, T (1995). Force of Nature: The Life of Linus Pauling (https://archive.org/details/forceofna
turelif00hage). Simon and Schuster. ISBN 978-0684809090.
Kneipp J, Balakrishnan G, Chen R, Shen TJ, Sahu SC, Ho NT, Giovannelli JL, Simplaceanu V,
Ho C, Spiro T (2005). "Dynamics of allostery in hemoglobin: roles of the penultimate tyrosine H
bonds". J Mol Biol. 356 (2): 335–53. doi:10.1016/j.jmb.2005.11.006 (https://doi.org/10.1016%2F
j.jmb.2005.11.006). PMID 16368110 (https://pubmed.ncbi.nlm.nih.gov/16368110).

Hardison, Ross C. (2012). "Evolution of Hemoglobin and Its Genes" (https://www.ncbi.nlm.nih.gov/pmc/artic


les/PMC3543078). Cold Spring Harbor Perspectives in Medicine. 2 (12): a011627.
doi:10.1101/cshperspect.a011627 (https://doi.org/10.1101%2Fcshperspect.a011627). ISSN 2157-1422 (https://
www.worldcat.org/issn/2157-1422). PMC 3543078 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC354307
8). PMID 23209182 (https://pubmed.ncbi.nlm.nih.gov/23209182).

External links
Proteopedia Hemoglobin (http://www.proteopedia.org/wiki/index.php/Hemoglobin)
National Anemia Action Council (https://web.archive.org/web/20080613202658/http://www.ane
mia.org/) – anemia.org
New hemoglobin type causes mock diagnosis with pulse oxymeters (http://www.life-of-science.
net/medicine/news/new-hemoglobin-type-discovered-causing-mock-diagnosis-of-cardiac-insuff
iciency.html)
Animation of hemoglobin: from deoxy to oxy form (https://vimeo.com/92241783)

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