Editing Hemoglobin (section)

==Binding of ligands other than oxygen==
Besides the oxygen [[ligand (biochemistry)|ligand]], which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include [[competitive inhibition|competitive inhibitors]] such as [[carbon monoxide]] (CO) and [[allosteric regulation|allosteric ligands]] such as carbon dioxide (CO<sub>2</sub>) 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 [[vasodilation|vasodilatory]] nitric oxide to tissues in which oxygen levels are low.<ref name="Jensen-2009">{{cite journal
|last=Jensen |first=Frank B
|title=The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow
|journal=Journal of Experimental Biology
|volume=212 |issue=Pt 21
|pages=3387–93
|year=2009
|pmid=19837879 |doi=10.1242/jeb.023697
|s2cid=906177
}}</ref>

===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.<ref>{{cite book |last=Hall |first=John E. |title=Guyton and Hall textbook of medical physiology |year=2010 |publisher=Saunders/Elsevier |location=Philadelphia, Pa. |isbn=978-1-4160-4574-8 |page=502 |edition=12th}}</ref><ref name="Rhodes-2019">{{cite book |last1=Rhodes |first1=Carl E. |last2=Denault |first2=Deanna |last3=Varacallo |first3=Matthew |title=Physiology, Oxygen Transport |date=2019-03-04 |publisher=StatPearls Publishing |place=Treasure Island (FL) |pmid=30855920 |via=NCBI Bookshelf |url=https://www.ncbi.nlm.nih.gov/books/NBK538336/ |access-date=2019-05-04 |url-status=live |archive-url=https://web.archive.org/web/20210827215723/https://www.ncbi.nlm.nih.gov/books/NBK538336/ |archive-date=2021-08-27 |quote=It is important to note that in the setting of carboxyhemoglobinemia, it is not a reduction in oxygen-carrying capacity that causes pathology, but an impaired delivery of bound oxygen to target tissues.}}</ref> Since carbon monoxide is a colorless, odorless, and tasteless gas, and poses a potentially fatal threat, [[carbon monoxide detector]]s 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 [[carbon monoxide poisoning|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<sup>−</sup>), [[sulfur monoxide]] (SO), and [[sulfide]] (S<sup>2−</sup>), including [[hydrogen sulfide]] (H<sub>2</sub>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]] (Fe<sup>2+</sup>) 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]] (Fe<sup>3+</sup>) state without oxygen converts hemoglobin into "hem'''i'''globin" 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===
{{Further|Oxygen-hemoglobin dissociation curve}}
Carbon ''di''oxide 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 [[proton]]s:

:CO<sub>2</sub> + H<sub>2</sub>O → H<sub>2</sub>CO<sub>3</sub> → HCO<sub>3</sub><sup>−</sup> + H<sup>+</sup>

[[File:Hemoglobin saturation curve.svg|left|thumb|The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of [[oxygen]] to hemoglobin.]]
Hence, blood with high carbon dioxide levels is also lower in [[pH]] (more [[acid]]ic). 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.<ref>Nelson, D. L.; Cox, M. M. (2000). ''Lehninger Principles of Biochemistry'', 3rd ed. New York: Worth Publishers. p. 217, {{ISBN|1572599316}}.</ref> Carbon dioxide binds to hemoglobin and forms [[carbaminohemoglobin]].<ref>{{cite book |edition=11 |publisher=Elsevier Saunders |isbn=978-0-7216-0240-0 |page=511 |last=Guyton |first=Arthur C. |author2=John E. Hall |title=Textbook of Medical Physiology |location=Philadelphia |year=2006}}</ref> 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 O<sub>2</sub>-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 hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to 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 O<sub>2</sub> in lungs), and efficient in unloading (unloading O<sub>2</sub> in tissues).<ref>{{YouTube|6AfRX6oh9-E|Lecture – 12 Myoglobin and Hemoglobin}}</ref>

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.<ref>{{cite book |title=Biochemistry |edition=Eighth |publisher=W. H. Freeman |year=2015 |location=New York |isbn=978-1-4641-2610-9}}{{page needed|date=December 2021}}</ref>

Animals other than humans use different molecules to bind to hemoglobin and change its O<sub>2</sub> affinity under unfavorable conditions. Fish use both [[adenosine triphosphate|ATP]] and [[guanosine triphosphate|GTP]]. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.<ref name="Rutjes-2007">{{cite journal |last=Rutjes |first=H. A. |author2=Nieveen, M. C. |author3=Weber, R. E. |author4=Witte, F. |author5=Van den Thillart, G. E. E. J. M. |title=Multiple strategies of Lake Victoria cichlids to cope with lifelong hypoxia include hemoglobin switching |journal=AJP: Regulatory, Integrative and Comparative Physiology |date=20 June 2007 |volume=293 |issue=3 |pages=R1376–83 |pmid=17626121 |doi=10.1152/ajpregu.00536.2006}}</ref> 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.<ref name="Gronenborn-1984">{{cite journal |last=Gronenborn |first=Angela M. |author2=Clore, G. Marius |author3=Brunori, Maurizio |author4=Giardina, Bruno |author5=Falcioni, Giancarlo |author6=Perutz, Max F. |title=Stereochemistry of ATP and GTP bound to fish haemoglobins |journal=Journal of Molecular Biology |volume=178 |issue=3 |pages=731–42 |year=1984 |pmid=6492161 |doi=10.1016/0022-2836(84)90249-3}}</ref> Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.<ref name="Weber-1988">{{cite journal |last=Weber |first=Roy E. |author2=Frank B. Jensen |title=Functional adaptations in hemoglobins from ectothermic vertebrates |journal=Annual Review of Physiology |year=1988 |volume=50 |pages=161–79 |pmid=3288089 |doi=10.1146/annurev.ph.50.030188.001113}}</ref>

A variant hemoglobin, called [[fetal hemoglobin]] (HbF, α<sub>2</sub>γ<sub>2</sub>), 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 [[Anion Exchanger 1|AE1]].<ref>{{cite book |last=Rang |first=H.P. |author2=Dale M.M. |author3=Ritter J.M. |author4=Moore P.K. |title=Pharmacology, Fifth Edition |year=2003 |publisher=Elsevier |isbn=978-0-443-07202-4}}{{page needed|date=December 2021}}</ref>