myoglobin

Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals.{{cite journal | vauthors = Ordway GA, Garry DJ | title = Myoglobin: an essential hemoprotein in striated muscle | journal = The Journal of Experimental Biology | volume = 207 | issue = Pt 20 | pages = 3441–6 | date = Sep 2004 | pmid = 15339940 | doi = 10.1242/jeb.01172 | doi-access = free }}{{cite book | vauthors = Wick MR, Hornick JL | title=Diagnostic Immunohistochemistry | chapter=Immunohistology of Soft Tissue and Osseous Neoplasms | publisher=Elsevier | year=2011 | isbn=978-1-4160-5766-6 | doi=10.1016/b978-1-4160-5766-6.00008-x | pages=83–136 | quote=Myoglobin is a 17.8-kD protein that is found in cardiac and skeletal muscle and that forms complexes with iron molecules. }}{{cite book | vauthors = Feher J | title=Quantitative Human Physiology | chapter=Oxygen and Carbon Dioxide Transport | publisher=Elsevier | year=2017 | isbn=978-0-12-800883-6 | doi=10.1016/b978-0-12-800883-6.00064-1 | pages=656–664 | quote= Highly oxidative muscle fibers contain a lot of myoglobin. It has two functions in muscle: it stores oxygen for use during heavy exercise, and it enhances diffusion through the cytosol by carrying the oxygen. By binding O2, myoglobin (Mb) provides a second diffusive pathway for O2 through the cell cytosol. }}{{cite book | vauthors = Wilson MT, Reeder BJ | title=Encyclopedia of Respiratory Medicine | chapter=MYOGLOBIN | publisher=Elsevier | year=2006 | isbn=978-0-12-370879-3 | doi=10.1016/b0-12-370879-6/00250-7 | pages=73–76 | quote=Myoglobin (Mb) is a heme-containing globular protein that is found in abundance in myocyte cells of heart and skeletal muscle. }}{{cite book | vauthors = Boncyk JC | title=Complications in Anesthesia | chapter=Perioperative Hypoxia | publisher=Elsevier | year=2007 | isbn=978-1-4160-2215-2 | doi=10.1016/b978-1-4160-2215-2.50052-1 | pages=193–199 | quote=Myoglobin serves both as an O2 buffer and to store O2 in muscle. All known vertebrate myoglobins and β-hemoglobin subunits are similar in structure, but myoglobin binds O2 more avidly at low Po2 (Fig. 47-5) because it is a monomer (i.e., it does not undergo a significant conformational change with oxygenation). Thus, myoglobin remains fully saturated at O2 tensions between 15 and 30 mm Hg and unloads its O2 to the muscle mitochondria only at very low O2 tensions. }} Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobin has a higher affinity for oxygen and does not have cooperative binding with oxygen like hemoglobin does.{{cite journal | vauthors = Hardison RC | title = Evolution of Hemoglobin and Its Genes | journal = Cold Spring Harb Perspect Med | volume = 2 | issue = 12 | pages = a011627 | date = Dec 2012 | pmid = 23209182 | doi = 10.1101/cshperspect.a011627 | pmc = 3543078 }} Myoglobin consists of non-polar amino acids at the core of the globulin, where the heme group is non-covalently bounded with the surrounding polypeptide of myoglobin. In humans, myoglobin is found in the bloodstream only after muscle injury.{{cite book | vauthors = Chung MJ, Brown DL | chapter = Diagnosis of acute myocardial infarction. | veditors = Brown DL | title = Cardiac Intensive Care-E-Book | date = July 2018 | doi=10.1016/B978-0-323-52993-8.00009-6 | pages=91–98.e3 | isbn = 9780323529938 | s2cid = 260507329 | quote=Myoglobin is not specific for myocardial necrosis, however, especially in the presence of skeletal muscle injury and renal insufficiency. }}{{cite book | vauthors = Sekhon N, Peacock WF | title=Biomarkers in Cardiovascular Disease | chapter=Biomarkers to Assist in the Evaluation of Chest Pain | publisher=Elsevier | year=2019 | isbn=978-0-323-54835-9 | doi=10.1016/b978-0-323-54835-9.00011-9 | pages=115–128 | s2cid=59548142 | quote=myoglobin is not specific for the death of cardiac myocytes, and levels can be elevated in renal disease as well as damage to skeletal muscle.}}{{cite book | vauthors = Nelson DL, Cox MM | title = Lehninger Principles of Biochemistry | publisher = Worth Publishers | location = New York | year = 2000 | page = 206 | edition = 3rd | isbn = 0-7167-6203-X | url=https://books.google.com/books?id=5Ek9J4p3NfkC&q=myoglobin}} (Google books link is the 2008 edition)

High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin. Myoglobin is found in Type I muscle, Type II A, and Type II B; although many older texts describe myoglobin as not found in smooth muscle, this has proved erroneous: there is also myoglobin in smooth muscle cells.{{cite journal | vauthors = Qiu Y, Sutton L, Riggs AF | title = Identification of myoglobin in human smooth muscle | journal = Journal of Biological Chemistry | volume = 273 | issue = 36 | pages = 23426–32 | date = Sep 1998 | doi = 10.1074/jbc.273.36.23426 | pmid = 9722578 | doi-access = free }}

Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography.[https://www.nsf.gov/news/news_summ.jsp?cntn_id=100689 (U.S.) National Science Foundation: Protein Data Bank Chronology (Jan. 21, 2004)]. Retrieved 3.17.2010 This achievement was reported in 1958 by John Kendrew and associates.{{cite journal | vauthors = Kendrew JC, Bodo G, Dintzis HM, Parrish RG, Wyckoff H, Phillips DC | title = A three-dimensional model of the myoglobin molecule obtained by x-ray analysis | journal = Nature | volume = 181 | issue = 4610 | pages = 662–6 | date = Mar 1958 | pmid = 13517261 | doi = 10.1038/181662a0 | bibcode = 1958Natur.181..662K | s2cid = 4162786 }} For this discovery, Kendrew shared the 1962 Nobel Prize in Chemistry with Max Perutz.{{cite journal | vauthors = Stoddart C |title=Structural biology: How proteins got their close-up |journal=Knowable Magazine |date=1 March 2022 |doi=10.1146/knowable-022822-1|doi-access=free |url=https://knowablemagazine.org/article/living-world/2022/structural-biology-how-proteins-got-their-closeup |access-date=25 March 2022}}[http://nobelprize.org/chemistry/laureates/1962/index.html The Nobel Prize in Chemistry 1962] Despite being one of the most studied proteins in biology, its physiological function is not yet conclusively established: mice genetically engineered to lack myoglobin can be viable and fertile, but show many cellular and physiological adaptations to overcome the loss. Through observing these changes in myoglobin-depleted mice, it is hypothesised that myoglobin function relates to increased oxygen transport to muscle, and to oxygen storage; as well, it serves as a scavenger of reactive oxygen species.{{cite book | vauthors = Garry DJ, Kanatous SB, Mammen PP | title = Hypoxia and the Circulation | chapter = Molecular Insights into the Functional Role of Myoglobin | series = Advances in Experimental Medicine and Biology | volume = 618 | pages = [https://archive.org/details/hypoxiacirculati00inte/page/181 181–93] | date = 2007 | publisher = Springer | pmid = 18269197 | doi = 10.1007/978-0-387-75434-5_14 | isbn = 978-0-387-75433-8 | chapter-url = https://archive.org/details/hypoxiacirculati00inte/page/181 }}

In humans, myoglobin is encoded by the MB gene.{{cite journal | vauthors = Akaboshi E | title = Cloning of the human myoglobin gene | journal = Gene | volume = 33 | issue = 3 | pages = 241–9 | year = 1985 | pmid = 2989088 | doi = 10.1016/0378-1119(85)90231-8 }}

Myoglobin can take the forms oxymyoglobin (MbO₂), carboxymyoglobin (MbCO), and metmyoglobin (met-Mb), analogously to hemoglobin taking the forms oxyhemoglobin (HbO₂), carboxyhemoglobin (HbCO), and methemoglobin (met-Hb).{{cite book | vauthors = Harvey JW | title=Clinical Biochemistry of Domestic Animals | chapter=Iron Metabolism and Its Disorders | publisher=Elsevier | year=2008 | isbn=978-0-12-370491-7 | doi=10.1016/b978-0-12-370491-7.00009-x | pages=259–285 | quote=Myoglobin is an oxygen-binding protein located primarily in muscles. Myoglobin serves as a local oxygen reservoir that can temporarily provide oxygen when blood oxygen delivery is insufficient during periods of intense muscular activity. Iron within the heme group must be in the Fe+2 state to bind oxygen. If iron is oxidized to the Fe+3 state, metmyoglobin is formed. }}

Differences from hemoglobin

Like hemoglobin, myoglobin is a cytoplasmic protein that binds oxygen on a heme group. It harbors only one globulin group, whereas hemoglobin has four. Although its heme group is identical to those in Hb, Mb has a higher affinity for oxygen than does hemoglobin but fewer total oxygen-storage capacities.{{cite book | vauthors = Wilson MT, Reeder BJ | chapter = Myoglobin |date=2006 | title = Encyclopedia of Respiratory Medicine |pages=73–76 | veditors = Laurent GJ, Shapiro SD |place=Oxford |publisher=Academic Press |doi=10.1016/b0-12-370879-6/00250-7 |isbn=978-0-12-370879-3 }} The newest discovery reveals that myoglobin facilitates oxygen diffusion down a gradient, enhancing oxygen transport in mitochondria.{{cn|date=June 2024}}

Role in cuisine

Myoglobin contains hemes, pigments responsible for the color of red meat. The color that meat takes is partly determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous (+2) oxidation state bound to an oxygen molecule (O₂). Meat cooked well done is brown because the iron atom is now in the ferric (+3) oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink, because the iron atom is bound to NO, nitric oxide (true of, e.g., corned beef or cured hams). Grilled meats can also take on a reddish pink "smoke ring" that comes from the heme center binding to carbon monoxide.{{cite book | vauthors = McGee H | title = On Food and Cooking: The Science and Lore of the Kitchen |publisher=Scribner |location=New York |year=2004 |isbn=0-684-80001-2 |page=148 }} Raw meat packed in a carbon monoxide atmosphere also shows this same pink "smoke ring" due to the same principles. Notably, the surface of this raw meat also displays the pink color, which is usually associated in consumers' minds with fresh meat. This artificially induced pink color can persist, reportedly up to one year.{{cite journal | vauthors = Fraqueza MJ, Barreto AS | title = Gas mixtures approach to improve turkey meat shelf life under modified atmosphere packaging: the effect of carbon monoxide | journal = Poultry Science | volume = 90 | issue = 9 | pages = 2076–84 | date = Sep 2011 | pmid = 21844276 | doi = 10.3382/ps.2011-01366 | doi-access = free }} Hormel and Cargill (meat processing companies in the US) are both reported to use this meat-packing process, and meat treated this way has been in the consumer market since 2003.{{cite web | url = http://www.startribune.com/business/11223451.html | title = Meat companies defend use of carbon monoxide | agency = Associated Press | date = 2007-10-30 | work = Business | publisher = Minneapolis Star Tribune | access-date = 2013-02-11 | archive-url = https://web.archive.org/web/20131225075127/http://www.startribune.com/business/11223451.html | archive-date = 2013-12-25 | url-status = dead }}

Meat alternatives have used various ways to recreate the "meaty" taste associated with myoglobin. Impossible Foods uses leghemoglobin, a heme-containing globin from soy root nodule, produced as a recombinant protein in Komagataella ("Pichia pastoris") yeast.{{cite journal | vauthors = Shelton K, Najera K, Ajredini S, Navarro J, Frangias T |title=The Molecular Magic of "Meatless" Meats: Structural and Sequence Similarities between Soy Leghemoglobin and Bovine Globins |journal=The FASEB Journal |date=April 2020 |volume=34 |issue=S1 |pages=1 |doi=10.1096/fasebj.2020.34.s1.04866|doi-access=free }}{{cite web | vauthors = Bandoim L |date=December 20, 2019 |title=What The FDA's Decision About Soy Leghemoglobin Means For Impossible Burger |website=Forbes |url=https://www.forbes.com/sites/lanabandoim/2019/12/20/what-the-fdas-decision-about-soy-leghemoglobin-means-for-impossible-burger/#5e0a8c7457f6 |access-date=March 4, 2020}} Motif FoodWorks produces a recombinant bovine myoglobin using Komagataella yeast,{{cite web |title='A gamechanger for flavor in meat alternatives...' Motif FoodWorks to launch heme-binding protein delivering 'flavor and aroma of real meat' |url=https://www.foodnavigator-usa.com/Article/2021/09/17/Motif-FoodWorks-to-launch-myoglobin-a-yeast-derived-heme-binding-protein-delivering-the-flavor-and-aroma-of-real-meat |website=foodnavigator-usa.com |date=17 September 2021}} considered GRAS by the FDA.{{cite web |title=Re: GRAS Notice No. GRN 001001 |url=https://www.fda.gov/media/155001/download |website=fda.gov |date=2021-12-03}} Moolec Science has engineered a soybean that produces porcine myoglobin in its seeds called "Piggy Sooy"; it was approved by the USDA in April 2024.{{cite web |title=Moolec Becomes First Molecular Farming Company to Achieve USDA Approval for Plant-Grown Animal Proteins |url=https://finance.yahoo.com/news/moolec-becomes-first-molecular-farming-100000041.html |website=Yahoo Finance |date=22 April 2024}}

Role in disease

Myoglobin is released from damaged muscle tissue, which contain very high concentrations of myoglobin.{{cite book | vauthors = Berridge BR, Van Vleet JF, Herman E | title=Haschek and Rousseaux's Handbook of Toxicologic Pathology | chapter=Cardiac, Vascular, and Skeletal Muscle Systems | publisher=Elsevier | year=2013 | isbn=978-0-12-415759-0 | doi=10.1016/b978-0-12-415759-0.00046-7 | pages=1567–1665 | quote=Myoglobin is a low molecular weight oxygen binding heme protein that is found exclusively in heart and skeletal muscle cells. In blood, myoglobin is bound primarily to plasma globulins, a complex which is filtered by the kidneys. If the plasma concentration exceeds the plasma binding capacity (1.5 mg/dl in humans), myoglobin begins to appear in the urine. High concentrations of myoglobin can change the color of the urine to a dark red-brown color.}} The released myoglobin enters the bloodstream, where high levels may indicate rhabdomyolysis. The myoglobin is filtered by the kidneys, but is toxic to the renal tubular epithelium and so may cause acute kidney injury.{{cite journal | vauthors = Naka T, Jones D, Baldwin I, Fealy N, Bates S, Goehl H, Morgera S, Neumayer HH, Bellomo R | title = Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report | journal = Critical Care | volume = 9 | issue = 2 | pages = R90-5 | date = Apr 2005 | pmid = 15774055 | pmc = 1175920 | doi = 10.1186/cc3034 | doi-access = free }} It is not the myoglobin itself that is toxic (it is a protoxin), but the ferrihemate portion that is dissociated from myoglobin in acidic environments (e.g., acidic urine, lysosomes).{{cn|date=June 2024}}

Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain.{{cite journal | vauthors = Weber M, Rau M, Madlener K, Elsaesser A, Bankovic D, Mitrovic V, Hamm C | title = Diagnostic utility of new immunoassays for the cardiac markers cTnI, myoglobin and CK-MB mass | journal = Clinical Biochemistry | volume = 38 | issue = 11 | pages = 1027–30 | date = Nov 2005 | pmid = 16125162 | doi = 10.1016/j.clinbiochem.2005.07.011 }} However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB, cardiac troponin, ECG, and clinical signs should be taken into account to make the diagnosis.{{cite book | vauthors = Dasgupta A, Wahed A | title=Clinical Chemistry, Immunology and Laboratory Quality Control | chapter=Cardiac Markers | publisher=Elsevier | year=2014 | isbn=978-0-12-407821-5 | doi=10.1016/b978-0-12-407821-5.00008-5 | pages=127–144 | quote=Myoglobin is a heme protein found in both skeletal and cardiac muscle. Myoglobin is typically released in the circulation as early as 1 h after myocardial infarction,... Myoglobin has poor clinical specificity due to the presence of large quantities of myoglobin in skeletal muscle. Some studies suggest adding the myoglobin test to the troponin I test in order to improve diagnostic value [4]. Myoglobin, being a small protein, is excreted in urine, and a high level of serum myoglobin is encountered in patients with acute renal failure (uremic syndrome). Acute renal failure is also a complication of rhabdomyolysis, ...}}

Structure and bonding

Myoglobin belongs to the globin superfamily of proteins, and as with other globins, consists of eight alpha helices connected by loops. Human myoglobin contains 154 amino acids.{{UniProt Full|P02144}}

Myoglobin contains a porphyrin ring with an iron at its center. A proximal histidine group (His-93) is attached directly to iron, and a distal histidine group (His-64) hovers near the opposite face. The distal imidazole is not bonded to the iron, but is available to interact with the substrate O₂. This interaction encourages the binding of O₂, but not carbon monoxide (CO), which still binds about 240× more strongly than O₂.{{cn|date=June 2024}}

The binding of O₂ causes substantial structural change at the Fe center, which shrinks in radius and moves into the center of N4 pocket. O₂-binding induces "spin-pairing": the five-coordinate ferrous deoxy form is high spin and the six coordinate oxy form is low spin and diamagnetic.{{Citation needed|reason=Reliable source needed for the whole sentence|date=March 2017}}

File:MbO2MO.png|Molecular orbital description of Fe-O₂ interaction in myoglobin.{{cite journal | vauthors = Drago RS | title = Free radical reactions of transition metal systems | journal = Coordination Chemistry Reviews | year = 1980 | volume = 32 | pages = 97–110 | doi = 10.1016/S0010-8545(00)80372-0 | issue = 2 }}

File:1a6m Oxy-Myoglobin.jpg|This is an image of an oxygenated myoglobin molecule. The image shows the structural change when oxygen is bound to the iron atom of the heme prosthetic group. The oxygen atoms are colored in green, the iron atom is colored in red, and the heme group is colored in blue.

File:Myoglobine.gif|Myoglobin

Synthetic analogues

Many models of myoglobin have been synthesized as part of a broad interest in transition metal dioxygen complexes. A well known example is the picket fence porphyrin, which consists of a ferrous complex of a sterically bulky derivative of tetraphenylporphyrin.{{cite journal | vauthors = Collman JP, Brauman JI, Halbert TR, Suslick KS | title = Nature of O2 and CO binding to metalloporphyrins and heme proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 10 | pages = 3333–7 | date = Oct 1976 | pmid = 1068445 | pmc = 431107 | doi = 10.1073/pnas.73.10.3333 | bibcode = 1976PNAS...73.3333C | doi-access = free }} In the presence of an imidazole ligand, this ferrous complex reversibly binds O₂. The O₂ substrate adopts a bent geometry, occupying the sixth position of the iron center. A key property of this model is the slow formation of the μ-oxo dimer, which is an inactive diferric state. In nature, such deactivation pathways are suppressed by protein matrix that prevents close approach of the Fe-porphyrin assemblies.{{cite book | vauthors = Lippard SJ, Berg JM | title = Principles of Bioinorganic Chemistry | publisher = University Science Books | location = Mill Valley, CA | year = 1994 | isbn = 0-935702-73-3 }}

:File:PicketFenceGenericRevised.png. The R groups flank the O₂-binding site.]]

References

External links

{{OMIM|160000}} human genetics
[https://web.archive.org/web/20060623011231/http://pdbdev.sdsc.edu:48346/pdb/molecules/mb1.html RCSB PDB featured molecule]
[https://www.nytimes.com/2006/02/21/national/21meat.html "Which Cut Is Older? (It's a Trick Question)"], The New York Times, February 21, 2006 article regarding meat industry use of carbon monoxide to keep meat looking red.
[https://www.nytimes.com/2006/03/01/dining/01meat.html "Stores React to Meat Reports"], The New York Times, March 1, 2006 article on the use of carbon monoxide to make meat appear fresh.
{{PDBe-KB2|P02144|Human Myoglobin}}

Category:Hemoproteins

Category:Human proteins