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[[File:Mboxygenation.png|thumb|420 px|Binding of oxygen to a heme prosthetic group]] |
[[File:Mboxygenation.png|thumb|420 px|Binding of oxygen to a heme prosthetic group]] |
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'''Heme''' ([[American English]]), or '''haem''' ([[Commonwealth English]], both pronounced /[[Help:IPA/English|hi:m]]/ {{respell|HEEM}}), is a ring-shaped iron-containing molecular [[Prosthetic_group|component of]] [[hemoglobin]], which is necessary to bind [[oxygen]] in the [[bloodstream]]. It is composed of four [[pyrrole]] rings with 2 [[Vinyl_group|vinyl]] and 2 [[propionic acid]] side chains.<ref>{{Cite book |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780124201699000084 |title=Dictionary of Toxicology |publisher=Academic Press |year=2015 |isbn=978-0-12-420169-9 |editor-last=Hodgson |editor-first=Ernest |edition=3rd |pages=173–184 |language=en |chapter=H |doi=10.1016/B978-0-12-420169-9.00008-4 |access-date=2024-02-21 |editor-last2=Roe |editor-first2=R. Michael |editor-last3=Mailman |editor-first3=Richard B |editor-last4=Chambers |editor-first4=Janice E}}</ref> Heme is [[biosynthesized]] in both the [[bone marrow]] and the [[liver]].<ref name="bloomer98">{{cite journal|doi=10.1111/j.1440-1746.1998.01548.x|title=Liver metabolism of porphyrins and haem|year=1998|last1=Bloomer|first1=Joseph R.|journal=Journal of Gastroenterology and Hepatology|volume=13|issue=3|pages=324–329|pmid=9570250|s2cid=25224821|doi-access=free}}</ref> |
'''Heme''' ([[American English]]), or '''haem''' ([[Commonwealth English]], both pronounced /[[Help:IPA/English|hi:m]]/ {{respell|HEEM}}), is a ring-shaped iron-containing molecular [[Prosthetic_group|component of]] [[hemoglobin]], which is necessary to bind [[oxygen]] in the [[bloodstream]]. It is composed of four [[pyrrole]] rings with 2 [[Vinyl_group|vinyl]] and 2 [[propionic acid]] side chains.<ref>{{Cite book |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780124201699000084 |title=Dictionary of Toxicology |publisher=Academic Press |year=2015 |isbn=978-0-12-420169-9 |editor-last=Hodgson |editor-first=Ernest |edition=3rd |pages=173–184 |language=en |chapter=H |doi=10.1016/B978-0-12-420169-9.00008-4 |access-date=2024-02-21 |editor-last2=Roe |editor-first2=R. Michael |editor-last3=Mailman |editor-first3=Richard B |editor-last4=Chambers |editor-first4=Janice E}}</ref> Heme is [[biosynthesized]] in both the [[bone marrow]] and the [[liver]].<ref name="bloomer98">{{cite journal|doi=10.1111/j.1440-1746.1998.01548.x|title=Liver metabolism of porphyrins and haem|year=1998|last1=Bloomer|first1=Joseph R.|journal=Journal of Gastroenterology and Hepatology|volume=13|issue=3|pages=324–329|pmid=9570250|s2cid=25224821|doi-access=free}}</ref> |
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Heme plays a critical role in multiple different [[redox]] reactions in |
Heme plays a critical role in multiple different [[redox]] reactions in mammal, due to its ability to carry the oxygen moiety. Reactions include [[oxidative metabolism]] ([[Cytochrome_c_oxidase|cytochrome c oxidase]], [[succinate dehydrogenase]]), [[xenobiotic]] [[detoxification]] via [[cytochrome P450]] pathways (including [[Drug_metabolism|metabolism]] of some drugs), gas sensing ([[Guanylate_cyclase|guanyl cyclases]], [[nitric oxide]] synthase), and [[microRNA]] processing (DGCR8).<ref>{{Cite journal |last1=Dutt |first1=Sohini |last2=Hamza |first2=Iqbal |last3=Bartnikas |first3=Thomas Benedict |date=2022-08-22 |title=Molecular Mechanisms of Iron and Heme Metabolism |journal=Annual Review of Nutrition |language=en |volume=42 |issue=1 |pages=311–335 |doi=10.1146/annurev-nutr-062320-112625 |issn=0199-9885 |pmc=9398995 |pmid=35508203}}</ref><ref>{{Citation |last1=Ogun |first1=Aminat S. |title=Biochemistry, Heme Synthesis |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK537329/ |access-date=2024-02-22 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30726014 |last2=Joy |first2=Neena V. |last3=Valentine |first3=Menogh}}</ref> |
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Heme is a [[coordination complex]] "consisting of an iron ion coordinated to a [[ |
Heme is a [[coordination complex]] "consisting of an iron ion coordinated to a tetra-[[porphyrin]] acting as a [[tetradentate ligand]], and to one or two axial ligands".<ref>{{cite book|chapter-url=https://goldbook.iupac.org/html/H/H02773.html|title=IUPAC Compendium of Chemical Terminology|first=International Union of Pure and Applied|last=Chemistry|publisher=IUPAC|access-date=28 April 2018|doi=10.1351/goldbook.H02773|url-status=live|archive-url=https://web.archive.org/web/20170822011820/http://goldbook.iupac.org/html/H/H02773.html|archive-date=22 August 2017|chapter=Hemes (heme derivatives)|year=2009|isbn=978-0-9678550-9-7}}</ref> The definition is loose, and many depictions omit the axial ligands.<ref>A standard biochemistry text defines heme as the "iron-porphyrin prosthetic group of heme proteins"(Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. {{ISBN|1-57259-153-6}}.)</ref> Among the metalloporphyrins deployed by [[metalloprotein]]s as [[prosthetic group]]s, heme is one of the most widely used<ref>{{Cite journal|last=Poulos|first=Thomas L.|date=2014-04-09|title=Heme Enzyme Structure and Function|url=|journal=Chemical Reviews|language=en|volume=114|issue=7|pages=3919–3962|doi=10.1021/cr400415k|issn=0009-2665|pmc=3981943|pmid=24400737}}</ref> and defines a family of proteins known as [[hemoprotein]]s. Hemes are most commonly recognized as components of [[hemoglobin]], the red [[pigment]] in [[blood]], but are also found in a number of other [[biologically]] important hemoproteins such as [[myoglobin]], [[cytochrome]]s, [[catalase]]s, [[heme peroxidase]], and [[Endothelial NOS|endothelial nitric oxide synthase]].<ref>{{cite journal|last=Paoli|first= M.|title=Structure-function relationships in heme-proteins.|journal=DNA Cell Biol.|year=2002|volume=21|issue=4|pages= 271–280|pmid=12042067|doi=10.1089/104454902753759690|hdl= 20.500.11820/67200894-eb9f-47a2-9542-02877d41fdd7|s2cid= 12806393|url= https://www.pure.ed.ac.uk/ws/files/9103491/Paoli_Marles_Wright_Smith_2002_Structure_function_relationships_in_heme_proteins.pdf|archive-url=https://web.archive.org/web/20180724145314/https://www.pure.ed.ac.uk/ws/files/9103491/Paoli_Marles_Wright_Smith_2002_Structure_function_relationships_in_heme_proteins.pdf|archive-date=2018-07-24|url-status=live}}</ref><ref>{{cite journal|last=Alderton|first= W.K.|title=Nitric oxide synthases: structure, function and inhibition.|journal=Biochem. J.|year=2001|volume=357|issue=3|pages= 593–615|pmid=11463332|doi=10.1042/bj3570593|pmc=1221991}}</ref> |
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The word ''haem'' is derived from [[Ancient Greek language|Greek]] {{lang|grc|αἷμα}} ''haima'' 'blood'. |
The word ''haem'' is derived from [[Ancient Greek language|Greek]] {{lang|grc|αἷμα}} ''haima'' meaning 'blood'. |
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[[Image:Haem-B-3D-vdW.png|thumb|right|200px|[[Space-filling model]] of the Fe-[[protoporphyrin IX]] subunit of heme B. Axial ligands omitted. Color scheme: grey=iron, blue=nitrogen, black=carbon, white=hydrogen, red=oxygen]] |
[[Image:Haem-B-3D-vdW.png|thumb|right|200px|[[Space-filling model]] of the Fe-[[protoporphyrin IX]] subunit of heme B. Axial ligands omitted. Color scheme: grey=iron, blue=nitrogen, black=carbon, white=hydrogen, red=oxygen]] |
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===Use of capital letters to designate the type of heme=== |
===Use of capital letters to designate the type of heme=== |
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The practice of designating hemes with upper case letters was formalized in a footnote in a paper by Puustinen and Wikstrom,<ref>{{cite journal|pmid=2068092|pmc=52034|title=The heme groups of cytochrome o from Escherichia coli|author = Puustinen A, Wikström M.|journal = Proc. Natl. Acad. Sci. U.S.A.|volume = 88|issue=14|pages = 6122–6|year = 1991 |bibcode=1991PNAS...88.6122P|doi=10.1073/pnas.88.14.6122|doi-access=free}}</ref> which explains under which conditions a capital letter should be used: "we prefer the use of capital letters to describe the heme structure as isolated. Lowercase letters may then be freely used for cytochromes and enzymes, as well as to describe individual protein-bound heme groups (for example, cytochrome bc, and aa3 complexes, cytochrome b<sub>5</sub>, heme c<sub>1</sub> of the bc<sub>1</sub> complex, heme a<sub>3</sub> of the aa<sub>3</sub> complex, etc)." In other words, the chemical compound would be designated with a capital letter, but specific instances in structures with lowercase. Thus cytochrome oxidase, which has two A hemes (heme a and heme a<sub>3</sub>) in its structure, contains two moles of heme A per mole protein. Cytochrome bc<sub>1</sub>, with hemes b<sub>H</sub>, b<sub>L</sub>, and c<sub>1</sub>, contains heme B and heme C in a 2:1 ratio. The practice seems to have originated in a paper by Caughey and York in which the product of a new isolation procedure for the heme of cytochrome aa3 was designated heme A to differentiate it from previous preparations: "Our product is not identical in all respects with the heme a obtained in solution by other workers by the reduction of the hemin a as isolated previously (2). For this reason, we shall designate our product heme A until the apparent differences can be rationalized."<ref>{{cite journal|title=Isolation and some properties of the green heme of cytochrome oxidase from beef heart muscle.|vauthors=Caughey WS, York JL|journal = J. Biol. Chem.|volume = 237|pages = 2414–6|year = 1962|issue=7|doi=10.1016/S0021-9258(19)63456-3|pmid=13877421|doi-access=free}}</ref> In a later paper,<ref>{{cite journal|title=Heme A of cytochrome c oxidase. Structure and properties: comparisons with hemes B, C, and S and derivatives|vauthors=Caughey WS, Smythe GA, O'Keeffe DH, Maskasky JE, Smith ML|journal = J. Biol. Chem.|volume = 250|issue = 19|pages = 7602–22|year = 1975|doi=10.1016/S0021-9258(19)40860-0|pmid=170266|doi-access=free}}</ref> Caughey's group uses capital letters for isolated heme B and C as well as A. |
The practice of designating hemes with upper case letters was formalized in a footnote in a paper by Puustinen and Wikstrom,<ref>{{cite journal|pmid=2068092|pmc=52034|title=The heme groups of cytochrome o from Escherichia coli|author = Puustinen A, Wikström M.|journal = Proc. Natl. Acad. Sci. U.S.A.|volume = 88|issue=14|pages = 6122–6|year = 1991 |bibcode=1991PNAS...88.6122P|doi=10.1073/pnas.88.14.6122|doi-access=free}}</ref> which explains under which conditions a capital letter should be used: "we prefer the use of capital letters to describe the heme structure as isolated. Lowercase letters may then be freely used for cytochromes and enzymes, as well as to describe individual protein-bound heme groups (for example, cytochrome bc, and aa3 complexes, cytochrome b<sub>5</sub>, heme c<sub>1</sub> of the bc<sub>1</sub> complex, heme a<sub>3</sub> of the aa<sub>3</sub> complex, etc)." In other words, the chemical compound would be designated with a capital letter, but specific instances in structures with lowercase. Thus cytochrome oxidase, which has two A hemes (heme a and heme a<sub>3</sub>) in its structure, contains two moles of heme A per mole protein. Cytochrome bc<sub>1</sub>, with hemes b<sub>H</sub>, b<sub>L</sub>, and c<sub>1</sub>, contains heme B and heme C in a 2:1 ratio. The practice seems to have originated in a paper by Caughey and York in which the product of a new isolation procedure for the heme of cytochrome aa3 was designated heme A to differentiate it from previous preparations: "Our product is not identical in all respects with the heme a obtained in solution by other workers by the reduction of the hemin a as isolated previously (2). For this reason, we shall designate our product heme A until the apparent differences can be rationalized.".<ref>{{cite journal|title=Isolation and some properties of the green heme of cytochrome oxidase from beef heart muscle.|vauthors=Caughey WS, York JL|journal = J. Biol. Chem.|volume = 237|pages = 2414–6|year = 1962|issue=7|doi=10.1016/S0021-9258(19)63456-3|pmid=13877421|doi-access=free}}</ref> In a later paper,<ref>{{cite journal|title=Heme A of cytochrome c oxidase. Structure and properties: comparisons with hemes B, C, and S and derivatives|vauthors=Caughey WS, Smythe GA, O'Keeffe DH, Maskasky JE, Smith ML|journal = J. Biol. Chem.|volume = 250|issue = 19|pages = 7602–22|year = 1975|doi=10.1016/S0021-9258(19)40860-0|pmid=170266|doi-access=free}}</ref> Caughey's group uses capital letters for isolated heme B and C as well as A. |
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==Synthesis== |
==Synthesis== |
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The pathway is initiated by the synthesis of [[δ-aminolevulinic acid]] (dALA or δALA) from the [[amino acid]] [[glycine]] and [[succinyl-CoA]] from the [[citric acid cycle]] (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ''ALA synthase'', is negatively regulated by glucose and heme concentration. Mechanism of inhibition of ALAs by heme or hemin is by decreasing stability of mRNA synthesis and by decreasing the intake of mRNA in the mitochondria. This mechanism is of therapeutic importance: infusion of ''heme arginate'' or ''hematin'' and glucose can abort attacks of [[acute intermittent porphyria]] in patients with an [[inborn error of metabolism]] of this process, by reducing transcription of ALA synthase.<ref>{{cite thesis|url=http://escholarship.umassmed.edu/gsbs_diss/121/|title=Upregulation of Heme Pathway Enzyme ALA Synthase-1 by Glutethimide and 4,6-Dioxoheptanoic Acid and Downregulation by Glucose and Heme: A Dissertation|first=Kolluri|last=Sridevi|date=28 April 2018|journal=EScholarship@UMMS|access-date=28 April 2018|url-status=live|archive-url=https://web.archive.org/web/20160808080738/http://escholarship.umassmed.edu/gsbs_diss/121/|archive-date=8 August 2016|doi=10.13028/yyrz-qa79|publisher=University of Massachusetts Medical School}}</ref> |
The pathway is initiated by the synthesis of [[δ-aminolevulinic acid]] (dALA or δALA) from the [[amino acid]] [[glycine]] and [[succinyl-CoA]] from the [[citric acid cycle]] (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ''ALA synthase'', is negatively regulated by glucose and heme concentration. Mechanism of inhibition of ALAs by heme or hemin is by decreasing stability of mRNA synthesis and by decreasing the intake of mRNA in the mitochondria. This mechanism is of therapeutic importance: infusion of ''heme arginate'' or ''hematin'' and glucose can abort attacks of [[acute intermittent porphyria]] in patients with an [[inborn error of metabolism]] of this process, by reducing transcription of ALA synthase.<ref>{{cite thesis|url=http://escholarship.umassmed.edu/gsbs_diss/121/|title=Upregulation of Heme Pathway Enzyme ALA Synthase-1 by Glutethimide and 4,6-Dioxoheptanoic Acid and Downregulation by Glucose and Heme: A Dissertation|first=Kolluri|last=Sridevi|date=28 April 2018|journal=EScholarship@UMMS|access-date=28 April 2018|url-status=live|archive-url=https://web.archive.org/web/20160808080738/http://escholarship.umassmed.edu/gsbs_diss/121/|archive-date=8 August 2016|doi=10.13028/yyrz-qa79|publisher=University of Massachusetts Medical School}}</ref> |
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The organs mainly involved in heme synthesis are the [[liver]] (in which the rate of synthesis is highly variable, depending on the systemic heme pool) and the [[bone marrow]] (in which rate of synthesis of Heme is relatively constant and depends on the production of globin chain), although every cell requires heme to function properly. However, due to its toxic properties, proteins such as [[emopexin]] (Hx) are required to help maintain physiological stores of iron in order for them to be used in synthesis.<ref name="ReferenceA">{{cite journal|last1=Kumar|first1=Sanjay|last2=Bandyopadhyay|first2=Uday|title=Free heme toxicity and its detoxification systems in human|journal=Toxicology Letters|date=July 2005|volume=157|issue=3|pages=175–188|doi=10.1016/j.toxlet.2005.03.004|pmid=15917143}}</ref> Heme is seen as an intermediate molecule in catabolism of hemoglobin in the process of [[bilirubin metabolism]]. Defects in various enzymes in synthesis of heme can lead to group of disorder called porphyrias, |
The organs mainly involved in heme synthesis are the [[liver]] (in which the rate of synthesis is highly variable, depending on the systemic heme pool) and the [[bone marrow]] (in which rate of synthesis of Heme is relatively constant and depends on the production of globin chain), although every cell requires heme to function properly. However, due to its toxic properties, proteins such as [[emopexin]] (Hx) are required to help maintain physiological stores of iron in order for them to be used in synthesis.<ref name="ReferenceA">{{cite journal|last1=Kumar|first1=Sanjay|last2=Bandyopadhyay|first2=Uday|title=Free heme toxicity and its detoxification systems in human|journal=Toxicology Letters|date=July 2005|volume=157|issue=3|pages=175–188|doi=10.1016/j.toxlet.2005.03.004|pmid=15917143}}</ref> Heme is seen as an intermediate molecule in catabolism of hemoglobin in the process of [[bilirubin metabolism]]. Defects in various enzymes in synthesis of heme can lead to group of disorder called porphyrias, these include [[acute intermittent porphyria]], [[congenital erythropoetic porphyria]], [[porphyria cutanea tarda]], [[hereditary coproporphyria]], [[variegate porphyria]], [[erythropoietic protoporphyria]].<ref>{{Cite journal|last1=Puy|first1=Hervé|last2=Gouya|first2=Laurent|last3=Deybach|first3=Jean-Charles|date=March 2010|title=Porphyrias|url=https://linkinghub.elsevier.com/retrieve/pii/S0140673609619255|journal=The Lancet|language=en|volume=375|issue=9718|pages=924–937|doi=10.1016/S0140-6736(09)61925-5|pmid=20226990|s2cid=208791867}}</ref>{{Citation needed|date=December 2016}} |
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==Synthesis for food== |
==Synthesis for food== |
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==In health and disease== |
==In health and disease== |
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Under [[homeostasis]], the reactivity of heme is controlled by its insertion into the "heme pockets" of hemoproteins.{{Citation needed|date=December 2016}} Under oxidative stress however, some hemoproteins, e.g. hemoglobin, can release their heme prosthetic groups.<ref>{{cite journal|last1 = Bunn|first1 = H. F.|last2 = Jandl|first2 = J. H.|date = Sep 1966|title = Exchange of heme among hemoglobin molecules|journal = Proc. Natl. Acad. Sci. USA|volume = 56|issue = 3|pages = 974–978|pmid = 5230192|doi = 10.1073/pnas.56.3.974|pmc=219955|bibcode = 1966PNAS...56..974B|doi-access = free}}</ref><ref>{{cite journal|last1 = Smith|first1 = M. L.|last2 = Paul|first2 = J.|last3 = Ohlsson|first3 = P. I.|last4 = Hjortsberg|first4 = K.|last5 = Paul|first5 = K. G.|date = Feb 1991|title = Heme-protein fission under nondenaturing conditions|journal = Proc. Natl. Acad. Sci. USA|volume = 88|issue = 3|pages = 882–886|pmid = 1846966|doi=10.1073/pnas.88.3.882|bibcode = 1991PNAS...88..882S|pmc=50918|doi-access = free}}</ref> The non-protein-bound (free) heme produced in this manner becomes highly cytotoxic, most probably due to the iron atom contained within its protoporphyrin IX ring, which can act as a [[Fenton's reagent]] to catalyze in an unfettered manner the production of free radicals.<ref>{{cite journal|last1=Everse|first1=J.|first2=N.|last2=Hsia|title = The toxicities of native and modified hemoglobins|journal = Free Radical Biology and Medicine|volume = 22|issue = 6|pages = 1075–1099|date=1197|pmid = 9034247|doi = 10.1016/S0891-5849(96)00499-6}}</ref> It catalyzes the oxidation and aggregation of protein, the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Due to its lipophilic properties, it impairs lipid bilayers in organelles such as mitochondria and nuclei.<ref>{{cite journal|last1=Kumar|first1=Sanjay|last2=Bandyopadhyay|first2=Uday|title=Free heme toxicity and its detoxification systems in humans|journal=Toxicology Letters|date=July 2005|volume=157|issue=3|pages=175–188|doi=10.1016/j.toxlet.2005.03.004|pmid=15917143}}</ref> These properties of free heme can sensitize a variety of cell types to undergo [[programmed cell death]] in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such as [[malaria]]<ref name="pmid17496899">{{cite journal|last1=Pamplona|first1=A.|last2=Ferreira|first2=A.|last3=Balla|first3=J.|last4=Jeney|first4=V.|last5=Balla|first5=G.|last6=Epiphanio|first6=S.|last7=Chora|first7=A.|last8=Rodrigues|first8=C. D.|last9=Gregoire|first9=I. P.|last10=Cunha-Rodrigues|first10=M.|last11=Portugal|first11=S.|last12=Soares|first12=M. P.|last13=Mota|first13=M. M.|title = Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria|journal = Nature Medicine|volume = 13|issue = 6|pages = 703–710|date=Jun 2007|pmid = 17496899|doi = 10.1038/nm1586|s2cid=20675040}}</ref> and [[sepsis]].<ref>{{Cite journal |
Under [[homeostasis]], the reactivity of heme is controlled by its insertion into the "heme pockets" of hemoproteins.{{Citation needed|date=December 2016}} Under oxidative stress however, some hemoproteins, e.g. hemoglobin, can release their heme prosthetic groups.<ref>{{cite journal|last1 = Bunn|first1 = H. F.|last2 = Jandl|first2 = J. H.|date = Sep 1966|title = Exchange of heme among hemoglobin molecules|journal = Proc. Natl. Acad. Sci. USA|volume = 56|issue = 3|pages = 974–978|pmid = 5230192|doi = 10.1073/pnas.56.3.974|pmc=219955|bibcode = 1966PNAS...56..974B|doi-access = free}}</ref><ref>{{cite journal|last1 = Smith|first1 = M. L.|last2 = Paul|first2 = J.|last3 = Ohlsson|first3 = P. I.|last4 = Hjortsberg|first4 = K.|last5 = Paul|first5 = K. G.|date = Feb 1991|title = Heme-protein fission under nondenaturing conditions|journal = Proc. Natl. Acad. Sci. USA|volume = 88|issue = 3|pages = 882–886|pmid = 1846966|doi=10.1073/pnas.88.3.882|bibcode = 1991PNAS...88..882S|pmc=50918|doi-access = free}}</ref> The non-protein-bound (free) heme produced in this manner becomes highly cytotoxic, most probably due to the iron atom contained within its protoporphyrin IX ring, which can act as a [[Fenton chemistry|Fenton's reagent]] to catalyze in an unfettered manner the production of free radicals.<ref>{{cite journal|last1=Everse|first1=J.|first2=N.|last2=Hsia|title = The toxicities of native and modified hemoglobins|journal = Free Radical Biology and Medicine|volume = 22|issue = 6|pages = 1075–1099|date=1197|pmid = 9034247|doi = 10.1016/S0891-5849(96)00499-6}}</ref> It catalyzes the oxidation and aggregation of protein, the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Due to its lipophilic properties, it impairs lipid bilayers in organelles such as mitochondria and nuclei.<ref>{{cite journal|last1=Kumar|first1=Sanjay|last2=Bandyopadhyay|first2=Uday|title=Free heme toxicity and its detoxification systems in humans|journal=Toxicology Letters|date=July 2005|volume=157|issue=3|pages=175–188|doi=10.1016/j.toxlet.2005.03.004|pmid=15917143}}</ref> These properties of free heme can sensitize a variety of cell types to undergo [[programmed cell death]] in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such as [[malaria]]<ref name="pmid17496899">{{cite journal|last1=Pamplona|first1=A.|last2=Ferreira|first2=A.|last3=Balla|first3=J.|last4=Jeney|first4=V.|last5=Balla|first5=G.|last6=Epiphanio|first6=S.|last7=Chora|first7=A.|last8=Rodrigues|first8=C. D.|last9=Gregoire|first9=I. P.|last10=Cunha-Rodrigues|first10=M.|last11=Portugal|first11=S.|last12=Soares|first12=M. P.|last13=Mota|first13=M. M.|title = Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria|journal = Nature Medicine|volume = 13|issue = 6|pages = 703–710|date=Jun 2007|pmid = 17496899|doi = 10.1038/nm1586|s2cid=20675040}}</ref> and [[sepsis]].<ref>{{Cite journal |
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|pmid = 20881280 |
|pmid = 20881280 |
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|year = 2010 |
|year = 2010 |
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There is an association between high intake of heme iron sourced from meat and increased risk of [[colorectal cancer]].<ref>{{Cite journal |last1=Bastide |first1=Nadia M. |last2=Pierre |first2=Fabrice H. F. |last3=Corpet |first3=Denis E. |date=Feb 2011 |title=Heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved |url=https://pubmed.ncbi.nlm.nih.gov/21209396/ |journal=Cancer Prevention Research (Philadelphia, Pa.) |volume=4 |issue=2 |pages=177–184 |doi=10.1158/1940-6207.CAPR-10-0113 |issn=1940-6215 |pmid=21209396}}</ref> |
There is an association between high intake of heme iron sourced from meat and increased risk of [[colorectal cancer]].<ref>{{Cite journal |last1=Bastide |first1=Nadia M. |last2=Pierre |first2=Fabrice H. F. |last3=Corpet |first3=Denis E. |date=Feb 2011 |title=Heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved |url=https://pubmed.ncbi.nlm.nih.gov/21209396/ |journal=Cancer Prevention Research (Philadelphia, Pa.) |volume=4 |issue=2 |pages=177–184 |doi=10.1158/1940-6207.CAPR-10-0113 |issn=1940-6215 |pmid=21209396}}</ref> |
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The [[American Institute for Cancer Research]] (AICR) and World Cancer Research Fund International (WCRF) concluded in a 2018 report that there is limited but suggestive evidence that foods containing heme iron increase risk of colorectal cancer.<ref>[https://www.wcrf.org/wp-content/uploads/2021/02/Colorectal-cancer-report.pdf "Diet, nutrition, physical activity and colorectal cancer"]. wcrf.org. Retrieved 12 February 2022.</ref> A 2019 review found that heme iron intake is associated with increased [[breast cancer]] risk.<ref>{{cite journal|author=Chang, Vicky C; Cotterchio, Michelle; Khoo, Edwin|year=2019|title=Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis|journal=[[BMC Cancer]]|volume=19|issue=1|pages=543|doi=10.1186/s12885-019-5642-0|pmid=31170936|pmc=6555759|doi-access=free}}</ref> |
The [[American Institute for Cancer Research]] (AICR) and [[World Cancer Research Fund International]] (WCRF) concluded in a 2018 report that there is limited but suggestive evidence that foods containing heme iron increase risk of colorectal cancer.<ref>[https://www.wcrf.org/wp-content/uploads/2021/02/Colorectal-cancer-report.pdf "Diet, nutrition, physical activity and colorectal cancer"]. wcrf.org. Retrieved 12 February 2022.</ref> A 2019 review found that heme iron intake is associated with increased [[breast cancer]] risk.<ref>{{cite journal|author=Chang, Vicky C; Cotterchio, Michelle; Khoo, Edwin|year=2019|title=Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis|journal=[[BMC Cancer]]|volume=19|issue=1|pages=543|doi=10.1186/s12885-019-5642-0|pmid=31170936|pmc=6555759|doi-access=free}}</ref> |
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==Genes== |
==Genes== |
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Symbols: ~ | ¡ ¿ † ‡ ↔ ↑ ↓ • ¶ # ∞ ‹› «» ¤ ₳ ฿ ₵ ¢ ₡ ₢ $ ₫ ₯ € ₠ ₣ ƒ ₴ ₭ ₤ ℳ ₥ ₦ № ₧ ₰ £ ៛ ₨ ₪ ৳ ₮ ₩ ¥ ♠ ♣ ♥ ♦ 𝄫 ♭ ♮ ♯ 𝄪 © ® ™
Latin: A a Á á À à  â Ä ä Ǎ ǎ Ă ă Ā ā à ã Å å Ą ą Æ æ Ǣ ǣ B b C c Ć ć Ċ ċ Ĉ ĉ Č č Ç ç D d Ď ď Đ đ Ḍ ḍ Ð ð E e É é È è Ė ė Ê ê Ë ë Ě ě Ĕ ĕ Ē ē Ẽ ẽ Ę ę Ẹ ẹ Ɛ ɛ Ǝ ǝ Ə ə F f G g Ġ ġ Ĝ ĝ Ğ ğ Ģ ģ H h Ĥ ĥ Ħ ħ Ḥ ḥ I i İ ı Í í Ì ì Î î Ï ï Ǐ ǐ Ĭ ĭ Ī ī Ĩ ĩ Į į Ị ị J j Ĵ ĵ K k Ķ ķ L l Ĺ ĺ Ŀ ŀ Ľ ľ Ļ ļ Ł ł Ḷ ḷ Ḹ ḹ M m Ṃ ṃ N n Ń ń Ň ň Ñ ñ Ņ ņ Ṇ ṇ Ŋ ŋ O o Ó ó Ò ò Ô ô Ö ö Ǒ ǒ Ŏ ŏ Ō ō Õ õ Ǫ ǫ Ọ ọ Ő ő Ø ø Œ œ Ɔ ɔ P p Q q R r Ŕ ŕ Ř ř Ŗ ŗ Ṛ ṛ Ṝ ṝ S s Ś ś Ŝ ŝ Š š Ş ş Ș ș Ṣ ṣ ß T t Ť ť Ţ ţ Ț ț Ṭ ṭ Þ þ U u Ú ú Ù ù Û û Ü ü Ǔ ǔ Ŭ ŭ Ū ū Ũ ũ Ů ů Ų ų Ụ ụ Ű ű Ǘ ǘ Ǜ ǜ Ǚ ǚ Ǖ ǖ V v W w Ŵ ŵ X x Y y Ý ý Ŷ ŷ Ÿ ÿ Ỹ ỹ Ȳ ȳ Z z Ź ź Ż ż Ž ž ß Ð ð Þ þ Ŋ ŋ Ə ə
Greek: Ά ά Έ έ Ή ή Ί ί Ό ό Ύ ύ Ώ ώ Α α Β β Γ γ Δ δ Ε ε Ζ ζ Η η Θ θ Ι ι Κ κ Λ λ Μ μ Ν ν Ξ ξ Ο ο Π π Ρ ρ Σ σ ς Τ τ Υ υ Φ φ Χ χ Ψ ψ Ω ω {{Polytonic|}}
Cyrillic: А а Б б В в Г г Ґ ґ Ѓ ѓ Д д Ђ ђ Е е Ё ё Є є Ж ж З з Ѕ ѕ И и І і Ї ї Й й Ј ј К к Ќ ќ Л л Љ љ М м Н н Њ њ О о П п Р р С с Т т Ћ ћ У у Ў ў Ф ф Х х Ц ц Ч ч Џ џ Ш ш Щ щ Ъ ъ Ы ы Ь ь Э э Ю ю Я я ́
IPA: t̪ d̪ ʈ ɖ ɟ ɡ ɢ ʡ ʔ ɸ β θ ð ʃ ʒ ɕ ʑ ʂ ʐ ç ʝ ɣ χ ʁ ħ ʕ ʜ ʢ ɦ ɱ ɳ ɲ ŋ ɴ ʋ ɹ ɻ ɰ ʙ ⱱ ʀ ɾ ɽ ɫ ɬ ɮ ɺ ɭ ʎ ʟ ɥ ʍ ɧ ʼ ɓ ɗ ʄ ɠ ʛ ʘ ǀ ǃ ǂ ǁ ɨ ʉ ɯ ɪ ʏ ʊ ø ɘ ɵ ɤ ə ɚ ɛ œ ɜ ɝ ɞ ʌ ɔ æ ɐ ɶ ɑ ɒ ʰ ʱ ʷ ʲ ˠ ˤ ⁿ ˡ ˈ ˌ ː ˑ ̪ {{IPA|}}
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