Editing Heme

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[[File:Mboxygenation.png|thumb|420 px|Binding of oxygen to a heme prosthetic group]]

'''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 plays a critical role in multiple different [[redox]] reactions in mammals, due to its ability to carry the oxygen molecule. Reactions include [[oxidative metabolism]] ([[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>

Heme is a [[coordination complex]] "consisting of an iron ion coordinated to a [[tetrapyrrole]] 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>

The word ''haem'' is derived from [[Ancient Greek language|Greek]] {{lang|grc|αἷμα}} ''haima'' 'blood'.

It has been speculated that the original evolutionary function of [[hemoproteins]] was electron transfer in primitive [[sulfur]]-based [[photosynthesis]] pathways in ancestral [[cyanobacteria]]-like [[Living organisms|organisms]] before the appearance of molecular [[oxygen]].<ref>{{cite journal|last=Hardison|first= R.|title=The Evolution of Hemoglobin: Studies of a very ancient protein suggest that changes in gene regulation are an important part of the evolutionary story|journal=American Scientist|year=1999|volume=87|issue=2|pages= 126|doi= 10.1511/1999.20.809|s2cid= 123532036}}</ref>

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 b₅, heme c₁ of the bc₁ complex, heme a₃ of the aa₃ 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 a₃) in its structure, contains two moles of heme A per mole protein. Cytochrome bc₁, with hemes b_H, b_L, and c₁, 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 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, which include [[acute intermittent porphyria]], [[congenital erythropoetic porphyria]], [[porphyria cutanea tarda]], [[hereditary coproporphyria]], [[variegate porphyria]], and [[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>

In the first step, heme is converted to [[biliverdin]] by the enzyme [[heme oxygenase]] (HO).<ref>{{Cite journal|last=Maines|first=Mahin D.|date=July 1988|title=Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications|journal=The FASEB Journal|language=en|volume=2|issue=10|pages=2557–2568|doi=10.1096/fasebj.2.10.3290025|doi-access=free |pmid=3290025|s2cid=22652094|issn=0892-6638}}</ref> [[NADPH]] is used as the reducing agent, molecular oxygen enters the reaction, [[carbon monoxide]] (CO) is produced and the iron is released from the molecule as the [[ferrous]] ion (Fe²⁺).<ref>{{Cite book|title = Lehninger's Principles of Biochemistry|edition = 5th|publisher = W. H. Freeman and Company|year = 2008|isbn = 978-0-7167-7108-1|location = New York|pages = [https://archive.org/details/lehningerprincip00lehn_1/page/876 876]|url-access = registration|url = https://archive.org/details/lehningerprincip00lehn_1/page/876}}</ref> CO acts as a cellular messenger and functions in vasodilation.<ref>{{cite journal|last=Hanafy|first= K.A.|title=Carbon Monoxide and the brain: time to rethink the dogma.|journal= Curr. Pharm. Des.|year=2013|volume=19|issue=15|pages= 2771–5|pmid=23092321|doi=10.2174/1381612811319150013|pmc=3672861}}</ref>

In addition, heme degradation appears to be an evolutionarily-conserved response to [[oxidative stress]]. Briefly, when cells are exposed to [[free radical]]s, there is a rapid induction of the expression of the stress-responsive [[heme oxygenase-1]] (HMOX1) isoenzyme that catabolizes heme (see below).<ref>{{cite journal|last1=Abraham|first1=N.G.|last2=Kappas|first2=A.|title=Pharmacological and clinical aspects of heme oxygenase.|journal= Pharmacol. Rev.|year=2008|volume=60|issue=1|pages= 79–127|pmid=18323402|doi=10.1124/pr.107.07104|s2cid=12792155}}</ref> The reason why cells must increase exponentially their capability to degrade heme in response to oxidative stress remains unclear but this appears to be part of a cytoprotective response that avoids the deleterious effects of free heme. When large amounts of free heme accumulates, the heme detoxification/degradation systems get overwhelmed, enabling heme to exert its damaging effects.<ref name="ReferenceA"/>

This form of bilirubin is excreted from the liver in [[bile]]. Excretion of bilirubin from liver to biliary canaliculi is an active, energy-dependent and rate-limiting process. The [[Gut flora|intestinal bacteria]] deconjugate [[bilirubin diglucuronide]] releasing free bilirubin, which can either be reabsorbed or reduced to [[urobilinogen]] by the bacterial enzyme bilirubin reductase.<ref>{{Cite journal |last1=Hall |first1=Brantley |last2=Levy |first2=Sophia |last3=Dufault-Thompson |first3=Keith |last4=Arp |first4=Gabriela |last5=Zhong |first5=Aoshu |last6=Ndjite |first6=Glory Minabou |last7=Weiss |first7=Ashley |last8=Braccia |first8=Domenick |last9=Jenkins |first9=Conor |last10=Grant |first10=Maggie R. |last11=Abeysinghe |first11=Stephenie |last12=Yang |first12=Yiyan |last13=Jermain |first13=Madison D. |last14=Wu |first14=Chih Hao |last15=Ma |first15=Bing |date=2024-01-03|title=BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen |journal=Nature Microbiology |volume=9 |issue=1 |pages=173–184 |language=en |doi=10.1038/s41564-023-01549-x |issn=2058-5276|doi-access=free |pmid=38172624 |pmc=10769871 }}</ref>

{{Enzymatic reaction|substrate=[[bilirubin]]|product=[[urobilinogen]]|substrate_image=Bilirubin ZZ.png|product_image=Urobilinogen.png|reaction_direction_(forward/reversible/reverse)=forward|forward_enzyme=bilirubin reductase|product_image_size=220px|substrate_image_size=220px|minor_forward_substrate(s)=4 [[NAD(P)H]] + 4 H⁺|minor_forward_product(s)=4 NAD(P)⁺|minor_reverse_substrate(s)=|minor_reverse_product(s)=|reverse_enzyme=}}

Some urobilinogen is absorbed by intestinal cells and transported into the [[kidney]]s and excreted with [[urine]] ([[urobilin]], which is the product of oxidation of urobilinogen, and is responsible for the yellow colour of urine). The remainder travels down the digestive tract and is converted to [[stercobilinogen]]. This is oxidized to [[stercobilin]], which is excreted and is responsible for the brown color of [[feces]].<ref>{{Cite web|url=https://www.thoughtco.com/why-is-urine-yellow-feces-brown-606813|title=The Chemicals Responsible for the Color of Urine and Feces|last=Helmenstine|first=Anne Marie|website=ThoughtCo|language=en|access-date=2020-01-24}}</ref>

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

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>

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>

*''[[PPOX]]'': protoporphyrinogen [[oxidase]] (deficiency causes variegate porphyria)<ref>{{Cite journal |last1=Martinez di Montemuros |first1=F. |last2=Di Pierro |first2=E. |last3=Patti |first3=E. |last4=Tavazzi |first4=D. |last5=Danielli |first5=M. G. |last6=Biolcati |first6=G. |last7=Rocchi |first7=E. |last8=Cappellini |first8=M. D. |date=December 2002 |title=Molecular characterization of porphyrias in Italy: a diagnostic flow-chart |url=https://pubmed.ncbi.nlm.nih.gov/12699245/ |journal=Cellular and Molecular Biology (Noisy-Le-Grand, France) |volume=48 |issue=8 |pages=867–876 |issn=0145-5680 |pmid=12699245}}</ref>