The wordhaem is derived fromGreekαἷμαhaima 'blood'.
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
Hemoproteins have diverse biological functions including the transportation ofdiatomic gases, chemicalcatalysis, diatomic gas detection, andelectron transfer. The heme iron serves as a source or sink of electrons during electron transfer orredox chemistry. Inperoxidase reactions, theporphyrinmolecule also serves as an electron source, being able to delocalize radical electrons in the conjugated ring. In the transportation or detection of diatomic gases, the gas binds to the heme iron. During the detection of diatomic gases, the binding of the gasligand to the heme iron inducesconformational changes in the surrounding protein.[10] In general, diatomic gases only bind to the reduced heme, as ferrous Fe(II) while most peroxidases cycle between Fe(III) and Fe(IV) and hemeproteins involved in mitochondrial redox, oxidation-reduction, cycle between Fe(II) and Fe(III).
Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix.[12] For example, the ability ofhemoglobin to effectively deliveroxygen totissues is due to specificamino acid residues located near the heme molecule.[13] Hemoglobin reversibly binds to oxygen in the lungs when thepH is high, and thecarbon dioxide concentration is low. When the situation is reversed (low pH and high carbon dioxide concentrations), hemoglobin will release oxygen into the tissues. This phenomenon, which states that hemoglobin's oxygenbinding affinity isinversely proportional to bothacidity and concentration of carbon dioxide, is known as theBohr effect.[14] The molecularmechanism behind this effect is thesteric organization of theglobin chain; ahistidine residue, located adjacent to the heme group, becomes positively charged under acidic conditions (which are caused bydissolved CO2 in working muscles, etc.), releasing oxygen from the heme group.[15]
Structure of Fe-porphyrin subunit of heme B.Structure of Fe-porphyrin subunit of heme A.[16] Heme A is synthesized from heme B. In two sequential reactions a 17-hydroxyethylfarnesyl moiety is added at the 2-position and an aldehyde is added at the 8-position.[17]
The most common type isheme B; other important types includeheme A andheme C. Isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion ofcytochrome c oxidase.[18]
The following carbon numbering system of porphyrins is an older numbering used by biochemists and not the 1–24 numbering system recommended byIUPAC, which is shown in the table above.
Hemel is the derivative of heme B which is covalently attached to the protein oflactoperoxidase,eosinophil peroxidase, andthyroid peroxidase. The addition ofperoxide with theglutamyl-375 andaspartyl-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively.[19] Similar ester bonds with these two methyl groups are thought to form in eosinophil and thyroid peroxidases. Hemel is one important characteristic of animal peroxidases; plant peroxidases incorporate heme B. Lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones. Because lactoperoxidase destroys invading organisms in the lungs and excrement, it is thought to be an important protective enzyme.[20]
Hemem is the derivative of heme B covalently bound at the active site ofmyeloperoxidase. Hemem contains the twoester bonds at the heme 1- and 5-methyl groups also present in hemel of other mammalian peroxidases, such as lactoperoxidase and eosinophil peroxidase. In addition, a uniquesulfonamide ion linkage between the sulfur of a methionyl amino-acid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizingchloride andbromide ions to hypochlorite and hypobromite.Myeloperoxidase is present in mammalianneutrophils and is responsible for the destruction of invading bacteria and viral agents. It perhaps synthesizeshypobromite by "mistake". Both hypochlorite and hypobromite are very reactive species responsible for the production of halogenated nucleosides, which are mutagenic compounds.[21][22]
Heme D is another derivative of heme B, but in which thepropionic acid side chain at the carbon of position 6, which is also hydroxylated, forms a γ-spirolactone. Ring III is also hydroxylated at position 5, in a conformationtrans to the new lactone group.[23] Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension.[24]
Heme S is related to heme B by having aformyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of a few species of marine worms. The correct structures of heme B and heme S were first elucidated by German chemistHans Fischer.[25]
The names ofcytochromes typically (but not always) reflect the kinds of hemes they contain: cytochrome a contains heme A, cytochrome c contains heme C, etc. This convention may have been first introduced with the publication of the structure ofheme A.
Use of capital letters to designate the type of heme
The practice of designating hemes with upper case letters was formalized in a footnote in a paper by Puustinen and Wikstrom,[26] 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 bH, bL, 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."[27] In a later paper,[28] Caughey's group uses capital letters for isolated heme B and C as well as A.
The enzymatic process that produces heme is properly calledporphyrin synthesis, as all the intermediates aretetrapyrroles that are chemically classified as porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. Inbacteria, it also produces more complex substances such ascofactor F430 andcobalamin (vitamin B12).[29]
The pathway is initiated by the synthesis ofδ-aminolevulinic acid (dALA or δALA) from theamino acidglycine andsuccinyl-CoA from thecitric 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 ofheme arginate orhematin and glucose can abort attacks ofacute intermittent porphyria in patients with aninborn error of metabolism of this process, by reducing transcription of ALA synthase.[30]
The organs mainly involved in heme synthesis are theliver (in which the rate of synthesis is highly variable, depending on the systemic heme pool) and thebone 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 asemopexin (Hx) are required to help maintain physiological stores of iron in order for them to be used in synthesis.[31] Heme is seen as an intermediate molecule in catabolism of hemoglobin in the process ofbilirubin metabolism. Defects in various enzymes in synthesis of heme can lead to group of disorder called porphyrias, which includeacute intermittent porphyria,congenital erythropoetic porphyria,porphyria cutanea tarda,hereditary coproporphyria,variegate porphyria, anderythropoietic protoporphyria.[32]
Impossible Foods, producers of plant-basedmeat substitutes, use an accelerated heme synthesis process involving soybean rootleghemoglobin andyeast, adding the resulting heme to items such as meatless (vegan) Impossible burger patties. The DNA forleghemoglobin production was extracted from the soybean root nodules and expressed in yeast cells to overproduce heme for use in the meatless burgers.[33] This process claims to create a meaty flavor in the resulting products.[34][35]
Degradation begins inside macrophages of thespleen, which remove old and damagederythrocytes from the circulation.
In the first step, heme is converted tobiliverdin by the enzymeheme oxygenase (HO).[36]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 theferrous ion (Fe2+).[37] CO acts as a cellular messenger and functions in vasodilation.[38]
In addition, heme degradation appears to be an evolutionarily-conserved response tooxidative stress. Briefly, when cells are exposed tofree radicals, there is a rapid induction of the expression of the stress-responsiveheme oxygenase-1 (HMOX1) isoenzyme that catabolizes heme (see below).[39] 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.[31]
Bilirubin is transported into the liver by facilitated diffusion bound to a protein (serum albumin), where it is conjugated withglucuronic acid to become more water-soluble. The reaction is catalyzed by the enzyme UDP-glucuronosyltransferase.[41]
This form of bilirubin is excreted from the liver inbile. Excretion of bilirubin from liver to biliary canaliculi is an active, energy-dependent and rate-limiting process. Theintestinal bacteria deconjugatebilirubin diglucuronide releasing free bilirubin, which can either be reabsorbed or reduced tourobilinogen by the bacterial enzyme bilirubin reductase.[42]
Some urobilinogen is absorbed by intestinal cells and transported into thekidneys and excreted withurine (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 tostercobilinogen. This is oxidized tostercobilin, which is excreted and is responsible for the brown color offeces.[43]
Underhomeostasis, the reactivity of heme is controlled by its insertion into the "heme pockets" of hemoproteins.[citation needed] Under oxidative stress however, some hemoproteins, e.g. hemoglobin, can release their heme prosthetic groups.[44][45] 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 aFenton's reagent to catalyze in an unfettered manner the production of free radicals.[46] 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.[47] These properties of free heme can sensitize a variety of cell types to undergoprogrammed cell death in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such asmalaria[48] andsepsis.[49]
TheAmerican 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.[51] A 2019 review found that heme iron intake is associated with increasedbreast cancer risk.[52]
^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.ISBN1-57259-153-6.)
^Milani M (2005). "Structural bases for heme binding and diatomic ligand recognition in truncated hemoglobins".J. Inorg. Biochem.99 (1):97–109.doi:10.1016/j.jinorgbio.2004.10.035.PMID15598494.
^Hardison R (1999). "The Evolution of Hemoglobin: Studies of a very ancient protein suggest that changes in gene regulation are an important part of the evolutionary story".American Scientist.87 (2): 126.doi:10.1511/1999.20.809 (inactive 11 March 2025).S2CID123532036.{{cite journal}}: CS1 maint: DOI inactive as of March 2025 (link)
^Hegg EL (2004). "Heme A Synthase Does Not Incorporate Molecular Oxygen into the Formyl Group of Heme A".Biochemistry.43 (27):8616–8624.doi:10.1021/bi049056m.PMID15236569.
^abKumar S, Bandyopadhyay U (July 2005). "Free heme toxicity and its detoxification systems in human".Toxicology Letters.157 (3):175–188.doi:10.1016/j.toxlet.2005.03.004.PMID15917143.
^Kumar S, Bandyopadhyay U (July 2005). "Free heme toxicity and its detoxification systems in humans".Toxicology Letters.157 (3):175–188.doi:10.1016/j.toxlet.2005.03.004.PMID15917143.
^Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha-Rodrigues M, Portugal S, Soares MP, Mota MM (Jun 2007). "Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria".Nature Medicine.13 (6):703–710.doi:10.1038/nm1586.PMID17496899.S2CID20675040.
^Aurizi C, Lupia Palmieri G, Barbieri L, Macri A, Sorge F, Usai G, Biolcati G (February 2009). "Four novel mutations of the coproporphyrinogen III oxidase gene".Cellular and Molecular Biology.55 (1):8–15.PMID19267996.
