The word haem is derived from Greekαἷμαhaima '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 of diatomic gases, chemical catalysis, diatomic gas detection, and electron transfer. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry. In peroxidase reactions, the porphyrinmolecule 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 gas ligand to the heme iron induces conformational 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 of hemoglobin to effectively deliver oxygentotissues is due to specific amino acid residues located near the heme molecule.[13] Hemoglobin reversibly binds to oxygen in the lungs when the pH is high, and the carbon 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 oxygen binding affinityisinversely proportional to both acidity and concentration of carbon dioxide, is known as the Bohr effect.[14] The molecular mechanism behind this effect is the steric organization of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acidic conditions (which are caused by dissolved 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 is heme B; other important types include heme A and heme 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 of cytochrome 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 by IUPAC, which is shown in the table above.
Heme l is the derivative of heme B which is covalently attached to the protein of lactoperoxidase, eosinophil peroxidase, and thyroid peroxidase. The addition of peroxide with the glutamyl-375 and aspartyl-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. Heme l 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]
Heme m is the derivative of heme B covalently bound at the active site of myeloperoxidase. Heme m contains the two ester bonds at the heme 1- and 5-methyl groups also present in heme l of other mammalian peroxidases, such as lactoperoxidase and eosinophil peroxidase. In addition, a unique sulfonamide 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 oxidizing chloride and bromide ions to hypochlorite and hypobromite. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and viral agents. It perhaps synthesizes hypobromite 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 the propionic 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 conformation trans 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 a formyl 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 chemist Hans Fischer.[25]
The names of cytochromes 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 of heme A.
Use of capital letters to designate the type of heme[edit]
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 called porphyrin synthesis, as all the intermediates are tetrapyrroles that are chemically classified as porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In bacteria, it also produces more complex substances such as cofactor F430 and cobalamin (vitamin B12).[29]
The pathway is initiated by the synthesis of δ-aminolevulinic acid (dALA or δALA) from the amino acidglycine 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 arginateorhematin 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.[30]
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.[31] 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.[32]
Impossible Foods, producers of plant-based meat substitutes, use an accelerated heme synthesis process involving soybean root leghemoglobin and yeast, adding the resulting heme to items such as meatless (vegan) Impossible burger patties. The DNA for leghemoglobin 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 the spleen, which remove old and damaged erythrocytes from the circulation.
In the first step, heme is converted to biliverdin by the enzyme heme 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 the ferrous 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 to oxidative stress. Briefly, when cells are exposed to free radicals, there is a rapid induction of the expression of the stress-responsive heme 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 with glucuronic 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 in bile. Excretion of bilirubin from liver to biliary canaliculi is an active, energy-dependent and rate-limiting process. The intestinal bacteria deconjugate bilirubin diglucuronide releasing free bilirubin, which can either be reabsorbed or reduced to urobilinogen by the bacterial enzyme bilirubin reductase.[42]
Some urobilinogen is absorbed by intestinal cells and transported into the kidneys 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.[43]
Under homeostasis, 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 a Fenton'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 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[48] and sepsis.[49]
There is an association between high intake of heme iron sourced from meat and increased risk of colorectal cancer.[50]
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.[51] A 2019 review found that heme iron intake is associated with increased breast 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. S2CID123532036.
^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.
^Everse J, Hsia N (1197). "The toxicities of native and modified hemoglobins". Free Radical Biology and Medicine. 22 (6): 1075–1099. doi:10.1016/S0891-5849(96)00499-6. PMID9034247.
^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.
^Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A, Marguti I, Cardoso S, Sepúlveda N, Smith A, Soares MP (2010). "A central role for free heme in the pathogenesis of severe sepsis". Science Translational Medicine. 2 (51): 51ra71. doi:10.1126/scitranslmed.3001118. PMID20881280. S2CID423446.
