The word haem is derived from
Greekαἷμαhaima 'blood'.
Function
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
oxygen to
tissues 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 affinity is
inversely 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]
Types
Major hemes
There are several biologically important kinds of heme:
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]
Other hemes
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
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 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.[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]
Synthesis for food
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
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]
In health and disease
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]
Cancer
There is an association between high intake of heme iron sourced from meat and increased risk of
colorectal cancer.[50]
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