![Mboxygenation](https://upload.wikimedia.org/wikipedia/commons/c/cd/Mboxygenation.png)
Heme, or haem (pronounced /
hi:m/ ), is a
precursor
Precursor or Precursors may refer to:
*Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of unr ...
to
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, which is necessary to bind
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
in the
bloodstream
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. Heme is
biosynthesized
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
in both the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
and the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
.
[
]
In biochemical terms, heme is a
coordination complex
A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...
"consisting of an iron ion coordinated to a
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
acting as a
tetradentate ligand
In chemistry, tetradentate ligands are ligands that bind four donor atoms to a central atom to form a coordination complex. This number of donor atoms that bind is called denticity and is a method of classifying ligands.
Tetradentate ligands are ...
, and to one or two axial ligands." The definition is loose, and many depictions omit the axial ligands. Among the metalloporphyrins deployed by
metalloprotein
Metalloprotein is a generic term for a protein that contains a metal ion Cofactor (biochemistry), cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-bi ...
s as
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
s, heme is one of the most widely used and defines a family of proteins known as
hemoprotein
A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen ...
s. Hemes are most commonly recognized as components of
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, the red
pigment
A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...
in
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
, but are also found in a number of other
biologically
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
important hemoproteins such as
myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobi ...
,
cytochrome
Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bin ...
s,
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
s,
heme peroxidase
Heme, or haem (pronounced /Help:IPA/English, hi:m/ ), is a precursor (chemistry), precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, ...
, and
endothelial nitric oxide synthase
Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the ''NOS3'' gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms tha ...
.
The word ''haem'' is derived from
Greek
Greek may refer to:
Greece
Anything of, from, or related to Greece, a country in Southern Europe:
*Greeks, an ethnic group.
*Greek language, a branch of the Indo-European language family.
**Proto-Greek language, the assumed last common ancestor ...
''haima'' meaning "blood".
Function
Hemoproteins
A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen ...
have diverse biological functions including the transportation of
diatomic
Diatomic molecules () are molecules composed of only two atoms, of the same or different chemical elements. If a diatomic molecule consists of two atoms of the same element, such as hydrogen () or oxygen (), then it is said to be homonuclear. Ot ...
gases, chemical
catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, diatomic gas detection, and
electron transfer
Electron transfer (ET) occurs when an electron relocates from an atom or molecule to another such chemical entity. ET is a mechanistic description of certain kinds of redox reactions involving transfer of electrons.
Electrochemical processes ar ...
. The heme iron serves as a source or sink of electrons during electron transfer or
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
chemistry. In
peroxidase
Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides.
Functionality
Peroxidases typically ca ...
reactions, the
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
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
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
to the heme iron induces
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
s in the surrounding protein. 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).
It has been speculated that the original evolutionary function of
hemoproteins
A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen ...
was electron transfer in primitive
sulfur
Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula ...
-based
photosynthesis
Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
pathways in ancestral
cyanobacteria
Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
-like
organisms
In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and fungi; ...
before the appearance of molecular
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
.
Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
to effectively deliver
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
to
tissues is due to specific
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
residues located near the heme molecule. Hemoglobin reversibly binds to oxygen in the lungs when the
pH is high, and the
carbon dioxide
Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...
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
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
is
inversely proportional
In mathematics, two sequences of numbers, often experimental data, are proportional or directly proportional if their corresponding elements have a constant ratio, which is called the coefficient of proportionality or proportionality constan ...
to both
acidity
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
and concentration of carbon dioxide, is known as the
Bohr effect
The Bohr effect is a phenomenon first described in 1904 by the Danish physiologist Christian Bohr. Hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration o ...
.
The molecular
mechanism
Mechanism may refer to:
*Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission
*Mechanism (biology), explaining how a feature is created
*Mechanism (philosophy), a theory that a ...
behind this effect is the
steric
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
organization of the
globin
The globins are a superfamily of heme-containing globular proteins, involved in binding and/or transporting oxygen. These proteins all incorporate the globin fold, a series of eight alpha helical segments. Two prominent members include myo ...
chain; a
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
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.
Types
Major hemes
There are several biologically important kinds of heme:
The most common type is ''
heme B''; other important types include ''
heme A
Heme A (or haem A) is a heme, a coordination complex consisting of a macrocyclic ligand called a porphyrin, chelating an iron atom. Heme A is a biomolecule and is produced naturally by many organisms. Heme A, often appears a dichroic green/red whe ...
'' 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
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory electr ...
.
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
The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
which is shown in the table above.''
* Heme ''l'' is the derivative of heme B which is covalently attached to the protein of
lactoperoxidase
Lactoperoxidase is a peroxidase enzyme secreted from mammary, salivary and other mucosal glands including the lungs, bronchii and nose that functions as a natural and the first line of defense against bacteria and viruses. Lactoperoxidase is a m ...
,
eosinophil peroxidase
Eosinophil peroxidase is an enzyme found within the eosinophil granulocytes, innate immune cells of humans and mammals. This oxidoreductase protein is encoded by the gene ''EPX'', expressed within these myeloid cells. EPO shares many similarities ...
, and
thyroid peroxidase
Thyroid peroxidase, also called thyroperoxidase (TPO) or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine re ...
. The addition of
peroxide
In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable.
The most common peroxide is hydrogen p ...
with the
glutamyl
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
-375 and
aspartyl
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively.
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.
* Heme ''m'' is the derivative of heme B covalently bound at the active site of
myeloperoxidase
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry ou ...
. Heme ''m'' contains the two
ester bond
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
s 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
In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
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
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
and
bromide
A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...
ions to hypochlorite and hypobromite.
Myeloperoxidase
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry ou ...
is present in mammalian
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s and is responsible for the destruction of invading bacteria and viral agents. It perhaps synthesizes
hypobromite
The hypobromite ion, also called alkaline bromine water, is BrO−. Bromine is in the +1 oxidation state. The Br–O bond length is 1.82 Å. Hypobromite is the bromine compound analogous to hypochlorites found in common bleaches, and in immune cel ...
by "mistake". Both hypochlorite and hypobromite are very reactive species responsible for the production of halogenated nucleosides, which are mutagenic compounds.
* Heme D is another derivative of heme B, but in which the
propionic acid
Propionic acid (, from the Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula CH3CH2CO2H. It is a liq ...
side chain at the carbon of position 6, which is also hydroxylated, forms a γ-
spirolactone
Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirol ...
. Ring III is also hydroxylated at position 5, in a conformation ''trans'' to the new lactone group.
Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension.
* Heme S is related to heme B by having a
formal
Formal, formality, informal or informality imply the complying with, or not complying with, some set of requirements (forms, in Ancient Greek). They may refer to:
Dress code and events
* Formal wear, attire for formal events
* Semi-formal attire ...
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
Hans Fischer (; 27 July 1881 – 31 March 1945) was a German organic chemist and the recipient of the 1930 Nobel Prize for Chemistry "for his researches into the constitution of haemin and chlorophyll and especially for his synthesis of haem ...
.
The names of
cytochrome
Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bin ...
s 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
Heme A (or haem A) is a heme, a coordination complex consisting of a macrocyclic ligand called a porphyrin, chelating an iron atom. Heme A is a biomolecule and is produced naturally by many organisms. Heme A, often appears a dichroic green/red whe ...
.
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 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
5, heme c
1 of the bc
1 complex, heme a
3 of the aa
3 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
3) in its structure, contains two moles of heme A per mole protein. Cytochrome bc
1, with hemes b
H, b
L, and c
1, 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.". In a later paper, Caughey's group uses capital letters for isolated heme B and C as well as A.
Synthesis
The enzymatic process that produces heme is properly called
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
synthesis, as all the intermediates are
tetrapyrrole
Tetrapyrroles are a class of chemical compounds that contain four pyrrole or pyrrole-like rings. The pyrrole/pyrrole derivatives are linked by ( =- or -- units), in either a linear or a cyclic fashion. Pyrroles are a five-atom ring with four car ...
s 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
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, it also produces more complex substances such as
cofactor F430
F430 is the cofactor (sometimes called the coenzyme) of the enzyme methyl coenzyme M reductase (MCR).
MCR catalyzes the reaction that releases methane in the final step of methanogenesis:
: + HS–CoB → + CoB–S–S–CoM
It is found ...
and
cobalamin
Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...
(
vitamin B12).
The pathway is initiated by the synthesis of
δ-aminolevulinic acid
δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in p ...
(dALA or δALA) from the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
and
succinyl-CoA
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
from the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...
(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
Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. It is the most common of the acute porphyrias.
Signs and symptoms
The clinical p ...
in patients with an
inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
of this process, by reducing transcription of ALA synthase.
The organs mainly involved in heme synthesis are the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
(in which the rate of synthesis is highly variable, depending on the systemic heme pool) and the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
(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
Hemopexin
Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the ''HPX'' gene and belongs to the hemopexin family of proteins. Hemopexin is the plasma protein with the highest binding affi ...
(Hx) are required to help maintain physiological stores of iron in order for them to be used in synthesis.
Heme is seen as an intermediate molecule in catabolism of hemoglobin in the process of
bilirubin metabolism
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
. Defects in various enzymes in synthesis of heme can lead to group of disorder called porphyrias, these include
acute intermittent porphyria
Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. It is the most common of the acute porphyrias.
Signs and symptoms
The clinical p ...
,
congenital erythropoetic porphyria,
porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fift ...
,
hereditary coproporphyria
Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the ''CPOX'' gene, and is inherited in an autosom ...
,
variegate porphyria
Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the en ...
,
erythropoietic protoporphyria
Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the ...
.
Synthesis for food
Impossible Foods
Impossible Foods Inc. is a company that develops plant-based substitutes for meat products. The company's signature product, the Impossible Burger, was launched in July 2016. In partnership with Burger King, Impossible Whoppers were released ac ...
, producers of plant-based
meat substitute
A meat alternative or meat substitute (also called plant-based meat or fake meat, sometimes pejoratively) is a food product made from vegetarian or vegan ingredients, eaten as a replacement for meat. Meat alternatives typically approximate qua ...
s, use an accelerated heme synthesis process involving soybean root
leghemoglobin
3rd Leghemoglobin (also leghaemoglobin or legoglobin) is an oxygen-carrying phytoglobin found in the nitrogen-fixing root nodules of leguminous plants. It is produced by these plants in response to the roots being colonized by nitrogen-fixing b ...
and
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
, adding the resulting heme to items such as meatless (
vegan
Veganism is the practice of abstaining from the use of animal product—particularly in diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is known as a vegan. Di ...
) Impossible burger patties. The DNA for
leghemoglobin
3rd Leghemoglobin (also leghaemoglobin or legoglobin) is an oxygen-carrying phytoglobin found in the nitrogen-fixing root nodules of leguminous plants. It is produced by these plants in response to the roots being colonized by nitrogen-fixing b ...
production was extracted from the soybean root nodules and expressed in yeast cells to overproduce heme for use in the meatless burgers. This process claims to create a meaty flavor in the resulting products.
Degradation
![Heme Breakdown](https://upload.wikimedia.org/wikipedia/commons/d/d9/Heme_Breakdown.png)
Degradation begins inside macrophages of the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , which remove old and damaged
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
from the circulation.
In the first step, heme is converted to
biliverdin
Biliverdin (latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984-986. Elsevier Saunders, United States. It is the pi ...
by the enzyme
heme oxygenase
Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.
There are many heme degrading enzymes in nature. In general, only ...
(HO).
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
is used as the reducing agent, molecular oxygen enters the reaction,
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
(CO) is produced and the iron is released from the molecule as the
ferrous
In chemistry, the adjective Ferrous indicates a compound that contains iron(II), meaning iron in its +2 oxidation state, possibly as the divalent cation Fe2+. It is opposed to "ferric" or iron(III), meaning iron in its +3 oxidation state, such a ...
ion (Fe
2+). CO acts as a cellular messenger and functions in vasodilation.
In addition, heme degradation appears to be an evolutionarily-conserved response to
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. Briefly, when cells are exposed to
free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
s, there is a rapid induction of the expression of the stress-responsive
heme oxygenase-1
Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.
There are many heme degrading enzymes in nature. In general, only ...
(HMOX1) isoenzyme that catabolizes heme (see below). 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.
In the second reaction,
biliverdin
Biliverdin (latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984-986. Elsevier Saunders, United States. It is the pi ...
is converted to
bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
by
biliverdin reductase
Biliverdin reductase (BVR) is an enzyme () found in all tissues under normal conditions, but especially in reticulo-macrophages of the liver and spleen. BVR facilitates the conversion of biliverdin to bilirubin via the reduction of a double-b ...
(BVR):
Bilirubin is transported into the liver by facilitated diffusion bound to a protein (
serum albumin
Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Human serum albumin is encoded by the ''ALB'' gene. Other mammalian forms, such as bovine serum albumin, are chemical ...
), where it is conjugated with
glucuronic acid
Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea and ...
to become more water-soluble. The reaction is catalyzed by the enzyme UDP-
glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
.
This form of bilirubin is excreted from the liver in
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
. Excretion of bilirubin from liver to biliary canaliculi is an active, energy-dependent and rate-limiting process. The
intestinal bacteria
Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mic ...
deconjugate
bilirubin diglucuronide
Bilirubin di-glucuronide is a conjugated form of bilirubin formed in bilirubin metabolism. The hydrophilic character of bilirubin diglucuronide enables it to be water-soluble. It is pumped across the hepatic canalicular membrane into the bile by th ...
and convert bilirubin to
urobilinogen
Urobilinogen is a colorless by-product of bilirubin reduction. It is formed in the intestines by bacterial action on bilirubin. About half of the urobilinogen formed is reabsorbed and taken up via the portal vein to the liver, enters circulation an ...
s. Some urobilinogen is absorbed by intestinal cells and transported into the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s and excreted with
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
(
urobilin
Urobilin or urochrome is the chemical primarily responsible for the yellow color of urine. It is a linear tetrapyrrole compound that, along with the related colorless compound urobilinogen, are degradation products of the cyclic tetrapyrrole heme ...
, 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
Stercobilinogen (fecal urobilinogen) is a chemical created by bacteria in the gut. It is made of broken-down hemoglobin. It is further processed to become the chemical that gives feces its brown color.stercobilin
Stercobilin is a tetrapyrrolic bile pigment and is one end-product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: A cellular and molecular approach, 2005. 984-986. Elsevier Saunders, United States. Kay IT, Weimer M, Watson CJ (1963) ...
, which is excreted and is responsible for the brown color of
feces
Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...
.
In health and disease
Under
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
, the reactivity of heme is controlled by its insertion into the “heme pockets” of hemoproteins. Under oxidative stress however, some hemoproteins, e.g. hemoglobin, can release their heme prosthetic groups. 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
Fenton's reagent is a solution of hydrogen peroxide (H2O2) with ferrous iron (typically iron(II) sulfate, FeSO4) as a catalyst that is used to oxidize contaminants or waste waters as part of an advanced oxidation process. Fenton's reagent can be us ...
to catalyze in an unfettered manner the production of free radicals. 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. These properties of free heme can sensitize a variety of cell types to undergo
programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage durin ...
in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such as
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
and
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
.
Cancer
There is an association between high intake of heme iron sourced from meat and increased risk of
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...
. The heme content of red meat is 10 times higher than that of white meat such as chicken. A 2019 review found that heme iron intake is associated with increased
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
risk.
Genes
The following genes are part of the chemical pathway for making heme:
* ''
ALAD
Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme () that in humans is encoded by the ''ALAD'' gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate de ...
'': aminolevulinic acid, δ-,
dehydratase Dehydratases are a group of lyase enzymes that form double and triple bonds in a substrate through the removal of water. They can be found in many places including the mitochondria, peroxisome and cytosol. There are more than 150 different dehydra ...
(deficiency causes ala-dehydratase deficiency porphyria)
* ''
ALAS1
Delta-aminolevulinate synthase 1 also known as ALAS1 is a protein that in humans is encoded by the ''ALAS1'' gene. ALAS1 is an aminolevulinic acid synthase.
Delta-aminolevulinate synthase catalyzes the condensation of glycine with succinyl-CoA t ...
'': aminolevulinate, δ-, synthase 1
* ''
ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ''ALAS2'' gene. ALAS2 is an aminolevulinic acid synthase.
The product of this gene specifies an erythroid-specific mitochondrially located enzyme ...
'': aminolevulinate, δ-, synthase 2 (deficiency causes sideroblastic/hypochromic anemia)
* ''
CPOX'': coproporphyrinogen
oxidase
In biochemistry, an oxidase is an enzyme that catalyzes oxidation-reduction reactions, especially one involving dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydro ...
(deficiency causes hereditary coproporphyria)
* ''
FECH'':
ferrochelatase
Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyses the eighth and termina ...
(deficiency causes
erythropoietic protoporphyria
Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the ...
)
* ''
HMBS'': hydroxymethylbilane
synthase In biochemistry, a synthase is an enzyme that catalyses a synthesis process.
Note that, originally, biochemical nomenclature distinguished synthetases and synthases. Under the original definition, synthases do not use energy from nucleoside tripho ...
(deficiency causes acute intermittent porphyria)
* ''
PPOX
Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the ''PPOX'' gene.
Protoporphyrinogen oxidase is responsible for the seventh step in biosynthesis of protoporphyrin IX. This porphyrin is the precursor to hemoglobin, ...
'': protoporphyrinogen
oxidase
In biochemistry, an oxidase is an enzyme that catalyzes oxidation-reduction reactions, especially one involving dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydro ...
(deficiency causes variegate porphyria)
* ''
UROD
Uroporphyrinogen III decarboxylase (uroporphyrinogen decarboxylase, or UROD) is an enzyme () that in humans is encoded by the ''UROD'' gene.
Function
Uroporphyrinogen III decarboxylase is a homodimeric enzyme () that catalyzes the fifth step i ...
'':
uroporphyrinogen Uroporphyrinogens are cyclic tetrapyrroles with four propionic acid groups ("P" groups) and four acetic acid groups ("A" groups).
There are four forms, which vary based upon the arrangements of the "P" and "A" groups (in clockwise order):
* In th ...
decarboxylase
Carboxy-lyases, also known as decarboxylases, are carbon–carbon lyases that add or remove a carboxyl group from organic compounds. These enzymes catalyze the decarboxylation of amino acids, beta-keto acids and alpha-keto acids.
Classification ...
(deficiency causes porphyria cutanea tarda)
* ''
UROS
The Uru or Uros ( ure, Qhas Qut suñi) are an indigenous people of Bolivia. They live on an approximate and still growing 120 self-fashioned floating islands in Lake Titicaca near Puno. They form three main groups: the Uru-Chipaya, Uru-Murato ...
'':
uroporphyrinogen Uroporphyrinogens are cyclic tetrapyrroles with four propionic acid groups ("P" groups) and four acetic acid groups ("A" groups).
There are four forms, which vary based upon the arrangements of the "P" and "A" groups (in clockwise order):
* In th ...
III
synthase In biochemistry, a synthase is an enzyme that catalyses a synthesis process.
Note that, originally, biochemical nomenclature distinguished synthetases and synthases. Under the original definition, synthases do not use energy from nucleoside tripho ...
(deficiency causes congenital erythropoietic porphyria)
Notes and references
{{Authority control
Porphyrins
Biomolecules
Cofactors
Iron(II) compounds
Iron complexes