HEME

Heme A[1]
Heme A is synthesized from Heme B. In two sequential reactions a 17-hydroxyethylfarnesyl moiety (blue) is added at the 2-position and an aldehyde (purple) is added at the 8-position. Nomenclature is shown in green. ^[2]

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. For instance, cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase.

• Heme B is the most abundant heme; both hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B and the peroxidase family of enzymes also contain heme B. The COX-1 and COX-2 enzymes (cyclooxygenase) of recent fame, also contain heme B at one of two active sites. Generally, heme B is attached to the surrounding protein matrix (known as the apoprotein) through a single coordination bond between the heme iron and an amino acid side-chain. Both hemoglobin and myoglobin have a coordination bond to an evolutionary conserved histidine, while Nitric oxide synthase and Cytochrome P450 have a coordination bond to an evolutionary conserved cysteine bound to the iron center of heme B. Since the iron in heme B containing proteins is bound to the four nitrogens of the porphyrin (forming a plane) and a single electron donating atom of the protein, the iron is often in a pentacoordinate state. When bound with oxygen or the toxin carbon monoxide the iron is hexacoordinated.

• Heme A differs from heme B in that a methyl side chain at ring position 8 is oxidized into a formyl group, and one of the vinyl side chains, at ring position 2, has been replaced by an isoprenoid chain. Like heme B, heme A is often attached to the apoprotein through a coordination bond between the heme iron and a conserved amino acid side-chain. An example of a metalloprotein that contains heme A is cytochrome c oxidase. Both the formyl group and the isoprenoid side chain are thought to play important roles in conservation of the energy of oxygen reduction by cytochrome c oxidase.

• Heme O differs from the closely related heme A by having a methyl group at ring position 8 instead of the formyl group, the isoprenoid chain at position 2 is the same. Heme O, found in the bacterium E. coli, functions in a similar manner to heme A in mammalian oxygen reduction.

• Heme C differs from heme B in that the two vinyl side chains are covalently bound to the apoprotein itself through thioether linkages. In addition to these covalent bonds, the heme iron is also usually coordinated to two side chains of amino acids, making the iron hexacoordinate. For example, cytochrome c contains a single heme C that is coordinated to side chains of both histidine and methionine.^[3] bc₁ complex is another protein that contains a C type heme. Some hemeproteins, often from single cell organisms, may contain up to four hemes C. The correct structure of heme C was first published, in mid 20th century, by the Swedish biochemist K.-G. Paul.

• 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. 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 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. Heme M also contains the two ester bonds at the heme 1- and 5-methyls, much as the other mammalian peroxidases. In addition, a unique sulfonium ion linkage between the sulfur of a methionyl aminoacid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizing chloride and bromide ions. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and virus. It also synthesizes hypobromate by "mistake" which is a known mutagenic compound.

• Heme S is related to heme B by the having a formyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of marine worms. The correct structures of heme B and heme S were first elucidated by the great German chemist Hans Fischer.

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.

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 porphyrin molecule also serves as an electron source. 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.

It has been speculated that the orginal evolutionary function of hemoproteins was electron transfer in primitive sulfur-based photosynthesis pathways in ancestral cyanobacteria before the appearance of molecular oxygen. ^[4]

Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of hemoglobin to effectively deliver oxygen to tissues is due to specific amino acid residues located near the heme molecule. Hemoglobin binds oxygen in the pulmonary vasculature, where the pH is high and the pCO₂ is low, and releases it in the tissues, where the situations are reversed. This phenomenon is known as the Bohr effect. The molecular mechanism behind this effect is the steric organisation of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acid circumstances, sterically releasing oxygen from the heme group.

Synthesis

Details of heme synthesis can be found in the article on porphyrin.

Heme synthesis in the cytoplasm and mitochondrion.

The enzymatic process that produces heme is properly called porphyrin synthesis, as all the intermediates are tetrapyrroles that are chemically classified are porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In other species, it also produces similar substances such as cobalamin (vitamin B12).

The pathway is initiated by the synthesis of D-Aminolevulinic acid (dALA or δALA) from the amino acid glycine and succinyl-CoA from the citric acid cycle (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ALA synthase, is strictly regulated by intracellular iron levels and heme concentration. A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis, which prevents accumulation of the toxic intermediates. This mechanism is of therapeutic importance: infusion of heme arginate of hematin can abort attacks of porphyria in patients with an inborn error of metabolism of this process, by reducing transcription of ALA synthase.

The organs mainly involved in heme synthesis are the liver and the bone marrow, although every cell requires heme to function properly.

Genes

The following genes are part of the chemical pathway for making heme:

• ALAD: aminolevulinic acid, delta-, dehydratase
• ALAS1: aminolevulinate, delta-, synthase 1
• ALAS2: aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia)
• CPOX: coproporphyrinogen oxidase
• FECH: ferrochelatase (protoporphyria)
• HMBS: hydroxymethylbilane synthase
• PPOX: protoporphyrinogen oxidase
• UROD: uroporphyrinogen decarboxylase
• UROS: uroporphyrinogen III synthase (congenital erythropoietic porphyria)

See also

• chlorin
• corrin
• cobalamin
• respiration (physiology)

References

1. ^ Caughey, Winslow S., "et al" (1975). "Heme A of Cytochrome c Oxidase STRUCTURE AND PROPERTIES: COMPARISONS WITH HEMES B, C, AND S AND DERIVATIVES". J. Biol. Chem. 250 (19): 7602-7622.
2. ^ Hegg, Eric L., et al (2004). "Heme A Synthase Does Not Incorporate Molecular Oxygen into the Formyl Group of Heme A". Biochemistry 43 (27): 8616–8624.
3. ^ Yeh, S.R., Han, S., and Rousseau, D.L. (1998). "Cytochrome c folding and unfolding". Accounts of Chemical Research 31 (11): 727-735.
4. ^ 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.