Heme
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A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Heme groups can bind oxygen and several biological molecules of crucial importance contain heme groups, most notably the vital hemoglobin in the body's red blood cells. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins.
Types
There are three biologically important kinds of heme. The most common type is heme b; the others are heme a and heme c.- Heme b is not covalently bound to the containing protein (known as apoprotein) in which it is found. It is the most abundant heme: both hemoglobin and myoglobin are examples of proteins that contain heme b.
- Heme a differs from heme b in that a methyl side chain is oxidized into a formyl group, and one of the vinyl side chains has been replaced by an isoprenoid chain. Like heme b, heme a is not covalently bound to the apoprotein in which it is found. An example of a metalloprotein that has heme a is cytochrome c oxidase.
- Heme c differs from heme b in that the two vinyl side chains are covalently bound to the protein itself. Examples of proteins that contain a c type heme are cytochrome c and the bc1 complex.
Function
The main function of heme is the retention of O2 and delivering it for enzymatic reactions. The iron atom of every heme group can bind one molecule of O2. As the main site of oxidation in the cell is the mitochondrion, many heme-containing enzymes are located there, and part of the heme synthesis (see below) takes place there.Hemoglobin is not an enzyme, but a transporter. It 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. The main mechanism behind this phenomenon 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.
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
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