出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/02/22 17:55:34」(JST)
Heme (American English) or haem (British English) is a cofactor consisting of an Fe2+ (ferrous) ion contained in the centre of a large heterocyclic organic ring called a porphyrin, made up of four pyrrolic groups joined together by methine bridges. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are known as hemoproteins. Hemes are most commonly recognized as components of hemoglobin, the red pigment in blood, but are also found in a number of other biologically important hemoproteins such as myoglobin, cytochrome, catalase, and endothelial nitric oxide synthase.
Hemoproteins have diverse biological functions including the transportation of diatomic gases, chemical catalysis, diatomic gas detection, and electron transfer. The heme ion 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 ion. During the detection of diatomic gases, the binding of the gas ligand to the heme ion induces conformational changes in the surrounding protein.
It has been speculated that the original evolutionary function of hemoproteins was electron transfer in primitive sulfur-based photosynthesis pathways in ancestral cyanobacteria-like organisms before the appearance of molecular oxygen.[1]
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 organization of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acid (low pH) circumstances (which are caused by dissolved CO2 in working muscles, etc.), sterically releasing oxygen from the heme group.
There are several biologically important kinds of heme:
Heme A | Heme B | Heme C | Heme O | ||
---|---|---|---|---|---|
PubChem number | 7888115 | 444098 | 444125 | 6323367 | |
Chemical formula | C49H56O6N4Fe | C34H32O4N4Fe | C34H36O4N4S2Fe | C49H58O5N4Fe | |
Functional group at C3 | -CH(OH)CH2Far | -CH=CH2 | -CH(cystein-S-yl)CH3 | -CH(OH)CH2Far | |
Functional group at C8 | -CH=CH2 | -CH=CH2 | -CH(cystein-S-yl)CH3 | -CH=CH2 | |
Functional group at C18 | -CH=O | -CH3 | -CH3 | -CH3 |
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.
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.
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 as 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 negatively regulated by glucose and heme concentration. Mechanism of inhibition of ALAs by hemme 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.[6]
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. 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, these include acute intermittent porphyria, congenital erythropoetic porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria, erythropoietic protoporphyria.
Degradation begins inside macrophages of the spleen, which remove old and damaged (senescent) erythrocytes from the circulation. In the first step, heme is converted to biliverdin by the enzyme heme oxygenase (HMOX). 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 ferric ion (Fe3+). CO acts as a cellular messenger and functions in vasodilation.
In addition, heme degradation appears to be an evolutionary 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). 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.
HMOX1/2 heme --------------> biliverdin + Fe3+ / \ H+ + NADPH NADP+ O2 CO
In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR):
BVR biliverdin -----------> bilirubin / \ H+ + NADPH NADP+
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-glucuronide transferase (UDPGUTF).
UDPGUTF bilirubin + 2 UDP-glucuronate ------------> bilirubin diglucuronide \ 2 UMP + 2 Pi
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 and convert bilirubin to urobilinogens. 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, 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 color of feces.
Under homeostasis, 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.[7] The non-protein-bound (free) heme produced in this manner becomes highly cytotoxic, most probably due to the Fe atom contained within its protoporphyrin IX ring, which can act as a Fenton chemistry to catalyze in an unfettered manner the production of free radicals.[citation needed] This property 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[8] and sepsis.[9]
The following genes are part of the chemical pathway for making heme:
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リンク元 | 「ヘム」 |
拡張検索 | 「hemeralopia」「theme」「hemeprotein」「nonheme iron protein」 |
関連記事 | 「hem」 |
反応場所 | 酵素 | 補酵素 | 酵素阻害物質 | 酵素の障害による疾患 | ||||||
ミトコンドリア | サクシニルCoA succinyl-CoA |
グリシン glycine |
5-アミノレブリン酸 aminolevulinic acid aminolevulinate ALA |
CoA | CO2 | 5-アミノレブリン酸シンターゼ ALA synthase |
ビタミンB6 | |||
細胞質 | 5-アミノレブリン酸 aminolevulinic acid aminolevulinate ALA |
←2分子 | ポルホビリノゲン porphobilinogen PBG |
2H2O | ALA dehydratase | Pb | ||||
細胞質 | ポルホビリノゲン porphobilinogen PBG |
ヒドロキシメチルビラン | 4NH3 | ウロポルフィリゲノンIシンターゼ uroporphyrinogen I synthase |
急性間欠性ポルフィリン症 acute intermittent porphyria | |||||
細胞質 | ヒドロキシメチルビラン | ウロポルフィリノゲンIII | ウロポルフィリゲノンIIIシンターゼ uroporphyrinogen III synthase |
|||||||
細胞質 | ウロポルフィリノゲンIII | コプロポルフィリノゲンIII | 4CO2 | ウロポルフィリノゲンデカルボキシラーゼ | 晩発性皮膚ポルフィリン症 porphyria cutanea tarda | |||||
ミトコンドリア | コプロポルフィリノゲンIII | プロトポルフィリノゲンIX | 2CO2 | コプロポルフィリノゲンオキシダーゼ | ||||||
ミトコンドリア | プロトポルフィリノゲンIX | プロトポルフィリンIX | プロトポルフィリノゲンオキシダーゼ | |||||||
ミトコンドリア | プロトポルフィリンIX | Fe2+ | ヘム | フェロケラターゼ | Pb |
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