cytochrome P450

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/14 22:41:33」(JST)

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Cytochrome P450 Oxidase (CYP2C9)

シトクロムP450（英語: Cytochrome P450）は水酸化酵素ファミリーの総称である。略してCYP（シップ）と呼ばれることが多い。様々な基質を水酸化するので、多くの役割を果たす。肝臓において解毒を行う酵素として知られているが、ステロイドホルモンの生合成、脂肪酸の代謝や植物の二次代謝など、生物の正常活動に必要な反応にも関与している。しかしながら、進化的には一つのものから枝分かれしたものであると考えられており、NADPHなどの電子供与体と酸素を用いて基質を水酸化することも共通である。シトクロムP450は細胞内の小胞体に多く、一部はミトコンドリアに存在する。動物では肝臓に多く、特によく研究されている。

ゲノムプロジェクトによって一部の細菌を除く大部分の生物（大腸菌には見つかっていない）にその遺伝子があることが明らかにされつつあり、例えばヒトには57種の遺伝子がある。また、一般的に植物のシトクロムP450は基質特異性が高く、多くの種類が存在するとされており、例えばイネにおいては候補遺伝子が400以上も発見されている。しかし、機能がわかっているものは少ない。

構造[編集]

すべてのシトクロムP450は約500アミノ酸残基からなり、活性部位にヘムを持つ。保存されたシステイン残基と水分子がヘムの鉄原子にリガンドとして配位する。基質が酵素に結合すると、水がはずれ酸素が結合できるようになる。シトクロムとは以上のような構造的特徴、および反応過程で鉄が酸化・還元を受ける点で類似性があるが、シトクロムは一般に酵素でなく電子伝達タンパク質であって機能が異なる。一酸化炭素が還元型の酵素の活性部位の鉄原子に結合すると、450ナノメートル（可視光領域）の波長を持つ電磁波に対し吸収を示すので、ピグメント（色素）450という意味で大村恒雄と佐藤了により1964年に命名された^[1]。

分類・命名[編集]

シトクロムP450はアミノ酸配列の相同性に基づいて分類され、40%以上相同のものをファミリー、55%以上相同のものをサブファミリーとして分類する。たとえば「CYP1A1」というように表記し、最初の数字1は「ファミリー1」、Aは「サブファミリーA」、最後の数字1が特定の蛋白質（遺伝子はCYP1A1と斜体で表記する）を示す（別の生物種でも明らかに対応する場合には同じ名にする）。

ヒトの主なCYPの分類
群	亜群	分子種	主な基質
1	A	CYP1A1	ベンゾピレン
1	A	CYP1A2	アセトアミノフェン、プロプラノロール、カフェイン、テオフィリン
2	A	CYP2A6	テガフール、ニコチン
	B	CYP2B6	シクロホスファミド、ケタミン
	C	CYP2C8	パクリタキセル
		CYP2C9	イブプロフェン、ジクロフェナク、フェニトイン、ワルファリン
		CYP2C19	ジアゼパム、オメプラゾール、ランソプラゾール、クロピドグレル
	D	CYP2D6	タモキシフェン、フルボキサミン、ハロペリドール、プロプラノロール、コデイン
	E	CYP2E1	ハロタン、エンフルラン、アセトアミノフェン、アセトン、エタノール、トルエン、ベンゼン
3	A	CYP3A4	アミオダロン、カルバマゼピン、エリスロマイシン、タクロリムス、タモキシフェン、パクリタキセル、ドセタキセル
3	A	CYP3A5	テストステロン、クラリスロマイシン

機能[編集]

異物代謝（解毒作用など）[編集]

さまざまなシトクロムP450の基質は脂溶性で、蓄積すると毒になるものが多い。たとえば、ポリ塩化ビフェニル (PCB)、フェノバルビタールをはじめとする薬物、ステロイドなどである。これら基質の多くにはシトクロムP450の発現を誘導する性質もある。シトクロムP450はこれらの分子を水酸化して、排出されやすい水溶性の物質に変える。一方、ベンゾピレンなどの発癌物質では逆にシトクロムP450による水酸化で発癌性が生じることが明らかにされている。

薬物相互作用[編集]

カルシウム拮抗剤などでグレープフルーツ果汁との併用により副作用が増強することがある。これはCYP3A4の活性が阻害され薬物の代謝が遅くなるためとされ酵素阻害と呼ばれる。逆にセント・ジョーンズ・ワート（セイヨウオトギリソウ）はCYP3A4を誘導し薬物の代謝を速め酵素誘導と呼ばれる。このほかにもシトクロムP450が関係した薬物の相互作用がありうるので注意が必要である。その他、CYP2D6などの遺伝的多型により各種薬物の代謝速度に個人差が現れることが知られている。

コレステロール生合成など[編集]

CYP51は現在シトクロムP450の存在が知られるすべての生物種に見つかっており最も基本的な分子種と考えられている。これは多くの生物でステロイド生合成の基本となるステロール14α-脱メチル化酵素活性を有しており、特に真菌では生存に必要なエルゴステロールの合成に関与するため、アゾール系などのシトクロムP450阻害剤が殺菌剤・抗真菌薬として用いられる。

動物のステロイドホルモン合成においてもエストロゲン合成に関わるCYP19（アロマターゼ）など重要なものがある。またプロスタサイクリン（プロスタグランジンPGI₂）などの合成にも関与するものがある。

アントシアニンの生合成（青いバラ関連）[編集]

アントシアニンは花の色素として重要な色素であり、アントシアニジンに糖が結合したものである。呈する色の違いは、アントシアニジンB環の3位と5位の水酸化の違いによるものである。アントシアニジンの代表的なものには、ペラルゴニジン（橙-赤）、シアニジン（赤-紫）、デルフィニジン（紫-赤）がある。
3大切花と呼ばれる、バラ、キク、カーネーションは、世界市場においてそれぞれ27%、20%、6%のシェアを持つ。これらにおいて今までは青い花がなかったのは、これらにはデルフィニジンを作るために必要な水酸化酵素 (CYP75A) がなかったためである。サントリーは青いカーネーションである「ムーンダスト」を1997年に発売した。また、青いバラの開発にも成功したと2004年に発表した。これらにはそれぞれペチュニア、パンジー由来の遺伝子が導入されている。

転写調節[編集]

CYP1-CYP4はそれぞれ薬物代謝に関与するが（上記参照）、これらの酵素の誘導は薬物がリガンドとしてある受容体に結合することにより行われる。関与する受容体は以下の通りである。

CYP1ファミリー → 芳香族炭化水素受容体 (Aryl Hydrocarbon Receptor、AhR)
CYP2ファミリー → 構成的アンドロスタン受容体 (constitutive active Recptor、CAR)
CYP3ファミリー → プレグナンX受容体 (pregnane X Recptor、PXR)
CYP4ファミリー → ペルオキシソーム増殖剤応答性受容体α (Peroxisome Proliferated-Activated Receptor α、PPARα)

これらの受容体がリガンド結合後、DNA上のプロモーター領域に結合して各CYP遺伝子の転写亢進を行う。

脚注[編集]

[ヘルプ]

^ Omura, T.; Sato, R. The carbon monoxide-binding pigment of liver microsomes: I. Evidence for its hemoprotein nature. J. Biol. Chem. 1964, 239, 2370-2378. PMID 14209971.

外部リンク[編集]

ウィキメディア・コモンズには、シトクロムP450に関連するカテゴリがあります。

シトクロムP450分類の最新情報（英語）
P450データ集 Webサイト「生活環境化学の部屋」
P450各分子種が代謝する薬物（発掘!やくやく大事典）

wiki en

[Wiki en表示]

The cytochrome P450 superfamily of monooxygenases (officially abbreviated as CYP) is a large and diverse group of enzymes that catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals. CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for about 75% of the total number of different metabolic reactions.^[1]

The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O₂ + NADPH + H⁺ → ROH + H₂O + NADP⁺

Cytochromes P450 (CYPs) belong to the superfamily of proteins containing a heme cofactor and, therefore, are hemoproteins. CYPs use a variety of small and large molecules as substrates in enzymatic reactions.They are in general the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term P450 is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with CO.

CYP enzymes have been identified in all domains of life - animals, plants, fungi, protists, bacteria, archaea, and even in viruses.^[2] However, the enzymes have not been found in E. coli.^[3]^[4] More than 18,000 distinct CYP proteins are known.^[5]

Most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen). Based on the nature of the electron transfer proteins CYPs can be classified into several groups:^[6]

Microsomal P450 systems in which electrons are transferred from NADPH via cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).
Mitochondrial P450 systems, that employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to P450.
Bacterial P450 systems, that employ a ferredoxin reductase and a ferredoxin to transfer electrons to P450.
CYB5R/cyb5/P450 systems in which both electrons required by the CYP come from cytochrome b5.
FMN/Fd/P450 systems originally found in Rhodococcus sp. in which a FMN-domain-containing reductase is fused to the CYP.
P450 only systems, which do not require external reducing power. Notable ones include CYP5 (thromboxane synthase), CYP8 (prostacyclin synthase), and CYP74A (allene oxide synthase).

1 Nomenclature
2 Mechanism
3 P450s in humans
- 3.1 Drug metabolism
  - 3.1.1 Drug interaction
  - 3.1.2 Interaction of other substances
- 3.2 Other specific CYP functions
- 3.3 CYP families in humans
4 P450s in other species
- 4.1 Animals
- 4.2 Microbial
- 4.3 Fungi
- 4.4 Plants
5 P450s in biotechnology
6 InterPro subfamilies
7 References
8 External links

Nomenclature[edit]

Genes encoding CYP enzymes, and the enzymes themselves, are designated with the abbreviation CYP, followed by a number indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to italicise the name when referring to the gene. For example, CYP2E1 is the gene that encodes the enzyme CYP2E1 – one of the enzymes involved in paracetamol (acetaminophen) metabolism. The CYP nomenclature is the official naming convention, although occasionally (and incorrectly) CYP450 or CYP₄₅₀ is used. However, some gene or enzyme names for CYPs may differ from this nomenclature, denoting the catalytic activity and the name of the compound used as substrate. Examples include CYP5A1, thromboxane A₂ synthase, abbreviated to TBXAS1 (ThromBoXane A₂ Synthase 1), and CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).^[7]

The current nomenclature guidelines suggest that members of new CYP families share >40% amino acid identity, while members of subfamilies must share >55% amino acid identity. There are nomenclature committees that assign and track both base gene names (Cytochrome P450 Homepage) and allele names (CYP Allele Nomenclature Committee).

Mechanism[edit]

Main article: P450-containing systems

The P450 catalytic cycle

The active site of cytochrome P450 contains a heme iron center. The iron is tethered to the P450 protein via a thiolate ligand derived from a cysteine residue. This cysteine and several flanking residues are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].^[8] Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

The substrate binds to the active site of the enzyme, in close proximity to the heme group, on the side opposite to the peptide chain. The bound substrate induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron,^[9] and sometimes changing the state of the heme iron from low-spin to high-spin.^[10] This gives rise to a change in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectrometry and is referred to as the "type I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro^[11]
The change in the electronic state of the active site favors the transfer of an electron from NAD(P)H via cytochrome P450 reductase or another associated reductase^[12] This takes place by way of the electron transfer chain, as described above, reducing the ferric heme iron to the ferrous state.
Molecular oxygen binds covalently to the distal axial coordination position of the heme iron. The cysteine ligand is a better electron donor than histidine, which is normally found in heme-containing proteins. As a consequence, the oxygen is activated to a greater extent than in other heme proteins. However, this sometimes allows the iron-oxygen bond to dissociate, causing the so-called "uncoupling reaction", which releases a reactive superoxide radical and interrupts the catalytic cycle.^[9]
A second electron is transferred via the electron-transport system, from either cytochrome P450 reductase, ferredoxins, or cytochrome b5, reducing the dioxygen adduct to a negatively charged peroxo group. This is a short-lived intermediate state.
The peroxo group formed in step 4 is rapidly protonated twice by local transfer from water or from surrounding amino-acid side-chains, releasing one water molecule, and forming a highly reactive species commonly referred to as P450 Compound 1 ( or Compound I). This highly reactive intermediate was not "seen in action" until 2010,^[13] although it had been studied theoretically for many years.^[9] P450 Compound 1 is most likely an iron(IV)oxo (or ferryl) species with an additional oxidizing equivalent delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo ^[9] is lacking.^[13]
Depending on the substrate and enzyme involved, P450 enzymes can catalyze any of a wide variety of reactions. A hypothetical hydroxylation is shown in this illustration. After the product has been released from the active site, the enzyme returns to its original state, with a water molecule returning to occupy the distal coordination position of the iron nucleus.

S: An alternative route for mono-oxygenation is via the "peroxide shunt": Interaction with single-oxygen donors such as peroxides and hypochlorites can lead directly to the formation of the iron-oxo intermediate, allowing the catalytic cycle to be completed without going through steps 2, 3, 4, and 5.^[11] A hypothetical peroxide "XOOH" is shown in the diagram.

C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm.

P450s in humans[edit]

Human CYPs are primarily membrane-associated proteins^[14] located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenous and exogenous chemicals. Some CYPs metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.^[15]

Drug metabolism[edit]

Proportion of antifungal drugs metabolized by different families of CYPs.^[16]

Further information: Drug metabolism

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism.^[1] Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYPs to form their active compounds.

Drug interaction[edit]

Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the CYP (enzyme inhibition). This is a major source of adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system. Such drug interactions are especially important to take into account when using drugs of vital importance to the patient, drugs with important side-effects and drugs with small therapeutic windows, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.

A classical example includes anti-epileptic drugs. Phenytoin, for example, induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Substrates for the latter may be drugs with critical dosage, like amiodarone or carbamazepine, whose blood plasma concentration may either increase because of enzyme inhibition in the former, or decrease because of enzyme induction in the latter.^{[citation needed]}

Interaction of other substances[edit]

Naturally occurring compounds may also induce or inhibit CYP activity. For example, bioactive compounds found in grapefruit juice and some other fruit juices, including bergamottin, dihydroxybergamottin, and paradicin-A, have been found to inhibit CYP3A4-mediated metabolism of certain medications, leading to increased bioavailability and, thus, the strong possibility of overdosing.^[17] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.^[18]

Other examples:

Saint-John's wort, a common herbal remedy induces CYP3A4, but also inhibits CYP1A1, CYP1B1, and CYP2D6.^[19]^[20]

Tobacco smoking induces CYP1A2 (example CYP1A2 substrates are clozapine, olanzapine, and fluvoxamine)^[21]

At relatively high concentrations, starfruit juice has also been shown to inhibit CYP2A6 and other CYPs.^[22] Watercress is also a known inhibitor of the Cytochrome P450 CYP2E1, which may result in altered drug metabolism for individuals on certain medications (ex., chlorzoxazone).^[23]

Other specific CYP functions[edit]

Steroidogenesis, showing many of the enzyme activities that are performed by cytochrome P450 enzymes. HSD: Hydroxysteroid dehydrogenase

A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones (steroidogenesis) by the adrenals, gonads, and peripheral tissue:

CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria effects “the activity formerly known as 20,22-desmolase” (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol side-chain scission).
CYP11B1 (encoding the protein P450c11β) found in the inner mitochondrial membrane of adrenal cortex has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
CYP11B2 (encoding the protein P450c11AS), found only in the mitochondria of the adrenal zona glomerulosa, has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
CYP17A1, in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
CYP21A1 (P450c21) in adrenal cortex conducts 21-hydroxylase activity.
CYP19A (P450arom, aromatase) in endoplasmic reticulum of gonads, brain, adipose tissue, and elsewhere catalyzes aromatization of androgens to estrogens.

CYP families in humans[edit]

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.^[24] This is a summary of the genes and of the proteins they encode. See the homepage of the Cytochrome P450 Nomenclature Committee for detailed information.^[15]

Family	Function	Members	Names
CYP1	drug and steroid (especially estrogen) metabolism	3 subfamilies, 3 genes, 1 pseudogene	CYP1A1, CYP1A2, CYP1B1
CYP2	drug and steroid metabolism	13 subfamilies, 16 genes, 16 pseudogenes	CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
CYP3	drug and steroid (including testosterone) metabolism	1 subfamily, 4 genes, 2 pseudogenes	CYP3A4, CYP3A5, CYP3A7, CYP3A43
CYP4	arachidonic acid or fatty acid metabolism	6 subfamilies, 12 genes, 10 pseudogenes	CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
CYP5	thromboxane A₂ synthase	1 subfamily, 1 gene	CYP5A1
CYP7	bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus	2 subfamilies, 2 genes	CYP7A1, CYP7B1
CYP8	varied	2 subfamilies, 2 genes	CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
CYP11	steroid biosynthesis	2 subfamilies, 3 genes	CYP11A1, CYP11B1, CYP11B2
CYP17	steroid biosynthesis, 17-alpha hydroxylase	1 subfamily, 1 gene	CYP17A1
CYP19	steroid biosynthesis: aromatase synthesizes estrogen	1 subfamily, 1 gene	CYP19A1
CYP20	unknown function	1 subfamily, 1 gene	CYP20A1
CYP21	steroid biosynthesis	2 subfamilies, 1 gene, 1 pseudogene	CYP21A2
CYP24	vitamin D degradation	1 subfamily, 1 gene	CYP24A1
CYP26	retinoic acid hydroxylase	3 subfamilies, 3 genes	CYP26A1, CYP26B1, CYP26C1
CYP27	varied	3 subfamilies, 3 genes	CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D₃ 1-alpha hydroxylase, activates vitamin D₃), CYP27C1 (unknown function)
CYP39	7-alpha hydroxylation of 24-hydroxycholesterol	1 subfamily, 1 gene	CYP39A1
CYP46	cholesterol 24-hydroxylase	1 subfamily, 1 gene	CYP46A1
CYP51	cholesterol biosynthesis	1 subfamily, 1 gene, 3 pseudogenes	CYP51A1 (lanosterol 14-alpha demethylase)

P450s in other species[edit]

Animals[edit]

Many animals have as many or more CYP genes than humans do. For example, mice have genes for 101 CYPs, and sea urchins have even more (perhaps as many as 120 genes).^[25] Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., CYP19 and CYP5). However, gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, although many genes with close homology to CYPs with known function have been found.

The classes of CYPs most often investigated in non-human animals are those either involved in development (e.g., retinoic acid or hormone metabolism) or involved in the metabolism of toxic compounds (such as heterocyclic amines or polyaromatic hydrocarbons). Often there are differences in gene regulation or enzyme function of CYPs in related animals that explain observed differences in susceptibility to toxic compounds.

CYPs have been extensively examined in mice, rats, dogs, and less so in zebrafish, in order to facilitate use of these model organisms in drug discovery and toxicology. Recently CYPs have also been discovered in avian species, in particular turkeys, that may turn out to be a great model for cancer research in humans.^[26] CYP1A5 and CYP3A37 in turkeys were found to be very similar to the human CYP1A2 and CYP3A4 respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.^[27]

CYPs have also been heavily studied in insects, often to understand pesticide resistance. For example, CYP6G1 is linked to insecticide resistance in DDT-resistant Drosophila melanogaster^[28] and CYP6Z1 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing DDT.^[29]

Microbial[edit]

Microbial cytochromes P450 are often soluble enzymes and are involved in critical metabolic processes. Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

Cytochrome P450cam (CYP101) originally from Pseudomonas putida has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography. This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster-containing protein cofactor.

Cytochrome P450 eryF (CYP107A1) originally from the actinomycete bacterium Saccharopolyspora erythraea is responsible for the biosynthesis of the antibiotic erythromycin by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.

Cytochrome P450 BM3 (CYP102A1) from the soil bacterium Bacillus megaterium catalyzes the NADPH-dependent hydroxylation of several long-chain fatty acids at the ω–1 through ω–3 positions. Unlike almost every other known CYP (except CYP505A1, cytochrome P450 foxy), it constitutes a natural fusion protein between the CYP domain and an electron donating cofactor. Thus, BM3 is potentially very useful in biotechnological applications.^[30]^[31]

Cytochrome P450 119 (CYP119) isolated from the thermophillic archea Sulfolobus acidocaldarius ^[32] has been used in a variety of mechanistic studies.^[13] Because thermophillic enzymes evolved to function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.

Fungi[edit]

The commonly used azole class antifungal drugs work by inhibition of the fungal cytochrome P450 14α-demethylase. This interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane. (This is useful only because humans' P450 have a different sensitivity; this is how this class of antifungals work.)^[33]

Significant research is ongoing into fungal P450s, as a number of fungi are pathogenic to humans (such as Candida yeast and Aspergillus) and to plants.

Cunninghamella elegans is a candidate for use as a model for mammalian drug metabolism.

Plants[edit]

Plant cytochromes P450 are involved in a wide range of biosynthetic reactions, leading to various fatty acid conjugates, plant hormones, defensive compounds, or medically important drugs. Terpenoids, which represent the largest class of characterized natural plant compounds, are often substrates for plant CYPs.

P450s in biotechnology[edit]

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists.^[34] Recent progress towards realizing the potential of using P450s towards difficult oxidations have included: (i) eliminating the need for natural co-factors by replacing them with inexpensive peroxide containing molecules,^[35] (ii) exploring the compatibility of p450s with organic solvents,^[36] and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.^{[citation needed]}

InterPro subfamilies[edit]

InterPro subfamilies:

Cytochrome P450, B-class IPR002397
Cytochrome P450, mitochondrial IPR002399
Cytochrome P450, E-class, group I IPR002401
Cytochrome P450, E-class, group II IPR002402
Cytochrome P450, E-class, group IV IPR002403

References[edit]

^ ^a ^b Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chem. Res. Toxicol. 21 (1): 70–83. doi:10.1021/tx700079z. PMID 18052394. (Metabolism in this context is the chemical modification or degradation of drugs.)
^ Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL (2009). "The first virally encoded cytochrome P450". Journal of Virology 83 (16): 8266-9. PMID 19515774
^ Roland Sigel; Sigel, Astrid; Sigel, Helmut (2007). The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. New York: Wiley. ISBN 0-470-01672-8.
^ Danielson PB (December 2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Curr. Drug Metab. 3 (6): 561–97. doi:10.2174/1389200023337054. PMID 12369887.
^ Nelson D. "Cytochrome P450 Homepage". University of Tennessee. Retrieved 2010-05-04.
^ Hanukoglu, Israel (1996). "Electron Transfer Proteins of Cytochrome P450 Systems". Advances in Molecular and Cell Biology 14: 29–56. doi:10.1016/S1569-2558(08)60339-2. ISSN 1569-2558.
^ "NCBI sequence viewer". Retrieved 2007-11-19.
^ PROSITE consensus pattern for P450
^ ^a ^b ^c ^d Meunier B, de Visser SP, Shaik S (September 2004). "Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes". Chem. Rev. 104 (9): 3947–80. doi:10.1021/cr020443g. PMID 15352783.
^ Poulos TL, Finzel BC, Howard AJ (June 1987). "High-resolution crystal structure of cytochrome P450cam". J. Mol. Biol. 195 (3): 687–700. doi:10.1016/0022-2836(87)90190-2. PMID 3656428.
^ ^a ^b Ortiz de Montellano, Paul R.; Paul R. Ortiz de Montellano (2005). Cytochrome P450: structure, mechanism, and biochemistry (3rd ed.). New York: Kluwer Academic/Plenum Publishers. ISBN 0-306-48324-6.
^ Sligar SG, Cinti DL, Gibson GG, Schenkman JB (October 1979). "Spin state control of the hepatic cytochrome P450 redox potential". Biochem. Biophys. Res. Commun. 90 (3): 925–32. doi:10.1016/0006-291X(79)91916-8. PMID 228675.
^ ^a ^b ^c Rittle J, Green MT (November 2010). "Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics". Science 330 (6006): 933–937. Bibcode:2010Sci...330..933R. doi:10.1126/science.1193478. PMID 21071661.
^ Berka K et al. J. Phys. Chem. A, 2011 doi:10.1021/jp204488j
^ ^a ^b "P450 Table".
^ doctorfungus > Antifungal Drug Interactions Content Director: Russell E. Lewis, Pharm.D. Retrieved on Jan 23, 2010
^ Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". Am J Cardiovasc Drugs 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971.
^ Zeratsky K (2008-11-06). "Grapefruit juice: Can it cause drug interactions?". Ask a food & nutrition specialist. MayoClinic.com. Retrieved 2009-02-09.
^ Chaudhary A, Willett KL (January 2006). "Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort". Toxicology 217 (2–3): 194–205. doi:10.1016/j.tox.2005.09.010. PMID 16271822.
^ Strandell J, Neil A, Carlin G (February 2004). "An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies". Phytomedicine 11 (2–3): 98–104. doi:10.1078/0944-7113-00379. PMID 15070158.
^ Kroon LA (September 2007). "Drug interactions with smoking". Am J Health Syst Pharm 64 (18): 1917–21. doi:10.2146/ajhp060414. PMID 17823102.
^ Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver cytochrome P450 by star fruit juice". J Pharm Pharm Sci 10 (4): 496–503. PMID 18261370.
^ Leclercq I, Desager JP, Horsmans Y (August 1998). "Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress". Clin Pharmacol Ther. 64 (2): 144–9. doi:10.1016/S0009-9236(98)90147-3. PMID 9728894.
^ Nelson D (2003). Cytochromes P450 in humans. Retrieved May 9, 2005.
^ Goldstone JV, Hamdoun A, Cole BJ, Howard-Ashby M, Nebert DW, Scally M, Dean M, Epel D, Hahn ME, Stegeman JJ (December 2006). "The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome". Dev. Biol. 300 (1): 366–84. doi:10.1016/j.ydbio.2006.08.066. PMC 3166225. PMID 17097629.
^ Rawal S, Kim JE, Coulombe, R Jr (December 2010). "Aflatoxin B1 in poultry: toxicology, metabolism and prevention". Res. Vet. Sci. 89 (3): 325–31. doi:10.1016/j.rvsc.2010.04.011. PMID 20462619.
^ Rawal S, Coulombe, RA Jr (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37". Toxicol. Appl. Pharmacol. 254 (3): 349–54. doi:10.1016/j.taap.2011.05.010. PMID 21616088.
^ McCart C, Ffrench-Constant RH (June 2008). "Dissecting the insecticide-resistance- associated cytochrome P450 gene Cyp6g1". Pest Manag Sci 64 (6): 639–45. doi:10.1002/ps.1567. PMID 18338338.
^ Chiu TL, Wen Z, Rupasinghe SG, Schuler MA (1 Jul 2008). "Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT". Proc Natl Acad Sci U S A 105 (26): 8855–60. Bibcode:2008PNAS..105.8855C. doi:10.1073/pnas.0709249105. PMC 2449330. PMID 18577597.
^ Narhi L, Fulco A (5 June 1986). "Characterization of a catalytically self-sufficient 119,000-dalton cytochrome P-450 monooxygenase induced by barbiturates in Bacillus megaterium". J Biol Chem 261 (16): 7160–9. PMID 3086309.
^ Girvan H, Waltham T, Neeli R, Collins H, McLean K, Scrutton N, Leys D, Munro A (2006). "Flavocytochrome P450 BM3 and the origin of CYP102 fusion species". Biochem Soc Trans 34 (Pt 6): 1173–7. doi:10.1042/BST0341173. PMID 17073779.
^ R. L. Wright, K. Harris, B. Solow, R. H. White, P. J. Kennelly (1996). "Cloning of a potential cytochrome P450 from the archaeon Sulfolobus solfataricus". FEBS Lett 384 (3): 235–9. doi:10.1016/0014-5793(96)00322-5. PMID 8617361.
^ Vanden Bossche H, Marichal P, Gorrens J, Coene MC (September 1990). "Biochemical basis for the activity and selectivity of oral antifungal drugs". Br J Clin Pract Suppl 71: 41–6. PMID 2091733.
^ Chefson A, Auclair K (2006). "Progress towards the easier use of P450 enzymes". Mol Biosyst. 10 (10): 462–9. doi:10.1039/b607001a. PMID 17216026.
^ Chefson A, Zhao J, Auclair K (2006). "Replacement of natural cofactors by selected hydrogen peroxide donors or organic peroxides results in improved activity for CYP3A4 and CYP2D6". Chembiochem 6 (6): 916–9. doi:10.1002/cbic.200600006. PMID 16671126.
^ Chefson A, Auclair K. (2007). "CYP3A4 activity in the presence of organic cosolvents, ionic liquids, or water-immiscible organic solvents". Chembiochem 10 (10): 1189–97. doi:10.1002/cbic.200700128. PMID 17526062.

External links[edit]

Wikimedia Commons has media related to Cytochrome P450.

Degtyarenko K (2009-01-09). "Directory of P450-containing Systems". International Centre for Genetic Engineering and Biotechnology. Retrieved 2009-02-10.
Estabrook R (2003). "A passion for P450s (remembrances of the early history of research on cytochrome P450)". Drug Metab Dispos 31 (12): 1461–73. doi:10.1124/dmd.31.12.1461. PMID 14625342.
Feyereisen R (2005-12-19). "The Insect P450 Site". Institut National de la Recherche Agronomique. Retrieved 2009-02-10.
Flockhart DA (2007). "Cytochrome P450 drug interaction table". Indiana University-Purdue University Indianapolis. Retrieved 2009-02-10.
Fowler L, Mercer A. "Cytochrome P450 Animated Tutorial". School of Pharmacy, London. Retrieved 2009-02-10.
Preissner S (2010). "Cytochrome P450 database". Nucleic Acids Research.
Sim SC (2008-09-04). "Human Cytochrome P450 (CYP) Allele Nomenclature Committee". Karolinska Institutet. Retrieved 2009-02-10.
Hazai E (2012-02-12). "Cytochrome P450 enzyme-substrate selectivity prediction".
Performance of P450 inhibition Studies The performance of in vitro cytochrome P450 inhibition studies studies including analysis of the data.
DDI Regulatory Guidance Request a guide to drug-drug interaction regulatory recommendations.
Expanding the toolbox of cytochrome P450s through enzyme engineering Video by the Turner Group, University of Manchester, UK

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「シトクロムP450」

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Cytochrome P450
	; Cytochrome P450 Oxidase (CYP2C9)
Identifiers
Symbol	p450
Pfam	PF00067
InterPro	IPR001128
PROSITE	PDOC00081
SCOP	2cpp
SUPERFAMILY	2cpp
OPM superfamily	41
OPM protein	2bdm
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

　　[★]

英: cytochrome P-450, cytochrome P450, P450, CYP P450, CYP, cytochrome P
同: シトクロムP-450、チトクロムP450、チトクロムP-450、チトクロームP-450、P-450
関: シトクロム cytochrome CYP。薬物代謝酵素

シトクロムP450

モノオキシゲナーゼ
分子状酸素とNADPHを利用し、様々な基質をヒドロキシル化

RH + NADPH + O₂ + H⁺　→ ROH + NADP⁺ + H₂O

シトクロムP450は水酸化酵素ファミリーの総称
肝臓に多く存在し、解毒を行う。

水酸化により可溶化し、グルクロン酸抱合を行い、尿として排出できるようにする。

ステロイドホルモンの生合成
脂肪酸の代謝
細胞内の小胞体に多い
一部はミトコンドリアに存在