P450

• 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

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。

分類・命名

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
		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
		CYP3A5	テストステロン、クラリスロマイシン

機能

異物代謝（解毒作用など）

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

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

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）

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

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

関連項目

• 酸化酵素
• 廣部雅昭

外部リンク

• 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）

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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

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.

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. However, the enzymes have not been found in E. coli. More than 18,000 distinct CYP proteins are known.

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:

• 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).

Nomenclature

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).

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

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]. 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:

1. 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, and sometimes changing the state of the heme iron from low-spin to high-spin. 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
2. 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 This takes place by way of the electron transfer chain, as described above, reducing the ferric heme iron to the ferrous state.
3. 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.
4. 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.
5. 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, although it had been studied theoretically for many years. 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 is lacking.
6. 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. 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

Human CYPs are primarily membrane-associated proteins 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.

Drug metabolism

Proportion of antifungal drugs metabolized by different families of CYPs.

Further information: Drug metabolism

CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism. 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

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

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. Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.

Other examples:

• Saint-John's wort, a common herbal remedy induces CYP3A4, but also inhibits CYP1A1, CYP1B1, and CYP2D6.

• Tobacco smoking induces CYP1A2 (example CYP1A2 substrates are clozapine, olanzapine, and fluvoxamine)

• At relatively high concentrations, starfruit juice has also been shown to inhibit CYP2A6 and other CYPs. 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).

Other specific CYP functions

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

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies. 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.

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

Animals

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). 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. 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.

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 and CYP6Z1 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing DDT.

Microbial

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.

• Cytochrome P450 119 (CYP119) isolated from the thermophillic archea Sulfolobus acidocaldarius has been used in a variety of mechanistic studies. 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

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.)

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

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

The remarkable reactivity and substrate promiscuity of P450s have long attracted the attention of chemists. 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, (ii) exploring the compatibility of p450s with organic solvents, and (iii) the use of small, non-chiral auxiliaries to predictably direct P450 oxidation.^{[citation needed]}

InterPro subfamilies

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

External links

• 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

UpToDate Contents

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• 1. 薬理ゲノム学の概要 overview of pharmacogenomics
• 2. まれな先天性副腎過形成 uncommon congenital adrenal hyperplasias
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English Journal

• Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy.

• Wilkinson-Berka JL, Rana I, Armani R, Agrotis A.SourceDepartment of Immunology, Central Clinical School, Monash University, 99 Commercial Road, Alfred Medical Research and Education Precinct (AMREP), Alfred Centre, Melbourne, Victoria 3004, Australia.
• Clinical science (London, England : 1979).Clin Sci (Lond).2013 May 1;124(10):597-615. doi: 10.1042/CS20120212.
• Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, al
• PMID 23379642

• Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct.

• Gálvez-Peralta M, Shi Z, Chen J, Miller ML, Nebert DW.SourceDepartment of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati OH.
• International journal of cancer. Journal international du cancer.Int J Cancer.2013 May 1;132(9):2065-75. doi: 10.1002/ijc.27897. Epub 2012 Dec 4.
• Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) and other enzymes can activate PAHs to reactive oxygenated intermediates involved in mutagenesis and tumor initiation; also, CYP1 enzymes c
• PMID 23047765

• Pregnane glycosides interfere with steroidogenic enzymes to down-regulate corticosteroid production in human adrenocortical H295R cells.

• Komarnytsky S, Esposito D, Poulev A, Raskin I.SourceBiotech Center, SEBS, Rutgers University, New Brunswick, New Jersey; Plants for Human Health Institute, FBNS, North Carolina State University, Kannapolis, North Carolina. komarnytsky@ncsu.edu.
• Journal of cellular physiology.J Cell Physiol.2013 May;228(5):1120-6. doi: 10.1002/jcp.24262.
• A group of bioactive steroidal glycosides (pregnanes) with anorectic activity in animals was isolated from several genera of milkweeds including Hoodia and Asclepias. In this study, we investigated the effects, structure-activity relationships, and mechanism of action of pregnane glycosides on stero
• PMID 23065845

Japanese Journal

• Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women

• Kobayashi Sumitaka,Sata Fumihiro,Sasaki Seiko,Ban Susumu,Miyashita Chihiro,Okada Emiko,Limpar Mariko,Yoshioka Eiji,Kajiwara Jumboku,Todaka Takashi,Saijo Yasuaki,Kishi Reiko
• Toxicology Letters 219(3), 269-278, 2013-06-07
• … Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). …
• NAID 120005295676

• 2,2',3,4',5,5'-六塩素化ビフェニル(CB146)のin vitro代謝の動物種差

• 太田 千穂,原口 浩一,加藤 善久,遠藤 哲也,古賀 信幸,Ohta Chiho,Haraguchi Koichi,Kato Yoshihisa,Endo Tetsuya,Koga Nobuyuki,オオタ チホ,ハラグチ コウイチ,カトウ ヨシヒサ,エンドウ テツヤ,コガ ノブユキ
• 福岡医学雑誌 104(4), 161-169, 2013-04-25
• … These results suggest that 3'-OH-CB146 is formed by PB-inducible cytochrome P450 (CYP2B enzymes) in animal and human livers and 4-OH-CB146 is a major metabolite in rat and human liver. …
• NAID 120005303404

• ダイオキシン母体曝露による胎児副腎ステロイド合成系への影響と性差

• 武田 知起,服部 友紀子,藤井 美彩紀,田浦 順樹,石井 祐次,山田 英之,Takeda Tomoki,Hattori Yukiko,fujii Misaki,Taura Junki,Ishii Yuji,Yamada Hideyuki,タケダ トモキ,ハットリ ユキコ,フジイ ミサキ,タウラ ジュンキ,イシイ ユウジ,ヤマダ ヒデユキ
• 福岡医学雑誌 104(4), 143-151, 2013-04-25
• … Our previous studies have revealed that single oral administration of TCDD (1µg/kg) to pregnant rats at gestational day (GD) 15 attenuates the fetal expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17 by targeting the fetal production of pituitary gonadotropins. …
• NAID 120005303402

Related Links

• シトクロムP450 - 薬学用語解説 - 日本薬学会

cytochrome P450 細菌から植物，哺乳動物に至るまでのほとんどすべての生物に存在する、分子量約45000から60000の酸化酵素で，異物（薬物）代謝においては主要な第一相反応の酵素。約500アミノ酸残基からなり、活性部位にヘムを ...

• 薬物代謝（シトクロムP450など）

薬物代謝（シトクロムP450など） シトクロムP450（CYP）の働き 薬物が体内に入ると、必ず代謝される。このとき、薬物代謝に最も重要となるのがシトクロムP450(CYP)である。 薬物の多くは脂溶性が高い。なぜならば、多くの薬物は ...

Related Pictures

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★リンクテーブル★

リンク元	「シトクロムP450」「P45017α欠損症」
拡張検索	「チトクロムP450レダクターゼ」「チトクロムP450酵素CYP2D6」「チトクロムP450酵素CYP2E1」「P450scc」

「シトクロムP450」

　　[★]

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

シトクロムP450

「P45017α欠損症」

　　[★]

英

cytochrome P450 17α-hydroxylase deficiency

関

P450

「チトクロムP450レダクターゼ」

　　[★]

英

cytochrome P450 reductase

関

チトクロムP450還元酵素

「チトクロムP450酵素CYP2D6」

　　[★]

英

cytochrome P-450 CYP2D6

関

CYP2D6タンパク質

「チトクロムP450酵素CYP2E1」

　　[★]

英

cytochrome P-450 CYP2E1

関

CYP2E1タンパク質

「P450scc」

　　[★]

同

cytochrome P450 side chain cleavage enzyme