Cytochrome P450/ja

シトクロムP450（P450sまたはCYPs）は、ヘムを補因子として含む酵素のスーパーファミリーの一つであり、そのほとんどがモノオキシゲナーゼとして機能するが、それだけに限定されるわけではない。哺乳類では、これらのタンパク質はステロイド類、脂肪酸類、異種物質類を酸化し、様々な化合物のクリアランス、ホルモン合成と分解、ステロイドホルモン合成、薬物代謝、防御化合物、脂肪酸、ホルモンの生合成に重要である。CYP450酵素はゼノバイオティクスを親水性の誘導体に変換し、排泄されやすくする。触媒する変換のほとんどすべてにおいて、P450はヒドロキシル化に影響を及ぼす。

P450酵素は、動物、植物、菌類、原生生物、細菌、古細菌、およびウイルスのすべての界で同定されている。例えば、大腸菌では見つかっていない。2018年現在、30万以上の異なるCYPタンパク質が知られている。

P450は一般に電子伝達鎖の末端酸化酵素であり、大別するとP450含有系となる。"P450"という用語は、酵素が酸化還元状態で一酸化炭素と複合体化したときの吸収極大の分光光度波長（450 nm）にあるピークに由来する。ほとんどのP450は、鉄（そして最終的には分子状の酸素）を還元するために1つ以上の電子を供給するタンパク質パートナーを必要とする。

命名法

P450酵素をコードする遺伝子および酵素自体は、スーパーファミリーを表すルート記号CYPの後に、遺伝子ファミリーを表す数字、サブファミリーを表す大文字、個々の遺伝子を表す別の数字が続く。遺伝子に言及する際にはイタリック体で表記するのが慣例である。例えば、CYP2E1 はパラセタモール（アセトアミノフェン）の代謝に関与する酵素の一つであるCYP2E1をコードする遺伝子である。CYP命名法は公式の命名規則であるが、CYP450またはCYP₄₅₀が同義語として用いられることもある。これらの名称は、命名規則に従って（ファミリー番号450のP450を示すため）決して使用すべきではない。しかし、P450の遺伝子名や酵素名の中には、歴史的な名称（例えば、CYP102A1のP450_BM3）や、触媒活性や基質として使用される化合物の名称を示す機能名で呼ばれるものもある。例えば、CYP5A1、トロンボキサンA₂合成, TBXAS1（ThromBoXane A₂ Synthase 1）、CYP51A1, ラノステロール14-α-デメチラーゼ、基質（Lanosterol）と活性（DeMethylation）により、非公式にLDMと略されることもある。

現在の命名法ガイドラインでは、新しいCYPファミリーのメンバーは少なくとも40%のアミノ酸同一性を共有し、サブファミリーのメンバーは少なくとも55%のアミノ酸同一性を共有することが推奨されている。命名法委員会は、基本遺伝子名（Cytochrome P450 Homepage Archived 2010-06-27 at the Wayback Machine）と対立遺伝子名（CYP Allele Nomenclature Committee)の両方を割り当て、追跡している。

分類

詳細は「P450-containing systems/ja」を参照

電子伝達タンパク質の性質に基づき、P450はいくつかのグループに分類される：

ミクロソームP450系：電子がNADPHからシトクロムP450還元酵素（CPR、POR、CYPORなど様々）を介して移動する。シトクロムb₅（cyb₅）もまた、シトクロムb₅レダクターゼ（CYB₅R）によって還元された後、この系に還元力を寄与することができる。

ミトコンドリアP450システム：NADPHからP450に電子を移動させるためにアドレノドキシン還元酵素とアドレノドキシンを用いる。

バクテリアP450システム：P450に電子を伝達するためにフェレドキシン還元酵素とフェレドキシンを用いる。

CYB₅R/cyb₅/P450系：CYPが必要とする両方の電子がシトクロムb₅から来る。

FMN/Fd/P450システム：もともとはロドコッカス属で発見されたもので、FMNドメインを含む還元酵素がCYPに融合している。

P450系のみ：外部からの還元力を必要としない。代表的なものにトロンボキサン合成酵素（CYP5）、プロスタサイクリン合成酵素（CYP8）、CYP74A（アレンオキシド合成酵素）がある。

シトクロムP450が触媒する最も一般的な反応はモノオキシゲナーゼ反応であり、例えば、有機基質（RH）の脂肪族位に酸素の1原子を挿入し、もう1つの酸素原子は還元されて水になる：

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

多くの水酸化反応（水酸基の挿入）にはCYP酵素が使われる。

メカニズム

左下の「Fe(V)中間体」は単純化したもので、ラジカルヘム配位子を持つFe(IV)である。

構造

シトクロムP450の活性部位にはヘム鉄中心がある。鉄はシステインチオラートリガンドを介してタンパク質に結合している。このシステインといくつかの隣接残基は、既知のP450において高度に保存されており、正式なPROSITEシグネチャーコンセンサスパターン[FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD]を持っている。P450によって触媒される反応は多種多様であるため、多くのP450の活性と特性は多くの点で異なっている。一般的に、P450の触媒サイクルは以下のように進行する：

触媒サイクル

1. 基質はヘム基に近接し、チオラート軸とは反対側に結合する。 基質が結合すると、活性部位のコンフォメーションが変化し、多くの場合、水分子がヘム鉄の遠位軸配位位置からはずれ、ヘム鉄の状態が低スピンから高スピンへと変化する。
2. 基質が結合すると、NAD(P)HからシトクロムP450還元酵素または関連する別の還元酵素を介して電子移動が起こる。
3. 分子状酸素は、結果として生じる第一鉄ヘム中心に遠位軸配位で結合し、最初はオキシミオグロビンに似た酸素付加体を与える。
4. 第2の電子は、シトクロムP450還元酵素、フェレドキシン、|シトクロムb₅のいずれかから移動し、Fe-O₂付加体を還元して短命のペルオキソ状態を与える。
5. ステップ4で形成されたペルオキソ基は急速に2回プロトン化され、1分子の水を放出し、P450化合物1（または単に化合物I）と呼ばれる高反応性種を形成する。 この反応性の高い中間体は2010年に単離され、P450化合物1は、ポルフィリンとチオラート配位子上にさらに酸化当量が非局在化した鉄(IV)オキソ（またはフェリル）種である。代替的なフェリル鉄(V)-オキソの証拠は不足している。
6. 関与する基質と酵素に応じて、P450酵素は多種多様な反応のいずれかを触媒することができる。 この図に、仮定の水酸化反応を示す。 生成物が活性部位から放出された後、酵素は元の状態に戻り、水分子が鉄核の遠位配位位置を占めるように戻る。

シトクロムP450が、ヘムラジカルカチオンと結合した酸化鉄(IV)である「化合物I」の作用によって炭化水素をアルコールに変換する際に利用する酸素リバウンド機構。

1. モノ酸素化の代替経路は、"過酸化物シャント"（図中の経路 "S"）である。この経路は、過酸化物や次亜塩素酸塩のような酸素原子供与体による第二鉄-基質複合体の酸化を伴う。 仮想的な過酸化物 "XOOH "を図に示す。

スペクトロスコピー

基質の結合は酵素のスペクトル特性に反映され、390 nmで吸光度が増加し、420 nmで減少する。これは差スペクトルによって測定することができ、"type I"差スペクトルと呼ばれる（図の挿入グラフ参照）。 基質によっては、スペクトル特性に逆の変化、すなわち "逆タイプ I"スペクトルを引き起こすものもあり、その過程はまだ不明である。 ヘム鉄に直接結合する阻害剤とある種の基質は、430 nmに極大、390 nmに極小を持つタイプ II差スペクトルを生じる（図の挿入グラフ参照）。 還元当量がない場合、この複合体は安定なままである可能性があり、吸光度測定から結合の程度を試験管内で決定することができる。 C: 一酸化炭素（CO）が還元型P450に結合すると、触媒サイクルは中断される。この反応により、450 nmに極大を持つ古典的なCO差スペクトルが得られる。しかし、COの触媒阻害作用はCYPによって異なり、CYP3Aファミリーは比較的影響を受けにくい。

ヒトにおけるP450

ヒトのP450は、主にミトコンドリアの内膜か細胞の小胞体に存在する膜関連タンパク質である。P450は何千もの内因性および外因性化学物質を代謝する。P450の中には、CYP19（アロマターゼ）のように1つの基質（またはごく少数の基質）のみを代謝するものもあれば、複数の基質を代謝するものもある。これらの特徴の両方が、医学における中心的な重要性の理由である。シトクロムP450酵素は身体のほとんどの組織に存在し、ホルモンの合成と分解（エストロゲンとテストステロンの合成と代謝を含む）、コレステロールの合成、ビタミンDの代謝において重要な役割を担っている。シトクロムP450酵素はまた、主に肝臓において、薬物やビリルビンのような内因性代謝産物など、潜在的に毒性のある化合物を代謝する働きもする。

ヒトゲノムプロジェクトは、様々なシトクロームP450酵素をコードする57のヒト遺伝子を同定した。

薬物代謝

異なるP450ファミリーによって代謝される抗真菌薬の割合

。

詳細は「Drug metabolism/ja」を参照

P450は薬物代謝に関与する主要な酵素であり、代謝全体の約75％を占める。ほとんどの薬物は、P450によって直接または体外への排泄促進によって不活性化される。しかし、多くの物質はP450によって生物活性化され、抗血小板薬のような活性化合物を形成する。クロピドグレルやアヘンコデインのようにである。

CYP450酵素スーパーファミリーは57の活性サブセットからなり、7つがほとんどの医薬品の代謝に重要な役割を果たしている。第1相（解毒）におけるCYP450酵素（CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP3A5）の量の変動は、遺伝子発現に個人差があるため、個人によって様々な影響を及ぼす可能性がある。このばらつきは、酵素の遺伝子多型によるもので、酵素の機能と発現にばらつきが生じる。個人の薬物代謝を最適化するためには、遺伝子検査を行い、個人のCYP450多型に対応した機能性食品や特定の植物栄養素を決定する必要がある。このような遺伝的変異を理解することは、薬物療法の有効性を高め、副作用を軽減するための個別化に役立つ。

薬物相互作用

多くの薬物は、アイソザイムの生合成を誘導する（酵素誘導）か、P450の活性を直接阻害する（酵素阻害）かのどちらかによって、様々なP450アイソザイムの活性を増減させる可能性がある。古典的な例としては、CYP1A2、CYP2C9、CYP2C19、CYP3A4を誘導するフェニトインなどの抗てんかん薬が挙げられる。

Effects on P450 isozyme activity are a major source of adverse drug interactions, since changes in P450 enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the P450-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 P450 system. Such drug interactions are especially important to consider when using drugs of vital importance to the patient, drugs with significant side-effects, or drugs with a narrow therapeutic index, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.

Many substrates for CYP3A4 are drugs with a narrow therapeutic index, such as amiodarone or carbamazepine. Because these drugs are metabolized by CYP3A4, the mean plasma levels of these drugs may increase because of enzyme inhibition or decrease because of enzyme induction.

Nutritional Modulation of CYP450 Enzymes: Balancing Induction and Inhibition Cruciferous vegetables are induce CYP1A1 and aid in the upregulation of CYP1B1. These vegetables, along with berries, can also influence estrogen processing in the body. Berries are believed to reduce the activity of CYP1A1, while cruciferous vegetables may boost the activity of CYP1A enzymes over CYP1B1 enzymes.

Resveratrol, ellagic acid quercetin, found in many foods, affect CYP1A2 activity.

Interaction of other substances

Naturally occurring compounds may also induce or inhibit P450 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.
• 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 P450s. Watercress is also a known inhibitor of the cytochrome P450 CYP2E1, which may result in altered drug metabolism for individuals on certain medications (e.g., chlorzoxazone).
• Tributyltin has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.
• Goldenseal, with its two notable alkaloids berberine and hydrastine, has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).

Other specific P450 functions

Steroid hormones

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 affects "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.
• CYP21A2 (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.

Polyunsaturated fatty acids and eicosanoids

Certain cytochrome P450 enzymes are critical in metabolizing polyunsaturated fatty acids (PUFAs) to biologically active, intercellular cell signaling molecules (eicosanoids) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products. These CYPs possess cytochrome P450 omega hydroxylase and/or epoxygenase enzyme activity.

• CYP1A1, CYP1A2, and CYP2E1 metabolize endogenous PUFAs to signaling molecules: they metabolize arachidonic acid (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see 20-hydroxyeicosatetraenoic acid); eicosapentaenoic acid (i.e. EPA) to epoxyeicosatetraenoic acids (i.e. EEQs); and docosahexaenoic acid (i.e. DHA) to epoxydocosapentaenoic acids (i.e. EDPs).
• CYP2C8, CYP2C9, CYP2C18, CYP2C19, and CYP2J2 metabolize endogenous PUFAs to signaling molecules: they metabolize AA to epoxyeicosatetraenoic acids (i.e. EETs); EPA to EEQs; and DHA to EDPs.
• CYP2S1 metabolizes PUFA to signaling molecules: it metabolizes AA to EETs and EPA to EEQs.
• CYP3A4 metabolizes AA to EET signaling molecules.
• CYP4A11 metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
• CYP4F2, CYP4F3A, and CYP4F3B (see CYP4F3 for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA. They also inactivate or reduce the activity of signaling molecules: they metabolize leukotriene B4 (LTB4) to 20-hydroxy-LTB4, 5-hydroxyeicosatetraenoic acid (5-HETE) to 5,20-diHETE, 5-oxo-eicosatetraenoic acid (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, 12-hydroxyeicosatetraenoic acid (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
• CYP4F8 and CYP4F12 metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
• CYP4F11 inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and lipoxins to 20-hydroxy products.
• CYP4F22 ω-hydroxylates extremely long "very long chain fatty acids", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skin's water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the Lamellar ichthyosis subtype of Congenital ichthyosiform erythrodema in humans.

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	Genes	Pseudogenes
CYP1	drug and steroid (especially estrogen) metabolism, benzo[a]pyrene toxification (forming (+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide)	3 subfamilies, 3 genes, 1 pseudogene	CYP1A1, CYP1A2, CYP1B1	CYP1D1P
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	Too many to list
CYP3	drug and steroid (including testosterone) metabolism	1 subfamily, 4 genes, 4 pseudogenes	CYP3A4, CYP3A5, CYP3A7, CYP3A43	CYP3A51P, CYP3A52P, CYP3A54P, CYP3A137P
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	Too many to list
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	1 subfamilies, 1 gene, 1 pseudogene	CYP21A2	CYP21A1P
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 (vitamin A1 to A2)
CYP39	7-alpha hydroxylation of 24-hydroxycholesterol	1 subfamily, 1 gene	CYP39A1
CYP46	cholesterol 24-hydroxylase	1 subfamily, 1 gene, 1 pseudogene	CYP46A1	CYP46A4P
CYP51	cholesterol biosynthesis	1 subfamily, 1 gene, 3 pseudogenes	CYP51A1 (lanosterol 14-alpha demethylase)	CYP51P1, CYP51P2, CYP51P3

P450s in other species

Animals

Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge Amphimedon queenslandica to 235 genes in the cephalochordate Branchiostoma floridae. Mice have genes for 101 P450s, 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). Gene and genome sequencing is far outpacing biochemical characterization of enzymatic function, though many genes with close homology to CYPs with known function have been found, giving clues to their functionality.

The classes of P450s 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 P450s in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the CYP28A1 gene for detoxification of cacti rot is Drosophila mettleri. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.

P450s 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 P450s have also been discovered in avian species, in particular turkeys, that may turn out to be a useful 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 CYP6M2 in the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing pyrethroids.

Microbial

Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. E.coli). Some bacteria, predominantly actinomycetes, have numerous P450s. Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. CYP105A1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives) or are part of specialised metabolite biosynthetic pathways (e.g. CYP170B1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus). Although no P450 has yet been shown to be essential in a microbe, the CYP105 family is highly conserved with a representative in every streptomycete genome sequenced so far. Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the heterologously expressed proteins in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.

• Cytochrome P450 cam (CYP101A1) 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 (CYP119A1) isolated from the thermophillic archea Sulfolobus solfataricus 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

Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome. These enzymes lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds.

Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites. The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.

Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.

Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide. JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner. Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.

Cytochrome P450 aromatic O-demethylase, which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.

InterPro subfamilies

InterPro subfamilies:

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

Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates. are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.

These enzymes are of interest, because in assays, they can activate compounds to carcinogens. High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.

歴史

1963年、エスタブルック、クーパー、ローゼンタールは、ステロイドホルモン合成と薬物代謝における触媒としてのCYPの役割を説明した。植物では、これらのタンパク質は防御化合物、脂肪酸、ホルモンの生合成に重要である。

こちらも参照

• Steroidogenic enzyme/ja
• Cytochrome P450 oxidoreductase deficiency/ja
• CYP11 family/ja
• Cytochrome P450 engineering/ja

さらに読む

• Gelboin HV, Krausz K (March 2006). "Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm". Journal of Clinical Pharmacology. 46 (3): 353–372. doi:10.1177/0091270005285200. PMID 16490812. S2CID 33325397.
• Gelboin HV, Krausz KW, Gonzalez FJ, Yang TJ (November 1999). "Inhibitory monoclonal antibodies to human cytochrome P450 enzymes: a new avenue for drug discovery". Trends in Pharmacological Sciences. 20 (11): 432–438. doi:10.1016/S0165-6147(99)01382-6. PMID 10542439.
• "Cytochrome P450 Mediated Drug and Carcinogen Metabolism using Monoclonal Antibodies". home.ccr.cancer.gov. Retrieved 2018-04-02.
• Krausz KW, Goldfarb I, Buters JT, Yang TJ, Gonzalez FJ, Gelboin HV (November 2001). "Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19". Drug Metabolism and Disposition. 29 (11): 1410–1423. PMID 11602516.
• Gonzalez FJ, Gelboin HV (1994). "Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins". Drug Metabolism Reviews. 26 (1–2): 165–183. doi:10.3109/03602539409029789. PMID 8082563.
• Estabrook RW (December 2003). "A passion for P450s (Remembrances of the early history of research on cytochrome P450)". Drug Metabolism and Disposition. 31 (12): 1461–1473. doi:10.1124/dmd.31.12.1461. PMID 14625342. S2CID 43655270.

外部リンク

• Degtyarenko K (2009-01-09). "Directory of P450-containing Systems". International Centre for Genetic Engineering and Biotechnology. Archived from the original on 2016-07-16. Retrieved 2009-02-10.
• Flockhart DA (2008-09-04). "Human Cytochrome P450 (CYP) Allele Nomenclature Committee". Karolinska Institutet. Retrieved 2009-02-10.
• Preissner S (2010). "Cytochrome P450 database". Nucleic Acids Research. Archived from the original on 2011-11-03. Retrieved 2011-08-02.
• Sigaroudi A, Vollbrecht H (2019). "pharmacokinetic interaction table". Sigaroudi & Vollbrecht.
• Sim SC (2007). "Cytochrome P450 drug interaction table". Indiana University-Purdue University Indianapolis. Retrieved 2009-02-10.