Cytochrome P450

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Cytochrome P450 oxidase
)
Cytochrome P450
SCOP2
2cpp / SCOPe / SUPFAM
OPM superfamily39
OPM protein2bdm
CDDcd00302
Membranome265
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Cytochromes P450 (P450s or CYPs) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases.[1][2][3] In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of defensive compounds, fatty acids, and hormones.[2] CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's affect hydroxylation.

P450 enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses.[4] However, they are not omnipresent; for example, they have not been found in Escherichia coli.[3][5] As of 2018, more than 300,000 distinct CYP proteins are known.[6][7]

P450s 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 carbon monoxide. Most P450s require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen).

Nomenclature

CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).[8]

The current nomenclature guidelines suggest that members of new CYP families share at least 40% amino-acid identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names (Cytochrome P450 Homepage Archived 2010-06-27 at the Wayback Machine) and allele names (CYP Allele Nomenclature Committee).[9][10]

Classification

Based on the nature of the electron transfer proteins, P450s can be classified into several groups:[11]

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
which employ
adrenodoxin
to transfer electrons from NADPH to P450.
Bacterial P450 systems
which 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
reductase
is fused to the CYP.
P450 only systems
which do not require external reducing power. Notable ones include
thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase
).

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+

Many

hydroxyl
groups) use CYP enzymes.

Mechanism

radical heme ligand
.

Structure

The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a

thiolate ligand. This cysteine and several flanking residues are highly conserved in known P450s, and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[12]
Because of the vast variety of reactions catalyzed by P450s, the activities and properties of the many P450s differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

Catalytic cycle

  1. Substrate binds in proximity to the
    heme group, on the side opposite to the axial thiolate. Substrate binding 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,[13] and changing the state of the heme iron from low-spin to high-spin.[14]
  2. Substrate binding induces electron transfer from NAD(P)H via
  3. Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a dioxygen adduct similar to oxy-myoglobin.
  4. A second electron is transferred, from either cytochrome P450 reductase, ferredoxins, or cytochrome b5, reducing the Fe-O2 adduct to give a short-lived peroxo state.
  5. The peroxo group formed in step 4 is rapidly protonated twice, releasing one molecule of water and forming the highly reactive species referred to as P450 Compound 1 (or just Compound I). This highly reactive intermediate was isolated in 2010,
    delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron(V)-oxo[13] is lacking.[16]
  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.
Oxygen rebound mechanism utilized by cytochrome P450 for conversion of hydrocarbons to alcohols via the action of "compound I", an iron(IV) oxide bound to a heme radical cation.
  1. An alternative route for mono-oxygenation is via the "peroxide shunt" (path "S" in figure). This pathway entails oxidation of the ferric-substrate complex with oxygen-atom donors such as peroxides and hypochlorites.[17] A hypothetical peroxide "XOOH" is shown in the diagram.

Spectroscopy

Binding of substrate is reflected 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 spectroscopies 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[17] 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. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected.[18]

P450s in humans

Human P450s are primarily membrane-associated proteins

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.[20]

Drug metabolism

Proportion of antifungal drugs metabolized by different families of P450s.[21]

P450s are the major enzymes involved in

bioactivated by P450s to form their active compounds like the antiplatelet drug clopidogrel and the opiate codeine
.

The CYP450 enzyme superfamily comprises 57 active subsets, with seven playing a crucial role in the metabolism of most pharmaceuticals.[23] The fluctuation in the amount of CYP450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) in phase 1 (detoxification) can have varying effects on individuals, as genetic expression varies from person to person. This variation is due to the enzyme’s genetic polymorphism, which leads to variability in its function and expression. To optimize drug metabolism in individuals, genetic testing should be conducted to determine functional foods and specific phytonutrients that cater to the individual’s CYP450 polymorphism. Understanding these genetic variations can help personalize drug therapies for improved effectiveness and reduced adverse reactions.[24]

Drug interaction

Many drugs may increase or decrease the activity of various P450

enzyme inhibition). A classical example includes anti-epileptic drugs, such as phenytoin, which induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4
.

Effects on P450 isozyme activity are a major source of adverse

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

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.[27]

Resveratrol, ellagic acid quercetin, found in many foods, affect CYP1A2 activity.[27][28][29]

Interaction of other substances

Naturally occurring compounds may also induce or inhibit P450 activity. For example,

overdosing.[30] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.[31]

Other examples:

Other specific P450 functions

Steroid hormones

Steroidogenesis, showing many of the enzyme activities that are performed by cytochrome P450 enzymes.[39]
HSD: Hydroxysteroid dehydrogenase.

A subset of cytochrome P450 enzymes play important roles in the synthesis of

, and peripheral tissue:

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.

CYP families in humans

Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[41] 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.[20]

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
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
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

Mice have genes for 101 P450s, and sea urchins have even more (perhaps as many as 120 genes).[43]
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.,
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

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

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.[44] 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.[45]

CYPs have also been heavily studied in

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 (e.g.,

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.

Fungi

The commonly used

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.[57][58] These enzymes lead to various fatty acid conjugates, plant hormones, secondary metabolites, lignins, and a variety of defensive compounds.[59]

Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.[60] The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.[61]

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.[62]

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.[63] 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.[57] 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:

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.[64]

History

In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.[2]

See also

References

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Further reading

External links