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.
Genes encoding P450 enzymes, and the enzymes themselves, are designated with the
root symbolCYP for the
superfamily, 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 CYP450 or CYP450 is used synonymously. These names should never be used as according to the nomenclature convention (as they denote a P450 in family number 450). However, some gene or enzyme names for P450s are also referred to by historical names (e.g. P450BM3 for CYP102A1) or functional names, denoting the catalytic activity and the name of the compound used as substrate. Examples include
CYP5A1,
thromboxane A2 synthase, abbreviated to
TBXAS1 (ThromBoXane A2Synthase 1), and
CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate (Lanosterol) and activity (DeMethylation).[8]
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:
The active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a
cysteinethiolateligand. 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
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]
Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position, initially giving a
dioxygen adduct similar to oxy-myoglobin.
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,[16] P450 Compound 1 is 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[13] is lacking.[16]
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.
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[19] located either in the inner membrane of
mitochondria or in the
endoplasmic reticulum of cells. P450s metabolize thousands of
endogenous and
exogenous chemicals. Some P450s 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.[20]
P450s are the major enzymes involved in
drug metabolism, accounting for about 75% of the total metabolism.[22] Most drugs undergo deactivation by P450s, either directly or by facilitated
excretion from the body. However, many substances are
bioactivated by P450s to form their active compounds like the
antiplatelet drugclopidogrel 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]
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[25] or
carbamazepine.[26] 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.
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.[27] Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised.[28]
At relatively high concentrations,
starfruit juice has also been shown to inhibit
CYP2A6 and other P450s.[32]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).[33]
Tributyltin has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.[34]
Goldenseal, with its two notable alkaloids
berberine and
hydrastine, has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).[35]
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).
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.
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, (15-HETE) to 15,20-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.[37]
CYP families in humans
Humans have 57 genes and more than 59
pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.[38] 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]
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.[39]Mice have genes for 101 P450s, and
sea urchins have even more (perhaps as many as 120 genes).[40]
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.[41]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.[42]
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.,[46][47]). 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,[48]) or are part of specialised metabolite biosynthetic pathways (e.g.
CYP170B1 catalyses production of the
sesquiterpenoid albaflavenone in Streptomyces albus[49]). 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.[50] 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 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.[51][52]
Cytochrome P450 119 (
CYP119A1) isolated from the
thermophillic archea Sulfolobus solfataricus[53] has been used in a variety of mechanistic studies.[16] 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.
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.[55][56] These enzymes lead to various
fatty acid conjugates,
plant hormones,
secondary metabolites,
lignins, and a variety of defensive compounds.[57]
Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites.[58] The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.[59]
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.[60]
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.[61] 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.[55] 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.
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.[62]
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