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Cytochrome P-450: Structure, Mechanism, and Biochemistry
Cytochromes P CYPs are a superfamily of enzymes containing heme as a cofactor that function as monooxygenases. In plants, these proteins are important for the biosynthesis of defensive compounds , fatty acids, and hormones.
CYP enzymes have been identified in all kingdoms of life: animals , plants , fungi , protists , bacteria , and archaea , as well as in viruses. CYPs are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as Pcontaining systems.
Most CYPs require a protein partner to deliver one or more electrons to reduce the iron and eventually molecular oxygen. Genes encoding CYP enzymes, and the enzymes themselves, are designated with the root symbol CYP 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. 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. Based on the nature of the electron transfer proteins, CYPs can be classified into several groups: . The most common reaction catalyzed by cytochromes P is a monooxygenase reaction, e. Many hydroxylation reactions insertion of hydroxyl groups use CYP enzymes. The active site of cytochrome P contains a heme -iron center.
The iron is tethered to the protein via a cysteine thiolate ligand. If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro  C: If carbon monoxide CO binds to reduced P, the catalytic cycle is interrupted. 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 P 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 P 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 P enzymes. Also, many substances are bioactivated by CYPs to form their active compounds like the antiplatelet drug clopidogrel. 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.
Effects on CYP isozyme activity are 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 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. 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.
A subset of cytochrome P enzymes play important roles in the synthesis of steroid hormones steroidogenesis by the adrenals , gonads , and peripheral tissue:. Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P genes and 43 subfamilies. See the homepage of the cytochrome P Nomenclature Committee for detailed information.
Many animals have as many or more CYP genes than humans do. Reported numbers range from 35 genes in the sponge Amphimedon queenslandica to genes in the cephalochordate Branchiostoma floridae.
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 CYPs most often investigated in non-human animals are those either involved in development e. Often there are differences in gene regulation or enzyme function of CYPs in related animals that explain observed differences in susceptibility to toxic compounds ex.
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. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.
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 useful model for cancer research in humans. CYPs have also been heavily studied in insects , often to understand pesticide resistance.
Microbial cytochromes P are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of Ps is very variable with many bacteria having no identified Ps e. Some bacteria, predominantly actinomycetes, have numerous Ps e. Those so far identified are generally involved in either biotransformation of xenobiotic compounds e.
CYPA1 from Streptomyces griseolus metabolizes sulfonylurea herbicides to less toxic derivatives,  or are part of specialised metabolite biosynthetic pathways e. CYPB1 catalyses production of the sesquiterpenoid albaflavenone in Streptomyces albus . Although no P has yet been shown to be essential in a microbe, the CYP family is highly conserved with a representative in every streptomycete genome sequenced so far.
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 Ps do in vivo, what the natural substrate s are and how Ps 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.
This interrupts the conversion of lanosterol to ergosterol , a component of the fungal cell membrane. This is useful only because humans' P have a different sensitivity; this is how this class of antifungals work.
Significant research is ongoing into fungal Ps, 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. Plant cytochrome Ps are involved in a wide range of biosynthetic reactions and target a diverse range of biomolecules. These reactions lead to various fatty acid conjugates, plant hormones , secondary metabolites , lignins , and a variety of defensive compounds.
The number and diversity of P genes is responsible, in part, for the multitude of bioactive compounds. Cytochrome P aromatic O-demethylase , which is made of two distinct promiscuous parts: a cytochrome P 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. The remarkable reactivity and substrate promiscuity of Ps have long attracted the attention of chemists. 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. From Wikipedia, the free encyclopedia.
Class of enzymes. Main article: Pcontaining systems. Further information: Drug metabolism. This section may require cleanup to meet Wikipedia's quality standards. The specific problem is: broken links; fragmented paragraph. Please help improve this section if you can. September Learn how and when to remove this template message. Environmental Health Perspectives. Current Drug Metabolism. Journal of Virology.
New York: Wiley. January Human Genomics. University of Tennessee. Retrieved Cell Biol. Advances in Molecular and Cell Biology. Chemical Reviews. Journal of Molecular Biology. Biochemical and Biophysical Research Communications. Bibcode : Sci Ortiz de Montellano The Journal of Physical Chemistry A. Bibcode : JPCA.. Lewis, Pharm. Chemical Research in Toxicology. Metabolism in this context is the chemical modification or degradation of drugs.
Biochem Pharmacol. Pharmacy Times. American Journal of Cardiovascular Drugs. John's wort".
Challenges in Computational Enzymology View all 14 Articles. Cytochrome P enzymes have gained significant interest as selective oxidants in late-stage chemical synthesis. Their broad substrate scope enables them to be good candidates for their use in non-natural reactivity. Directed evolution evolves new enzyme biocatalysts that promote alternative reactivity for chemical synthesis. While directed evolution has proven useful in developing biocatalysts for specific purposes, this process is very time and labor intensive, and therefore not easily repurposed.
In this issue of Biochemical Society Transactions , Elliott and Jones review some of the techniques used to prepare, measure and analyse the electron transfer properties of metalloproteins, concentrating on scanning tunnelling microscopy-based techniques and advances in attachment of proteins to electrodes. The cover image, taken from Figure 2 in the review, shows the direct attachment of a protein cytochrome b to gold substrate through an engineered cysteine residue. For further information see pages 1—9. Andrew W. Munro, Kirsty J.
Cytochromes P CYPs are a superfamily of enzymes containing heme as a cofactor that function as monooxygenases. In plants, these proteins are important for the biosynthesis of defensive compounds , fatty acids, and hormones. CYP enzymes have been identified in all kingdoms of life: animals , plants , fungi , protists , bacteria , and archaea , as well as in viruses. CYPs are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as Pcontaining systems. Most CYPs require a protein partner to deliver one or more electrons to reduce the iron and eventually molecular oxygen. Genes encoding CYP enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily , followed by a number indicating the gene family , a capital letter indicating the subfamily, and another numeral for the individual gene.
Request PDF | Cytochrome P Structure, mechanism, and biochemistry: Third edition | In this third edition of Cytochrome P Structure, Mechanism, and.
Hence, molecular and computational biologists have in the last two decades shown strong interest in the discovery and design of novel BM3 variants with optimized activity and selectivity for substrate conversion. This led e. In order to further improve our understanding of CYP binding and reactions, we performed a co-crystallization study of mutant M11 and report here the three-dimensional structure M11 in complex with dithiothreitol DTT at a resolution of 2. The structure shows that DTT can coordinate to the Fe atom in the heme group. Editor: Claudio M.
Author s : E. Fontana , P. Dansette , S. DOI : The inhibition of human cytochrome Ps CYPs is one of the most common mechanisms which can lead to drug-drug interactions.
It seems that you're in Germany. We have a dedicated site for Germany. Paul Ortiz de Montellano has brought together a group of new authors as well as authors from previous editions to produce a timely volume that will be of considerable interest to a broad array of P researchers. The explosion of discovery of CYP cytochrome P genes through genome analysis—more than to date—provides the more than 10, scientists around the world who study these monooxygenases a rich source of interesting and important research problems.
Paul Ortiz de Montellano has brought together a group of new authors as well as authors from previous editions to produce a timely volume that will be of considerable interest to a broad array of P researchers. The explosion of discovery of CYP cytochrome P genes through genome analysis—more than to date—provides the more than 10, scientists around the world who study these monooxygenases a rich source of interesting and important research problems. Many have remained central elements over the 18 years that span the three editions of this book, including mechanisms of catalysis, oxygen activation and inhibition, gene regulation, and P structure.