Fetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the human fetus during the last seven months of development in the uterus and persists in the newborn until 2-4 months old. Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the developing fetus better access to oxygen from the mother's bloodstream. In newborns, fetal hemoglobin is nearly replaced by adult hemoglobin by 6 months postnatally, except in a few thalassemia cases in which there may be a delay in cessation of HbF production until 3–5 years of age. In adults, fetal hemoglobin production can be reactivated pharmacologically, useful in the treatment of diseases such as sickle-cell disease. Oxygenated blood is delivered to the fetus via the umbilical vein from the placenta, anchored to the wall of the mother's uterus; the chorion acts as a barrier between the maternal and fetal circulation so that there is no admixture of maternal and fetal blood.
Blood in the maternal circulation is delivered via open ended arterioles to the intervillous space of the chorionic plate, where it bathes the chorionic villi that carry umbilical capillary beds, thereby allowing gas exchange to occur between the maternal and fetal circulation. Deoxygenated maternal blood drains into open ended intervillous venules to return to maternal circulation. Due to the admixture of oxygenated and deoxygenated blood, maternal blood in the intervillous space is lower in oxygen than arterial blood; as such, fetal hemoglobin must be able to bind oxygen with greater affinity than adult hemoglobin in order to compensate for the lower oxygen tension of the maternal blood supplying the chorion. Fetal hemoglobin's affinity for oxygen is greater than that of adult hemoglobin. Notably, the P50 value for fetal hemoglobin is lower than adult hemoglobin; the P50 of fetal hemoglobin is 19 mmHg, whereas adult hemoglobin is 26.8 mmHg. As a result, the "oxygen saturation curve", which plots percent saturation vs. pO2, is left-shifted for fetal hemoglobin as compared to adult hemoglobin.
This greater affinity for oxygen is explained by the lack of fetal hemoglobin's interaction with 2,3-bisphosphoglycerate. In adult red blood cells, this substance decreases the affinity of hemoglobin for oxygen. 2,3-BPG is present in fetal red blood cells, but interacts less efficiently with fetal hemoglobin than adult hemoglobin. This is due to a change in a single amino acid found in the 2,3-BPG'binding pocket': from histidine to serine, which gives rise to the greater oxygen affinity. Whereas histidine is positively charged and interacts well with the negative charges found on the surface of 2,3-BPG, Serine has a neutrally charged side chain at physiological pH, interacts less well; this change results in less binding of 2,3-BPG to fetal Hb, as a result oxygen will bind to it with higher affinity than adult hemoglobin. For mothers to deliver oxygen to a fetus, it is necessary for the fetal hemoglobin to extract oxygen from the maternal oxygenated hemoglobin across the placenta; the higher oxygen affinity required for fetal hemoglobin is achieved by the protein subunit γ, instead of the β subunit.
Because the γ subunit has fewer positive charges than the β subunit, 2,3-BPG is less electrostatically bound to fetal hemoglobin compared to adult hemoglobin. This lowered affinity allows for adult hemoglobin to transfer its oxygen to the fetal bloodstream. After the first 10 to 12 weeks of development, the fetus' primary form of hemoglobin switches from embryonic hemoglobin to fetal hemoglobin. At birth, fetal hemoglobin comprises 50-95% of the infant's hemoglobin; these levels decline after six months as adult hemoglobin synthesis is activated while fetal hemoglobin synthesis is deactivated. Soon after, adult hemoglobin takes over as the predominant form of hemoglobin in normal children; however HbF has been traced in adults' blood. Certain genetic abnormalities can cause the switch to adult hemoglobin synthesis to fail, resulting in a condition known as hereditary persistence of fetal hemoglobin. Most types of normal hemoglobin, including hemoglobin A, hemoglobin A2, as well as hemoglobin F, are tetramers composed of four protein subunits and four heme prosthetic groups.
Whereas adult hemoglobin is composed of two α and two β subunits, fetal hemoglobin is composed of two α subunits and two γ subunits, is denoted as α2γ2. Because of its presence in fetal hemoglobin, the γ subunit is called the "fetal" hemoglobin subunit. In humans, the gamma subunit is encoded on chromosome 11. There are two similar copies of the gamma subunit gene: γG which has a glycine at position 136, γA which has an alanine; the gene that codes for the alpha subunit is located on chromosome 16 and is present in duplicate. When fetal hemoglobin production is switched off after birth, normal children begin producing adult hemoglobin. Children with sickle-cell disease instead begin producing a defective form of hemoglobin called hemoglobin S which aggregates together and forms filaments that cause red blood cells to change their shape from round to sickle-shaped; these defective red blood cells have a greater tendency to stack on top of one another and block blood vessels. These invariably lead to so-called painful vaso-occlusive episodes, which are a hallmark of the disease.
If fetal hemoglobin remains the pred
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells. The shorter arm is termed 11p. At about 21.5 genes per megabase, chromosome 11 is one of the most gene-rich, disease-rich, chromosomes in the human genome. More than 40% of the 856 olfactory receptor genes in the human genome are located in 28 single-gene and multi-gene clusters along the chromosome; the following are some of the gene count estimates of human chromosome 11. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 11.
For complete list, see the link in the infobox on the right. The following diseases and disorders are some of those related to genes on chromosome 11: National Institutes of Health. "Chromosome 11". Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 11". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
Methemoglobin is a form of metalloprotein hemoglobin, in which the iron in the heme group is in the Fe3+ state, not the Fe2+ of normal hemoglobin. Methemoglobin can not bind oxygen, it is bluish chocolate-brown in color. In human blood a trace amount of methemoglobin is produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown; the NADH-dependent enzyme methemoglobin reductase is responsible for converting methemoglobin back to hemoglobin. One to two percent of a person's hemoglobin is methemoglobin. A higher level of methemoglobin will tend to cause a pulse oximeter to read closer to 85% regardless of the true level of oxygen saturation. An abnormal increase of methemoglobin will increase the oxygen binding affinity of normal hemoglobin, resulting in a decreased unloading of oxygen to the tissues. Reduced cellular defense mechanisms Children younger than 4 months exposed to various environmental agents Pregnant women are considered vulnerable to exposure of high levels of nitrates in drinking water Cytochrome b5 reductase deficiency G6PD deficiency Hemoglobin M disease Pyruvate kinase deficiency Various pharmaceutical compounds Local anesthetic agents prilocaine and benzocaine.
Amyl nitrite, dapsone, nitrites, nitroprusside, phenazopyridine, primaquine and sulfonamides Environmental agents Aromatic amines Arsine Chlorobenzene Chromates Nitrates/nitrites Inherited disorders Some family members of the Fughate family in Kentucky, due to a recessive gene, had blue skin from an excess of methemoglobin. In cats Ingestion of Paracetamol Amyl nitrite is administered to treat cyanide poisoning, it works by converting hemoglobin to methemoglobin, which allows for the binding of cyanide and the formation of cyanomethemoglobin. The immediate goal of forming this cyanide adduct is to prevent the binding of free cyanide to the cytochrome a3 group in cytochrome c oxidase. Methemoglobin saturation is expressed as the percentage of hemoglobin in the methemoglobin state. 1-2% Normal Less than 10% metHb - No symptoms 10-20% metHb - Skin discoloration only 20-30% metHb - Anxiety, dyspnea on exertion 30-50% metHb - Fatigue, dizziness, palpitations 50-70% metHb - Coma, arrhythmias, acidosis Greater than 70% metHb - High risk of death Increased levels of methemoglobin are found in blood stains.
Upon exiting the body, bloodstains transit from bright red to dark brown, attributed to oxidation of oxy-hemoglobin to methemoglobin and hemichrome. Methemoglobinemia Blue baby syndrome Methemoglobin at the US National Library of Medicine Medical Subject Headings MetHb Formation The Blue people of Troublesome Creek
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in all mammals. It is distantly related to hemoglobin, the iron- and oxygen-binding protein in blood in the red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury, it is an abnormal finding, can be diagnostically relevant when found in blood. Myoglobin is the primary oxygen-carrying pigment of muscle tissues. High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with high abundance of myoglobin. Myoglobin is found in Type I muscle, Type II A and Type II B, but most texts consider myoglobin not to be found in smooth muscle. Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography; this achievement was reported in 1958 by associates. For this discovery, John Kendrew shared the 1962 Nobel Prize in chemistry with Max Perutz.
Despite being one of the most studied proteins in biology, its physiological function is not yet conclusively established: mice genetically engineered to lack myoglobin can be viable and fertile but show many cellular and physiological adaptations to overcome the loss. Through observing these changes in myoglobin-deplete mice, it is hypothesised that myoglobin function relates to increased oxygen transport to muscle, oxygen storage and as a scavenger of reactive oxygen species. In humans myoglobin is encoded by the MB gene. Myoglobin can take the forms oxymyoglobin and metmyoglobin, analogously to hemoglobin taking the forms oxyhemoglobin, carboxyhemoglobin, methemoglobin. Like hemoglobin, myoglobin is a cytoplasmic protein, it harbors only one heme group. Although its heme group is identical to those in Hb, Mb has a higher affinity for oxygen than does hemoglobin; this difference is related to its different role: whereas hemoglobin transports oxygen, myoglobin's function is to store oxygen. Myoglobin contains hemes, pigments responsible for the colour of red meat.
The colour that meat takes is determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous oxidation state bound to an oxygen molecule. Meat cooked well done is brown because the iron atom is now in the ferric oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink because the iron atom is bound to NO, nitric oxide. Grilled meats can take on a pink "smoke ring" that comes from the iron binding to a molecule of carbon monoxide. Raw meat packed in a carbon monoxide atmosphere shows this same pink "smoke ring" due to the same principles. Notably, the surface of this raw meat displays the pink color, associated in consumers' minds with fresh meat; this artificially induced pink color can persist up to one year. Hormel and Cargill are both reported to use this meat-packing process, meat treated this way has been in the consumer market since 2003. Myoglobin is released from damaged muscle tissue, which has high concentrations of myoglobin.
The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may cause acute kidney injury. It is not the myoglobin itself, toxic but the ferrihemate portion, dissociated from myoglobin in acidic environments. Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain. However, elevated myoglobin has low specificity for acute myocardial infarction and thus CK-MB, cardiac Troponin, ECG, clinical signs should be taken into account to make the diagnosis. Myoglobin belongs to the globin superfamily of proteins, as with other globins, consists of eight alpha helices connected by loops. Myoglobin contains 154 amino acids. Myoglobin contains a porphyrin ring with an iron at its center. A proximal histidine group is attached directly to iron, a distal histidine group hovers near the opposite face; the distal imidazole is not bonded to the iron but is available to interact with the substrate O2. This interaction encourages the binding of O2, but not carbon monoxide, which still binds about 240× more than O2.
The binding of O2 causes substantial structural change at the Fe center, which shrinks in radius and moves into the center of N4 pocket. O2-binding induces "spin-pairing": the five-coordinate ferrous deoxy form is high spin and the six coordinate oxy form is low spin and diamagnetic. Many models of myoglobin have been synthesized as part of a broad interest in transition metal dioxygen complexes. A well known example is the picket fence porphyrin, which consists of a ferrous complex of a sterically bulky derivative of tetraphenylporphyrin. In the presence of an imidazole ligand, this ferrous complex reversibly binds O2; the O2 substrate adopts a bent geometry. A key property of this model is the slow formation of the μ-oxo dimer, an inactive diferric state. In nature, such deactivation pathways are suppressed by protein matrix that prevents close approach of the Fe-porphyrin assemblies. Cytoglobin Hemoglobin Hemoprotein Neuroglobin Phytoglobin Myoglobinuria - The presence of myoglobin in the urine Ischemia-reperfusion injury of the appendicular musculoskeletal system Online Mendelian Inheritance in Man 160000 human genetics The Myoglobin Protein Protein Database featured mole
Zygosity is the degree of similarity of the alleles for a trait in an organism. Most eukaryotes have two matching sets of chromosomes. Diploid organisms have the same loci on each of their two sets of homologous chromosomes except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal sex-determination system. If both alleles of a diploid organism are the same, the organism is homozygous at that locus. If they are different, the organism is heterozygous at that locus. If one allele is missing, it is hemizygous; the DNA sequence of a gene varies from one individual to another. Those variations are called alleles. While some genes have only one allele because there is low variation, others have only one allele because deviation from that allele can be harmful or fatal, but most genes have two or more alleles. The frequency of different alleles varies throughout the population; some genes may have two alleles with equal distribution.
For other genes, one allele may be common, another allele may be rare. Sometimes, one allele is a disease-causing variation. Sometimes, the different variations in the alleles make no difference at all in the function of the organism. In diploid organisms, one allele is inherited from one from the female parent. Zygosity is a description of whether those two alleles have different DNA sequences. In some cases the term "zygosity" is used in the context of a single chromosome; the words homozygous and hemizygous are used to describe the genotype of a diploid organism at a single locus on the DNA. Homozygous describes a genotype consisting of two identical alleles at a given locus, heterozygous describes a genotype consisting of two different alleles at a locus, hemizygous describes a genotype consisting of only a single copy of a particular gene in an otherwise diploid organism, nullizygous refers to an otherwise-diploid organism in which both copies of the gene are missing. A cell is said to be homozygous for a particular gene when identical alleles of the gene are present on both homologous chromosomes.
The cell or organism in question is called a homozygote. True breeding organisms are always homozygous for the traits. An individual, homozygous-dominant for a particular trait carries two copies of the allele that codes for the dominant trait; this allele called the "dominant allele", is represented by a capital letter. When an organism is homozygous-dominant for a particular trait, the genotype is represented by a doubling of the symbol for that trait, such as "PP". An individual, homozygous-recessive for a particular trait carries two copies of the allele that codes for the recessive trait; this allele called the "recessive allele", is represented by the lowercase form of the letter used for the corresponding dominant trait. The genotype of an organism, homozygous-recessive for a particular trait is represented by a doubling of the appropriate letter, such as "pp". A diploid organism is heterozygous at a gene locus when its cells contain two different alleles of a gene; the cell or organism is called a heterozygote for the allele in question, therefore, heterozygosity refers to a specific genotype.
Heterozygous genotypes are represented by a capital letter and a lowercase letter, such as "Rr" or "Ss". Alternatively, a heterozygote for gene "R" is assumed to be "Rr"; the capital letter is written first. If the trait in question is determined by simple dominance, a heterozygote will express only the trait coded by the dominant allele, the trait coded by the recessive allele will not be present. In more complex dominance schemes the results of heterozygosity can be more complex. A heterozygous genotype can have a higher relative fitness than either the homozygous dominant or homozygous recessive genotype - this is called a heterozygote advantage. A chromosome in a diploid organism is hemizygous; the cell or organism is called a hemizygote. Hemizygosity is observed when one copy of a gene is deleted, or, in the heterogametic sex, when a gene is located on a sex chromosome. Hemizygosity must not be confused with haploinsufficiency, which describes a mechanism for producing a phenotype. For organisms in which the male is heterogametic, such as humans all X-linked genes are hemizygous in males with normal chromosomes, because they have only one X chromosome and few of the same genes are on the Y chromosome.
Transgenic mice generated through exogenous DNA microinjection of an embryo's pronucleus are considered to be hemizygous, because the introduced allele is expected to be incorporated into only one copy of any locus. A transgenic individual can be bred to homozygosity and maintained as an inbred line to reduce the need to confirm the genotype of each individual. In cultured mammalian cells, such as the Chinese hamster ovary cell line, a number of genetic loci are present in a functional hemizygous state, due to mutations or deletions in the other alleles. A nullizygous organism carries two mutant alleles for the same gene; the mutant alleles are both complete loss-of-function or'null' alleles, so homozygous null and n
Hemoglobin or haemoglobin, abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates as well as the tissues of some invertebrates. Haemoglobin in the blood carries oxygen from the gills to the rest of the body. There it releases the oxygen to permit aerobic respiration to provide energy to power the functions of the organism in the process called metabolism. A healthy individual has 12 to 16 grams of haemoglobin in every 100 ml of blood. In mammals, the protein makes up about 96% of the red blood cells' dry content, around 35% of the total content. Haemoglobin has an oxygen-binding capacity of 1.34 mL O2 per gram, which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind up to four oxygen molecules. Hemoglobin is involved in the transport of other gases: It carries some of the body's respiratory carbon dioxide as carbaminohemoglobin, in which CO2 is bound to the heme protein.
The molecule carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same time as oxygen. Haemoglobin is found outside red blood cells and their progenitor lines. Other cells that contain haemoglobin include the A9 dopaminergic neurons in the substantia nigra, alveolar cells, retinal pigment epithelium, mesangial cells in the kidney, endometrial cells, cervical cells and vaginal epithelial cells. In these tissues, haemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism. Haemoglobin and haemoglobin-like molecules are found in many invertebrates and plants. In these organisms, haemoglobins may carry oxygen, or they may act to transport and regulate other small molecules and ions such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant of the molecule, called leghaemoglobin, is used to scavenge oxygen away from anaerobic systems, such as the nitrogen-fixing nodules of leguminous plants, before the oxygen can poison the system.
In 1825 J. F. Engelhard discovered that the ratio of iron to protein is identical in the hemoglobins of several species. From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n × 16000, the first determination of a protein's molecular mass; this "hasty conclusion" drew a lot of ridicule at the time from scientists who could not believe that any molecule could be that big. Gilbert Smithson Adair confirmed Engelhard's results in 1925 by measuring the osmotic pressure of hemoglobin solutions; the oxygen-carrying property of hemoglobin was discovered by Hünefeld in 1840. In 1851, German physiologist Otto Funke published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution. Hemoglobin's reversible oxygenation was described a few years by Felix Hoppe-Seyler. In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.
This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures of globular proteins. The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard; the name hemoglobin is derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces; the most common type of hemoglobin in mammals contains four such subunits. Hemoglobin consists of protein subunits, these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides; the amino acid sequence of any polypeptide created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence that determines the protein's chemical properties and function. There is more than one hemoglobin gene: in humans, hemoglobin A is coded for by the genes, HBA1, HBA2, HBB.
The amino acid sequences of the globin proteins in hemoglobins differ between species. These differences grow with evolutionary distance between species. For example, the most common hemoglobin sequences in humans and chimpanzees are nearly identical, differing by only one amino acid in both the alpha and the beta globin protein chains; these differences grow larger between less related species. Within a species, different variants of hemoglobin always exist, although one sequence is a "most common" one in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants. Many of these mutant forms of hemoglobin cause no disease; some of these mutant forms of hemoglobin, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease, the first human disease whose mechanism was understood at the molecular level. A separate set of diseases called thalassemias involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation.
All these diseases produce anemia. Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to
Cytochromes P450 are proteins of the superfamily containing heme as a cofactor and, are hemeproteins. CYPs use a variety of 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 when it is in the reduced state and complexed with carbon monoxide. CYP enzymes have been identified in all kingdoms of life: animals, fungi, bacteria, in viruses. However, they are not omnipresent. More than 50,000 distinct CYP proteins are known. Most CYPs require a protein partner to deliver one or more electrons to reduce the iron. 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. Cytochrome b5 can contribute reducing power to this system after being reduced by cytochrome b5 reductase.
Mitochondrial P450 systems, which employ adrenodoxin reductase and 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 found in Rhodococcus species, 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 thromboxane synthase, prostacyclin synthase, CYP74A; 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 while the other oxygen atom is reduced to water: RH + O2 + NADPH + H+ → ROH + H2O + NADP+ Many hydroxylation reactions use CYP enzymes. Genes encoding CYP enzymes, 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, another numeral for the individual gene.
The convention is to italicise the name. For example, CYP2E1 is the gene that encodes the enzyme CYP2E1—one of the enzymes involved in paracetamol metabolism; the CYP nomenclature is the official naming convention, although CYP450 or CYP450 is used synonymously. 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, CYP51A1, lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate and activity; 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. There are nomenclature committees that track both base gene names and allele names; the active site of cytochrome P450 contains a heme-iron center. The iron is tethered to the protein via a cysteine thiolate ligand.
This cysteine and several flanking residues are conserved in known CYPs and have the formal PROSITE signature consensus pattern - - x - - - - - C - -. 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: 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 displacing a water molecule from the distal axial coordination position of the heme iron, changing the state of the heme iron from low-spin to high-spin. Substrate binding induces electron transfer from NADH via cytochrome P450 reductase or another associated reductase. Molecular oxygen binds to the resulting ferrous heme center at the distal axial coordination position giving a dioxygen adduct not unlike oxy-myoglobin. 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.
The peroxo group formed in step 4 is protonated twice, releasing one molecule of water and forming the reactive species referred to as P450 Compound 1. This reactive intermediate was isolated in 2010, P450 Compound 1 is an iron oxo species with an additional oxidizing equivalent delocalized over the porphyrin and thiolate ligands. Evidence for the alternative perferryl iron-oxo is lacking. 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"; this pathway entails oxidation of the ferric-substrate complex with oxygen-atom donors such as peroxides and hypochlorites. A hypothetical peroxide "XOOH" is shown in the di