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30-696: 3K9V , 3K9Y 1591 13081 ENSG00000019186 ENSMUSG00000038567 Q07973 Q64441 NM_000782 NM_001128915 NM_009996 NP_000773 NP_001122387 NP_034126 Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1 ) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D 3 ). It has also been identified as vitamin D3 24-hydroxylase .( EC 1.14.15.16 ) CYP24A1

60-492: A cofactor that mostly, but not exclusively, function as monooxygenases . However, they are not omnipresent; for example, they have not been found in Escherichia coli . In mammals, these enzymes oxidize steroids , fatty acids , xenobiotics , and participate in many biosyntheses. By hydroxylation, CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. P450s are, in general,

90-495: 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 C: If carbon monoxide (CO) binds to reduced P450,

120-451: A heme-iron center. The iron is tethered to the protein via a cysteine 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]. In general, the P450 catalytic cycle proceeds as follows: Mechanistic details, including

150-493: A means to ensure that viral translation is active when host translation is inhibited. These mechanisms of host translation inhibition are varied, and can be initiated by both virus and host, depending on the type of virus. However, in the case of most picornaviruses, such as poliovirus , this is accomplished by viral proteolytic cleavage of eIF4G so that it cannot interact with the 5'cap binding protein eIF4E . Interaction between these two eukaryotic initiation factors (eIFs) of

180-404: A tool for expressing multiple genes from a single transcriptional unit in a genetic vector . In such vectors, translation of the first cistron is initiated at the 5' cap, and translation of any downstream cistron is enabled by an IRES element appended at its 5' end. IRES elements are most commonly found in the 5' untranslated region , but may also occur elsewhere in mRNAs. The mRNA of viruses of

210-443: Is an enzyme expressed in the mitochondrion of humans and other species. It catalyzes hydroxylation reactions which lead to the degradation of 1,25-dihydroxyvitamin D 3 , the physiologically active form of vitamin D . Hydroxylation of the side chain produces calcitroic acid and other metabolites which are excreted in bile . CYP24A1 was identified in the early 1970s and was first thought to be involved in vitamin D metabolism as

240-458: Is expressed in tissues which are considered targets for vitamin D, including kidney, intestine and bone. Transcription of the CYP24A1 gene is markedly inducible by 1,25-(OH) 2 D 3 binding to the vitamin D receptor . The gene has a strong, positive vitamin D response element in the promoter . Through regulation of CYP24A1 expression, a negative feedback control system is created to limit

270-443: Is highly conserved between different species although the balance of functions can differ. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. This enzyme plays an important role in calcium homeostasis and the vitamin D endocrine system through its regulation of the level of vitamin D 3 . Click on genes, proteins and metabolites below to link to respective articles. CYP24A1

300-465: Is now considered responsible for the entire five-step, 24-oxidation pathway from 1,25-(OH) 2 D 3 producing calcitroic acid. CYP24A1 also is able to catalyze another pathway which starts with 23-hydroxylation of 1,25-(OH) 2 D 3 and culminates in 1,25-(OH) 2 D 3 -26,23-lactone. The side chains of the ergocalciferol (vitamin D 2 ) derivatives, 25-OH-D 2 and 1,25-(OH) 2 D 2 , are also hydroxylated by CYP24A1. The structure of CYP24A1

330-409: Is still under investigation. Testing of sequences for potential IRES function has generally relied on the use of bicistronic reporter assays . In these tests, a candidate IRES segment is introduced into a plasmid between two cistrons encoding two different reporter proteins. A promoter upstream of the first cistron drives transcription of both cistrons in a single mRNA. Cells are transfected with

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360-515: 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 CYP 450 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. P450 BM3 for CYP102A1) or functional names, denoting

390-707: The Dicistroviridae family possess two open reading frames (ORFs), and translation of each is directed by a distinct IRES. It has also been suggested that some mammalian cellular mRNAs also have IRESs, although this has been a matter of dispute. A number of these cellular IRES elements are located within mRNAs encoding proteins involved in stress survival , and other processes critical to survival. As of September 2009, there are 60 animal and 8 plant viruses reported to contain IRES elements and 115 mRNA sequences containing them as well. IRESs are often used by viruses as

420-852: The Wayback Machine ) and allele names ( CYP Allele Nomenclature Committee ). Based on the nature of the electron transfer proteins, P450s can be classified into several groups: 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: Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes, but many other hydroxylases exist. Alpha-ketoglutarate-dependent hydroxylases also rely on an Fe=O intermediate but lack hemes. Methane monooxygenase, which converts methane to methanol, are non-heme iron-and iron-copper-based enzymes. The active site of cytochrome P450 contains

450-414: The eIF4F complex is necessary for 40S ribosomal subunit recruitment to the 5' end of mRNAs, which is further thought to occur with mRNA 5'cap to 3' poly(A) tail loop formation. The virus may even use partially-cleaved eIF4G to aid in initiation of IRES-mediated translation. Cells may also use IRESs to increase translation of certain proteins during mitosis and programmed cell death . In mitosis,

480-457: The eukaryotic initiation factors (eIFs) eIF2 , eIF3 , eIF5 , and eIF5B , but do not require the factors eIF1 , eIF1A , and the eIF4F complex. In contrast, picornavirus IRESs do not bind the 40S subunit directly, but are recruited instead through the eIF4G -binding site. Many viral IRES (and cellular IRES) require additional proteins to mediate their function, known as IRES trans -acting factors (ITAFs). The role of ITAFs in IRES function

510-407: The iron (and eventually molecular oxygen ). Genes encoding P450 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 italicize the name when referring to the gene. For example, CYP2E1

540-480: The oxygen rebound mechanism , have been investigated with synthetic analogues, consisting of iron oxo heme complexes. 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,

570-401: The CYP24A1 gene have elevated serum calcium concentrations, elevated serum 1,25-(OH) 2 D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and sometimes reduced bone density. Variations in the gene may also be found in people with renal stones. Cytochrome P450 Cytochromes P450 ( P450s or CYPs ) are a superfamily of enzymes containing heme as

600-531: The apparent IRES function observed in bicistronic reporter tests. A promoter or splice acceptor within a test sequence can result in the production of monocistronic mRNA from which the downstream cistron is translated by conventional cap-dependent, rather than IRES-mediated, initiation. A later study that documented a variety of unexpected aberrant mRNA species arising from reporter plasmids revealed that splice acceptor sites can mimic both IRES and promoter elements in tests employing such plasmids, further highlighting

630-670: The catalytic activity and the name of the compound used as substrate. Examples include CYP5A1 , thromboxane A 2 synthase, abbreviated to TBXAS1 ( T hrom B o X ane A 2 S ynthase 1 ), and CYP51A1 , lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate ( L anosterol) and activity ( D e M ethylation). 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

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660-477: 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. Internal ribosome entry site IRES sequences were first discovered in 1988 in the poliovirus (PV) and encephalomyocarditis virus (EMCV) RNA genomes in

690-406: The cell dephosphorylates eIF4E so that it has little affinity for the 5'cap . As a result, the 40S ribosomal subunit , and the translational machinery is diverted to IRES within the mRNA. Many proteins involved in mitosis are encoded by IRES mRNA. In programmed cell death, cleavage of eIF-4G, such as performed by viruses, decreases translation. Lack of essential proteins contributes to the death of

720-432: The cell, as does translation of IRES mRNA sequences coding proteins involved in controlling cell death. To date, the mechanism of viral IRES function is better characterized than the mechanism of cellular IRES function, which is still a matter of debate. HCV -like IRESs directly bind the 40S ribosomal subunit to position their initiator codons are located in ribosomal P-site without mRNA scanning. These IRESs still use

750-471: The effects of 1,25-(OH) 2 D 3 . PTH and FGF23 also regulate CYP24A1 gene expression. Additionally, it is translationally regulated via IRES within the 5'UTR , which is responsive to an inflammatory environment. Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia . However, increasingly patients are also being diagnosed in adulthood, often when they present with hypercalcaemia. Patients with mutations of

780-575: The laboratories of Nahum Sonenberg and Eckard Wimmer , respectively. They are described as distinct regions of RNA molecules that are able to recruit the eukaryotic ribosome to the mRNA. This process is also known as cap-independent translation. It has been shown that IRES elements have a distinct secondary or even tertiary structure , but similar structural features at the levels of either primary or secondary structure that are common to all IRES segments have not been reported to date. Use of IRES sequences in molecular biology soon became common as

810-425: The need for caution in the interpretation of reporter assay results in the absence of careful RNA analysis. IRES sequences are often used in molecular biology to co-express multiple genes under the control of the same promoter, thereby mimicking a polycistronic mRNA. Within the past decades, IRES sequences have been used to develop hundreds of genetically modified rodent animal models. The advantage of this technique

840-667: The plasmid and assays are subsequently performed to quantitate expression of the two reporters in the cells. An increase in the ratio of expression of the downstream reporter relative to the upstream reporter is taken as evidence for IRES activity in the test sequence. However, without characterization of the mRNA species produced from such plasmids, other explanations for the increase in this ratio cannot be ruled out. For example, there are multiple known cases of suspected IRES elements that were later reported as having promoter function. Unexpected splicing activity within several reported IRES elements have also been shown to be responsible for

870-525: The renal 25-hydroxyvitamin D3-24-hydroxylase, modifying calcifediol (25-hydroxyvitamin D) to produce 24,25-dihydroxycholecalciferol (24,25-dihydroxyvitamin D). Subsequent studies using recombinant CYP24A1 showed that it could also catalyze multiple other hydroxylation reactions at the side chain carbons known as C-24 and C-23 in both 25-OH-D 3 and the active hormonal form, 1,25-(OH) 2 D 3 . It

900-403: 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

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