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Cytochrome P450 reductase (also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR) is a membrane-bound
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
required for
electron transfer Electron transfer (ET) occurs when an electron relocates from an atom, ion, or molecule, to another such chemical entity. ET describes the mechanism by which electrons are transferred in redox reactions. Electrochemical processes are ET reactio ...
from
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
to
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
and other
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
proteins including
heme oxygenase Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous iron, and carbon monoxide. There are many heme degrading enzymes in nature. In general, on ...
in the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
of the
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
cell.


Gene

Human POR gene has 16 exons and the exons 2-16 code for a 677-amino acid POR protein (NCBI NP_000932.2). There is a single copy of 50 kb POR gene (NCBI NM_000941.2) in humans on chromosome 7 (7q11.23).
Paralogs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
of POR include
nitric oxide synthase Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristal ...
(), NADPH:sulfite reductase (), and methionine synthase reductase ().


Protein structure

The 3D crystal structure of human POR has been determined.); The molecule is composed of four structural domains: the FMN-binding domain, the connecting domain, the FAD-binding domain, and NADPH-binding domain. The FMN-binding domain is similar to the structure of FMN-containing protein flavodoxin, whereas the FAD-binding domain and NADPH-binding domains are similar to those of flavoprotein ferredoxin-NADP+ reductase (FNR). The connecting domain is situated between the flavodoxin-like and FNR-like domains. Conformation flexibility of POR is a key requirement for interaction with different redox partners like Cytochrome P450 proteins, an
biasing the conformation of POR
with small molecule ligands may be a way to control interaction with partner proteins and influence metabolism.


Function

In ''Bacillus megaterium'' and ''Bacillus subtilis'', POR is a C-terminal domain of CYP102, a single-polypeptide self-sufficient soluble P450 system (P450 is an N-terminal domain). The general scheme of electron flow in the POR/P450 system is: The definitive evidence for the requirement of POR in cytochrome-P450-mediated reactions came from the work of Lu, Junk and Coon, who dissected the P450-containing mixed function oxidase system into three constituent components: POR, cytochrome P450, and lipids. Since all microsomal P450 enzymes require POR for catalysis, it is expected that disruption of POR would have devastating consequences. POR knockout mice are embryonic lethal, probably due to lack of electron transport to extrahepatic P450 enzymes since liver-specific knockout of POR yields phenotypically and reproductively normal mice that accumulate hepatic lipids and have remarkably diminished capacity of hepatic drug metabolism. The reduction of cytochrome P450 is not the only physiological function of POR. The final step of
heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
oxidation by mammalian
heme oxygenase Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous iron, and carbon monoxide. There are many heme degrading enzymes in nature. In general, on ...
requires POR and O2. In yeast, POR affects the ferrireductase activity, probably transferring electrons to the flavocytochrome ferric reductase.


Clinical significance

More than 200 variations in POR gene have been identified. Five missense mutations (A287P, R457H, V492E, C569Y, and V608F) and a splicing mutation in the POR genes have been found in patients who had hormonal evidence for combined deficiencies of two steroidogenic cytochrome P450 enzymes - P450c17
CYP17A1 Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously e ...
, which catalyzes steroid 17α-hydroxylation and 17,20 lyase reaction, and P450c21
21-hydroxylase Steroid 21-hydroxylase is a protein that in humans is encoded by the ''CYP21A2'' gene. The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the substrate acted upo ...
, which catalyzes steroid 21-hydroxylation. Another POR missense mutation Y181D has also been identified. Fifteen of nineteen patients having abnormal genitalia and disordered steroidogenesis were homozygous or apparent compound heterozygous for POR mutations that destroyed or dramatically inhibited POR activity.


POR Deficiency – Mixed Oxidase Disease

POR deficiency is the newest form of congenital adrenal hyperplasia first described in 2004. The index patient was a newborn 46,XX Japanese girl with craniosynostosis, hypertelorism, mid-face hypoplasia, radiohumeral synostosis, arachnodactyly and disordered steroidogenesis. However, the clinical and biochemical characteristics of patients with POR deficiency are long known in the literature as so-called mixed oxidase disease, as POR deficiency typically shows a steroid profile that suggests combined deficiencies of steroid 21-hydroxylase and 17α-hydroxylase/17,20 lyase activities. The clinical spectrum of POR deficiency ranges from severely affected children with ambiguous genitalia, adrenal insufficiency, and the Antley-Bixler skeletal malformation syndrome (ABS) to mildly affected individuals with polycystic ovary syndrome-like features. Some of the POR patients were born to mothers who became virilized during pregnancy, suggesting deficient placental aromatization of fetal androgens due to a lesion in microsomal
aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze man ...
resulting in low estrogen production, which was later confirmed by lower aromatase activities caused by POR mutations. However, it has also been suggested that fetal and maternal virilization in POR deficiency might be caused by increased dihydrotestosterone synthesis by the fetal gonad through an alternative " backdoor pathway" first described in the marsupials and later confirmed in humans. Gas chromatography/mass spectrometry analysis of urinary steroids from pregnant women carrying a POR-deficient fetus described in an earlier report also supports the existence of this pathway, and the relevance of the backdoor pathway along with POR dependent steroidogenesis have become clearer from recent studies. The role of POR mutations beyond CAH are being investigated; and questions such as how POR mutations cause bony abnormalities and what role POR variants play in drug metabolism by hepatic P450s are being addressed in recent publications. However, reports of ABS in some offspring of mothers who were treated with fluconazole, an antifungal agent which interferes with cholesterol biosynthesis at the level of CYP51 activity - indicate that disordered drug metabolism may result from deficient POR activity.


Williams syndrome

Williams syndrome Williams syndrome (WS), also Williams–Beuren syndrome (WBS), is a genetic disorder that affects many parts of the body. Facial features frequently include a broad forehead, underdeveloped chin, short nose, and full cheeks. Mild to moderate int ...
is a genetic disorder characterized by the deletion of genetic material approximately 1.2 Mb from the POR gene (POR). Cells with this genetic deletion show reduced transcription of POR, it seems, due to the loss of a
cis-regulatory element ''Cis''-regulatory elements (CREs) or ''cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morpho ...
that alters expression of this gene. Some persons with Williams syndrome show characteristics of POR deficiency, including
radioulnar synostosis Radioulnar synostosis is a rare condition where there is an abnormal connection ( synostosis) between the radius and ulna bones of the forearm. This can be present at birth (congenital), when it is a result of a failure of the bones to form separ ...
and other skeletal abnormalities. Cases of mild impairment of
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
and androgen synthesis have been noted, however, despite the fact that deficient POR impairs androgen synthesis, patients with Williams syndrome often show increased androgen levels. A similar increase in testosterone has been observed in a mouse model that has globally decreased POR expression.


See also

* Androgen backdoor pathway *
P450-containing systems Any enzyme system that includes cytochrome P450 protein or domain can be called a P450-containing system. P450 enzymes usually function as a terminal oxidase in multicomponent electron-transfer chains, called P450-containing monooxygenase systems, ...


References


External links

*
GeneReviews/NCBI/NIH/UW entry on Cytochrome P450 Oxidoreductase Deficiency
{{DEFAULTSORT:Cytochrome P450 Reductase * Steroid hormone biosynthesis