Просмотр кода страницы Английская Википедия:Cytochrome P450 reductase

{{Английская Википедия/Панель перехода}}
{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}

'''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]] required for [[electron transfer]] from [[NADPH]] to [[cytochrome P450]]<ref>{{cite journal |vauthors=Pandey AV, Flück CE |date=May 2013 |title=NADPH P450 oxidoreductase: structure, function, and pathology of diseases |journal=Pharmacology & Therapeutics |volume=138 |issue=2 |pages=229–54 |doi=10.1016/j.pharmthera.2013.01.010 |pmid=23353702}}</ref> and other [[heme]] proteins including [[heme oxygenase]] in the [[endoplasmic reticulum]]<ref name="Jensen_2010">{{cite journal | vauthors = Jensen K, Møller BL | title = Plant NADPH-cytochrome P450 oxidoreductases | journal = Phytochemistry | volume = 71 | issue = 2–3 | pages = 132–41 | date = February 2010 | pmid = 19931102 | doi = 10.1016/j.phytochem.2009.10.017 | bibcode = 2010PChem..71..132J | quote = CPR was shown to be localized in the endoplasmic reticulum in the early 1960s (Williams and Kamin, 1962). }}</ref> of the [[Eukaryote|eukaryotic]] [[Cell (biology)|cell]].

==Gene==
Human POR gene has 16 exons and the exons 2-16 code for a 677-amino acid <ref>{{cite journal | vauthors = Haniu M, McManus ME, Birkett DJ, Lee TD, Shively JE | title = Structural and functional analysis of NADPH-cytochrome P-450 reductase from human liver: complete sequence of human enzyme and NADPH-binding sites | journal = Biochemistry | volume = 28 | issue = 21 | pages = 8639–45 | date = October 1989 | pmid = 2513880 | doi = 10.1021/bi00447a054 }}</ref> 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]] of POR include [[nitric oxide synthase]] ({{EC number|1.14.13.39}}), NADPH:sulfite reductase ({{EC number|1.8.1.2}}), and methionine synthase reductase ({{EC number|1.16.1.8}}).{{Citation needed|date=May 2023}}

==Protein structure==
The 3D crystal structure of human POR has been determined.<ref name="pmid21808038">{{PDB|3QE2}}); {{cite journal | vauthors = Xia C, Panda SP, Marohnic CC, Martásek P, Masters BS, Kim JJ | title = Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 33 | pages = 13486–91 | date = August 2011 | pmid = 21808038 | pmc = 3158178 | doi = 10.1073/pnas.1106632108 | bibcode = 2011PNAS..10813486X | doi-access = free }}</ref> 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<sup>+</sup> 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, and [https://www.nature.com/articles/s41467-021-22562-w biasing the conformation of POR] with small molecule ligands may be a way to control interaction with partner proteins and influence metabolism.<ref>{{Cite journal| vauthors = Jensen SB, Thodberg S, Parween S, Moses ME, Hansen CC, Thomsen J, Sletfjerding MB, Knudsen C, Del Giudice R, Lund PM, Castano PR | display-authors = 6 |date=2021-04-15|title=Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase |journal=Nature Communications|language=en|volume=12|issue=1|pages=2260|doi=10.1038/s41467-021-22562-w | pmid = 33859207 | pmc = 8050233 | bibcode = 2021NatCo..12.2260J |doi-access=free}}</ref>

==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:
{{center|{{nowrap|NADPH → FAD → FMN → P450 → O<sub>2</sub>}}}}

The definitive  evidence for the requirement of POR in cytochrome-P450-mediated reactions came from the work of Lu, Junk and Coon,<ref>{{cite journal | vauthors = Lu AY, Junk KW, Coon MJ | title = Resolution of the cytochrome P-450-containing omega-hydroxylation system of liver microsomes into three components | journal = The Journal of Biological Chemistry | volume = 244 | issue = 13 | pages = 3714–21 | date = July 1969 | doi = 10.1016/S0021-9258(18)83427-5 | pmid = 4389465 | doi-access = free }}</ref> 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,<ref>{{cite journal | vauthors = Shen AL, O'Leary KA, Kasper CB | title = Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 6536–41 | date = February 2002 | pmid = 11742006 | doi = 10.1074/jbc.M111408200 | doi-access = free }}</ref>
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.<ref name="pmid12697746">{{cite journal | vauthors = Gu J, Weng Y, Zhang QY, Cui H, Behr M, Wu L, Yang W, Zhang L, Ding X | title = Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 25895–901 | date = July 2003 | pmid = 12697746 | doi = 10.1074/jbc.M303125200 | doi-access = free }}</ref>

The reduction of cytochrome P450 is not the only physiological function of POR. The final step of [[heme]] oxidation by mammalian [[heme oxygenase]] requires POR and O<sub>2</sub>. In yeast, POR affects the ferrireductase activity, probably transferring electrons to the flavocytochrome ferric reductase.<ref name="pmid9368374">{{cite journal | vauthors = Lesuisse E, Casteras-Simon M, Labbe P | title = Cytochrome P-450 reductase is responsible for the ferrireductase activity associated with isolated plasma membranes of Saccharomyces cerevisiae | journal = FEMS Microbiology Letters | volume = 156 | issue = 1 | pages = 147–52 | date = November 1997 | pmid = 9368374 | doi = 10.1016/S0378-1097(97)00418-7 }}</ref>

==Clinical significance==
More than 200 variations in POR gene have been identified.<ref>{{cite journal | vauthors = Pandey AV, Sproll P | title = Pharmacogenomics of human P450 oxidoreductase | journal = Frontiers in Pharmacology | volume = 5 | pages = 103 | year = 214 | pmid = 24847272 | pmc = 4023047 | doi = 10.3389/fphar.2014.00103 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Burkhard FZ, Parween S, Udhane SS, Flück CE, Pandey AV | title = P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 165 | issue = Pt A | pages = 38–50 | date = April 2016 | pmid = 27068427 | doi = 10.1016/j.jsbmb.2016.04.003 | doi-access = free }}</ref>

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]], which catalyzes steroid 17α-hydroxylation and 17,20 lyase reaction, and P450c21 [[21-hydroxylase]], which catalyzes steroid 21-hydroxylation.<ref name="Fluck_2004">{{cite journal | vauthors = Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonça BB, Fujieda K, Miller WL | title = Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome | journal = Nature Genetics | volume = 36 | issue = 3 | pages = 228–30 | date = March 2004 | pmid = 14758361 | doi = 10.1038/ng1300 | doi-access = free }}</ref> Another POR missense mutation Y181D has also been identified.<ref>{{cite journal | vauthors = Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM, Stewart PM, Shackleton CH | title = Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study | journal = Lancet | volume = 363 | issue = 9427 | pages = 2128–35 | date = June 2004 | pmid = 15220035 | doi = 10.1016/S0140-6736(04)16503-3 | s2cid = 32705841 }}</ref> 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.<ref>{{cite journal | vauthors = Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Flück CE, Miller WL | title = Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis | journal = American Journal of Human Genetics | volume = 76 | issue = 5 | pages = 729–49 | date = May 2005 | pmid = 15793702 | pmc = 1199364 | doi = 10.1086/429417 }}</ref>

=== POR Deficiency – Mixed Oxidase Disease ===
{{See also|Cytochrome P450 oxidoreductase deficiency}}
[[Cytochrome P450 oxidoreductase deficiency|POR deficiency]] is the newest form of congenital adrenal hyperplasia first described in 2004.<ref name="Fluck_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]] resulting in low estrogen production, which was later confirmed by lower aromatase activities caused by POR mutations.<ref>{{cite journal | vauthors = Parween S, Fernández-Cancio M, Benito-Sanz S, Camats N, Rojas Velazquez MN, López-Siguero JP, Udhane SS, Kagawa N, Flück CE, Audí L, Pandey AV | display-authors = 6 | title = Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 105 | issue = 4 | pages = e1272–e1290 | date = April 2020 | pmid = 32060549 | doi = 10.1210/clinem/dgaa076 | doi-access = free }}</ref><ref name="pmid17595315">{{cite journal | vauthors = Pandey AV, Kempná P, Hofer G, Mullis PE, Flück CE | title = Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase | journal = Molecular Endocrinology | volume = 21 | issue = 10 | pages = 2579–95 | date = October 2007 | pmid = 17595315 | doi = 10.1210/me.2007-0245 }}</ref> 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 "[[androgen backdoor pathway|backdoor pathway]]" first described in the marsupials and later confirmed in humans.<ref name="pmid21802064">{{cite journal | vauthors = Flück CE, Meyer-Böni M, Pandey AV, Kempná P, Miller WL, Schoenle EJ, Biason-Lauber A | title = Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation | journal = American Journal of Human Genetics | volume = 89 | issue = 2 | pages = 201–18 | date = August 2011 | pmid = 21802064 | pmc = 3155178 | doi = 10.1016/j.ajhg.2011.06.009 }}</ref> 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,<ref name="pmid31611378">{{cite journal | vauthors = Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, Krone N, Auchus RJ, Shackleton CH, Hanley NA, Arlt W | title = Alternative pathway androgen biosynthesis and human fetal female virilization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 44 | pages = 22294–22299 | date = October 2019 | pmid = 31611378 | pmc = 6825302 | doi = 10.1073/pnas.1906623116 | bibcode = 2019PNAS..11622294R | doi-access = free }}</ref><ref name="pmid15316970">{{cite journal | vauthors = Shackleton C, Marcos J, Arlt W, Hauffa BP | title = Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype | journal = American Journal of Medical Genetics Part A | volume = 129A | issue = 2 | pages = 105–12 | date = August 2004 | pmid = 15316970 | doi = 10.1002/ajmg.a.30171 | s2cid = 22583190 }}</ref> and the relevance of the backdoor pathway along with POR dependent steroidogenesis have become clearer from recent studies.<ref name="pmid21802064" /> 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.<ref name="pmid20849814">{{cite journal | vauthors = Flück CE, Mullis PE, Pandey AV | title = Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism | journal = Biochemical and Biophysical Research Communications | volume = 401 | issue = 1 | pages = 149–53 | date = October 2010 | pmid = 20849814 | doi = 10.1016/j.bbrc.2010.09.035 }}</ref><ref name="pmid20844025">{{cite journal | vauthors = Tomalik-Scharte D, Maiter D, Kirchheiner J, Ivison HE, Fuhr U, Arlt W | title = Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency | journal = European Journal of Endocrinology| volume = 163 | issue = 6 | pages = 919–24 | date = December 2010 | pmid = 20844025 | pmc = 2977993 | doi = 10.1530/EJE-10-0764 }}</ref><ref name="pmid20188793">{{cite journal | vauthors = Nicolo C, Flück CE, Mullis PE, Pandey AV | title = Restoration of mutant cytochrome P450 reductase activity by external flavin | journal = Molecular and Cellular Endocrinology | volume = 321 | issue = 2 | pages = 245–52 | date = June 2010 | pmid = 20188793 | doi = 10.1016/j.mce.2010.02.024 | s2cid = 29109570 }}</ref><ref name="pmid20940534">{{cite journal | vauthors = Sandee D, Morrissey K, Agrawal V, Tam HK, Kramer MA, Tracy TS, Giacomini KM, Miller WL | title = Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 11 | pages = 677–86 | date = November 2010 | pmid = 20940534 | doi = 10.1097/FPC.0b013e32833f4f9b | pmc = 5708132 }}</ref><ref name="pmid20697309">{{cite journal | vauthors = Agrawal V, Choi JH, Giacomini KM, Miller WL | title = Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 10 | pages = 611–8 | date = October 2010 | pmid = 20697309 | pmc = 2940949 | doi = 10.1097/FPC.0b013e32833e0cb5 }}</ref> 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.<ref>{{cite journal | vauthors = Flück CE, Pandey AV | title = Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 165 | issue = Pt A | pages = 64–70 | date = March 2016 | pmid = 27032764 | doi = 10.1016/j.jsbmb.2016.03.031 | s2cid = 23498012 }}</ref>

=== Williams syndrome ===
[[Williams syndrome]] is a genetic disorder characterized by the deletion of genetic material approximately 1.2 [[Megabase|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]] that alters expression of this gene.<ref name="pmid16826523">{{cite journal | vauthors = Merla G, Howald C, Henrichsen CN, Lyle R, Wyss C, Zabot MT, Antonarakis SE, Reymond A | title = Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes | journal = American Journal of Human Genetics | volume = 79 | issue = 2 | pages = 332–41 | date = August 2006 | pmid = 16826523 | pmc = 1559497 | doi = 10.1086/506371 }}</ref> Some persons with Williams syndrome show characteristics of POR deficiency, including [[radioulnar synostosis]] and other skeletal abnormalities.<ref name="pmid1771116">{{cite journal | vauthors = Charvat KA, Hornstein L, Oestreich AE | title = Radio-ulnar synostosis in Williams syndrome. A frequently associated anomaly | journal = Pediatric Radiology | volume = 21 | issue = 7 | pages = 508–10 | year = 1991 | pmid = 1771116 | doi = 10.1007/bf02011725 | s2cid = 33765973 }}</ref> Cases of mild impairment of [[cortisol]] and androgen synthesis have been noted,<ref name="pmid8835601">{{cite journal | vauthors = Ichinose M, Tojo K, Nakamura K, Matsuda H, Tokudome G, Ohta M, Sakai S, Sakai O | title = Williams syndrome associated with chronic renal failure and various endocrinological abnormalities | journal = Internal Medicine | volume = 35 | issue = 6 | pages = 482–8 | date = June 1996 | pmid = 8835601 | doi = 10.2169/internalmedicine.35.482 | doi-access = free }}</ref> however, despite the fact that deficient POR impairs androgen synthesis, patients with Williams syndrome often show increased androgen levels.<ref name="pmid8074154">{{cite journal | vauthors = Partsch CJ, Pankau R, Blum WF, Gosch A, Wessel A | title = Hormonal regulation in children and adults with Williams-Beuren syndrome | journal = American Journal of Medical Genetics | volume = 51 | issue = 3 | pages = 251–7 | date = July 1994 | pmid = 8074154 | doi = 10.1002/ajmg.1320510316 }}</ref> A similar increase in testosterone has been observed in a mouse model that has globally decreased POR expression.<ref name="pmid15328377">{{cite journal | vauthors = Wu L, Gu J, Cui H, Zhang QY, Behr M, Fang C, Weng Y, Kluetzman K, Swiatek PJ, Yang W, Kaminsky L, Ding X | title = Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 312 | issue = 1 | pages = 35–43 | date = January 2005 | pmid = 15328377 | doi = 10.1124/jpet.104.073353 | s2cid = 8292025 }}</ref>

== See also ==
* [[Androgen backdoor pathway]]
* [[P450-containing systems]]

== References ==
{{Reflist|33em}}

== External links ==
* {{MeshName|Cytochrome+P450+Reductase}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=abs  GeneReviews/NCBI/NIH/UW entry on Cytochrome P450 Oxidoreductase Deficiency]

{{Endocrinology}}
{{Flavoproteins}}
{{NADH or NADPH oxidoreductases}}
{{Enzymes}}
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{{DEFAULTSORT:Cytochrome P450 Reductase}}
[[Category:Cytochrome P450|*]]
[[Category:Steroid hormone biosynthesis]]
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