Biology:Cytochrome P450 reductase

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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[1] and other heme proteins including heme oxygenase in the endoplasmic reticulum[2] of the eukaryotic cell.

Gene

Human POR gene has 16 exons and the exons 2-16 code for a 677-amino acid [3] 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 1.14.13.39), NADPH:sulfite reductase (EC 1.8.1.2), and methionine synthase reductase (EC 1.16.1.8).[citation needed]

Protein structure

The 3D crystal structure of human POR has been determined.[4] 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, and biasing the conformation of POR with small molecule ligands may be a way to control interaction with partner proteins and influence metabolism.[5]

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:

NADPH → FAD → FMN → P450 → O2

The definitive evidence for the requirement of POR in cytochrome-P450-mediated reactions came from the work of Lu, Junk and Coon,[6] 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,[7] 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.[8]

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 O2. In yeast, POR affects the ferrireductase activity, probably transferring electrons to the flavocytochrome ferric reductase.[9]

Clinical significance

More than 200 variations in POR gene have been identified.[10][11]

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.[12] Another POR missense mutation Y181D has also been identified.[13] 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.[14]

POR Deficiency – Mixed Oxidase Disease

POR deficiency is the newest form of congenital adrenal hyperplasia first described in 2004.[12] 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.[15][16] 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.[17] 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,[18][19] and the relevance of the backdoor pathway along with POR dependent steroidogenesis have become clearer from recent studies.[17] 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.[20][21][22][23][24] 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.[25]

Williams syndrome

Williams syndrome 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 that alters expression of this gene.[26] Some persons with Williams syndrome show characteristics of POR deficiency, including radioulnar synostosis and other skeletal abnormalities.[27] Cases of mild impairment of cortisol and androgen synthesis have been noted,[28] however, despite the fact that deficient POR impairs androgen synthesis, patients with Williams syndrome often show increased androgen levels.[29] A similar increase in testosterone has been observed in a mouse model that has globally decreased POR expression.[30]

See also

References

  1. ↑ "NADPH P450 oxidoreductase: structure, function, and pathology of diseases". Pharmacology & Therapeutics 138 (2): 229–54. May 2013. doi:10.1016/j.pharmthera.2013.01.010. PMID 23353702. 
  2. ↑ "Plant NADPH-cytochrome P450 oxidoreductases". Phytochemistry 71 (2–3): 132–41. February 2010. doi:10.1016/j.phytochem.2009.10.017. PMID 19931102. Bibcode: 2010PChem..71..132J. "CPR was shown to be localized in the endoplasmic reticulum in the early 1960s (Williams and Kamin, 1962).". 
  3. ↑ "Structural and functional analysis of NADPH-cytochrome P-450 reductase from human liver: complete sequence of human enzyme and NADPH-binding sites". Biochemistry 28 (21): 8639–45. October 1989. doi:10.1021/bi00447a054. PMID 2513880. 
  4. ↑ PDB: 3QE2​); "Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency". Proceedings of the National Academy of Sciences of the United States of America 108 (33): 13486–91. August 2011. doi:10.1073/pnas.1106632108. PMID 21808038. Bibcode: 2011PNAS..10813486X. 
  5. ↑ "Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase" (in en). Nature Communications 12 (1): 2260. 2021-04-15. doi:10.1038/s41467-021-22562-w. PMID 33859207. Bibcode: 2021NatCo..12.2260J. 
  6. ↑ "Resolution of the cytochrome P-450-containing omega-hydroxylation system of liver microsomes into three components". The Journal of Biological Chemistry 244 (13): 3714–21. July 1969. doi:10.1016/S0021-9258(18)83427-5. PMID 4389465. 
  7. ↑ "Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase". The Journal of Biological Chemistry 277 (8): 6536–41. February 2002. doi:10.1074/jbc.M111408200. PMID 11742006. 
  8. ↑ "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". The Journal of Biological Chemistry 278 (28): 25895–901. July 2003. doi:10.1074/jbc.M303125200. PMID 12697746. 
  9. ↑ "Cytochrome P-450 reductase is responsible for the ferrireductase activity associated with isolated plasma membranes of Saccharomyces cerevisiae". FEMS Microbiology Letters 156 (1): 147–52. November 1997. doi:10.1016/S0378-1097(97)00418-7. PMID 9368374. 
  10. ↑ "Pharmacogenomics of human P450 oxidoreductase". Frontiers in Pharmacology 5: 103. 214. doi:10.3389/fphar.2014.00103. PMID 24847272. 
  11. ↑ "P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms". The Journal of Steroid Biochemistry and Molecular Biology 165 (Pt A): 38–50. April 2016. doi:10.1016/j.jsbmb.2016.04.003. PMID 27068427. 
  12. ↑ 12.0 12.1 "Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome". Nature Genetics 36 (3): 228–30. March 2004. doi:10.1038/ng1300. PMID 14758361. 
  13. ↑ "Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study". Lancet 363 (9427): 2128–35. June 2004. doi:10.1016/S0140-6736(04)16503-3. PMID 15220035. 
  14. ↑ "Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis". American Journal of Human Genetics 76 (5): 729–49. May 2005. doi:10.1086/429417. PMID 15793702. 
  15. ↑ "Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype". The Journal of Clinical Endocrinology and Metabolism 105 (4): e1272–e1290. April 2020. doi:10.1210/clinem/dgaa076. PMID 32060549. 
  16. ↑ "Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase". Molecular Endocrinology 21 (10): 2579–95. October 2007. doi:10.1210/me.2007-0245. PMID 17595315. 
  17. ↑ 17.0 17.1 "Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation". American Journal of Human Genetics 89 (2): 201–18. August 2011. doi:10.1016/j.ajhg.2011.06.009. PMID 21802064. 
  18. ↑ "Alternative pathway androgen biosynthesis and human fetal female virilization". Proceedings of the National Academy of Sciences of the United States of America 116 (44): 22294–22299. October 2019. doi:10.1073/pnas.1906623116. PMID 31611378. Bibcode: 2019PNAS..11622294R. 
  19. ↑ "Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype". American Journal of Medical Genetics Part A 129A (2): 105–12. August 2004. doi:10.1002/ajmg.a.30171. PMID 15316970. 
  20. ↑ "Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism". Biochemical and Biophysical Research Communications 401 (1): 149–53. October 2010. doi:10.1016/j.bbrc.2010.09.035. PMID 20849814. 
  21. ↑ "Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency". European Journal of Endocrinology 163 (6): 919–24. December 2010. doi:10.1530/EJE-10-0764. PMID 20844025. 
  22. ↑ "Restoration of mutant cytochrome P450 reductase activity by external flavin". Molecular and Cellular Endocrinology 321 (2): 245–52. June 2010. doi:10.1016/j.mce.2010.02.024. PMID 20188793. 
  23. ↑ "Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro". Pharmacogenetics and Genomics 20 (11): 677–86. November 2010. doi:10.1097/FPC.0b013e32833f4f9b. PMID 20940534. 
  24. ↑ "Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase". Pharmacogenetics and Genomics 20 (10): 611–8. October 2010. doi:10.1097/FPC.0b013e32833e0cb5. PMID 20697309. 
  25. ↑ "Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase". The Journal of Steroid Biochemistry and Molecular Biology 165 (Pt A): 64–70. March 2016. doi:10.1016/j.jsbmb.2016.03.031. PMID 27032764. 
  26. ↑ "Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes". American Journal of Human Genetics 79 (2): 332–41. August 2006. doi:10.1086/506371. PMID 16826523. 
  27. ↑ "Radio-ulnar synostosis in Williams syndrome. A frequently associated anomaly". Pediatric Radiology 21 (7): 508–10. 1991. doi:10.1007/bf02011725. PMID 1771116. 
  28. ↑ "Williams syndrome associated with chronic renal failure and various endocrinological abnormalities". Internal Medicine 35 (6): 482–8. June 1996. doi:10.2169/internalmedicine.35.482. PMID 8835601. 
  29. ↑ "Hormonal regulation in children and adults with Williams-Beuren syndrome". American Journal of Medical Genetics 51 (3): 251–7. July 1994. doi:10.1002/ajmg.1320510316. PMID 8074154. 
  30. ↑ "Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450". The Journal of Pharmacology and Experimental Therapeutics 312 (1): 35–43. January 2005. doi:10.1124/jpet.104.073353. PMID 15328377. 

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