Adrenodoxin reductase

Last updated
FDXR
Identifiers
Aliases FDXR , ADXR, Adrenodoxin reductase, ferredoxin reductase, ANOA, ADR
External IDs OMIM: 103270 MGI: 104724 HomoloGene: 3033 GeneCards: FDXR
Orthologs
SpeciesHumanMouse
Entrez

2232

14149

Ensembl

ENSG00000161513

ENSMUSG00000018861

UniProt

P22570

Q61578

RefSeq (mRNA)

NM_007997

RefSeq (protein)

NP_032023

Location (UCSC) Chr 17: 74.86 – 74.87 Mb Chr 11: 115.16 – 115.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Adrenodoxin reductase (Enzyme Nomenclature name: adrenodoxin-NADP+ reductase, EC 1.18.1.6), was first isolated from bovine adrenal cortex where it functions as the first enzyme in the mitochondrial P450 systems that catalyze essential steps in steroid hormone biosynthesis. [5] [6] Examination of complete genome sequences revealed that adrenodoxin reductase gene is present in most metazoans and prokaryotes. [7]

Contents

Nomenclature

The name of the enzyme was coined based on its function to reduce a [2Fe-2S] (2 iron, 2 sulfur) electron-transfer protein that was named adrenodoxin. Later, in some studies, the enzyme was also referred to as a "ferredoxin reductase", as adrenodoxin is a ferredoxin. In the human gene nomenclature, the standard name is ferredoxin reductase and the symbol is FDXR, with ADXR specified as a synonym.

The assignment of the name "ferredoxin reductase" has been criticized as a misnomer because determination of the structure of adrenodoxin reductase revealed that it is completely different from that of plant ferredoxin reductase and there is no homology between these two enzymes. [8] [9] [10] With more proteins with a ferroxodin-reducing activity discovered in both families as well as novel families, this enzyme activity is now seen as an example of convergent evolution. [11] [12]

Function

Adrenodoxin reductase is a flavoprotein as it carries a FAD type coenzyme. The enzyme functions as the first electron transfer protein of mitochondrial P450 systems such as P450scc. [6] The FAD coenzyme receives two electrons from NADPH and transfers them one at a time to the electron transfer protein adrenodoxin. [13] Adrenodoxin functions as a mobile shuttle that transfers electrons between ADXR and mitochondrial P450s. [14]

It catalyzes the following reaction:

NADPH + 2 oxidized adrenodoxin —→ 2 reduced adrenodoxin + NADP+ + H+

Gene structure

The cDNA for adrenodoxin reductase was first cloned in 1987. [15] In both bovine and human genomes there is only a single copy of the gene. [15] [16]

Sites of expression

ADXR gene is expressed in all tissues that have mitochondrial P450s. The highest levels of the enzyme are found in the adrenal cortex, granulosa cells of the ovary and leydig cells of the testis that specialize in steroid hormone synthesis. [6] [17] Immmunofluorescent staining shows that enzyme is localized in mitochondria. [18] The enzyme is also expressed in the liver, the kidney and the placenta.

Enzyme structure

Adrenodoxin reductase has two domains that bind NADPH and FAD separately. [7] The FAD and NADP binding sites of the enzyme were predicted by sequence analysis of the enzyme. [19]

While the FAD-binding site has a consensus sequence (Gly-x-Gly-x-x-Gly) that is similar to other Rossmann folds in FAD and NAD binding sites, [20] the NADPH binding site consensus sequence differs from the FAD-binding site by the substitution of an alanine instead of the last Gly (Gly-x-Gly-x-x-Ala). [19] [7] The location of these FAD and NADP binding sites were confirmed by the crystal structure of the enzyme. [10]

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000161513 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018861 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Omura T, Sanders E, Estabrook RW, Cooper DY, Rosenthal O (December 1966). "Isolation from adrenal cortex of a nonheme iron protein and a flavoprotein functional as a reduced triphosphopyridine nucleotide-cytochrome P-450 reductase". Archives of Biochemistry and Biophysics. 117 (3): 660–673. doi:10.1016/0003-9861(66)90108-1.
  6. 1 2 3 Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis". The Journal of Steroid Biochemistry and Molecular Biology. 43 (8): 779–804. doi:10.1016/0960-0760(92)90307-5. PMID   22217824. S2CID   112729.
  7. 1 2 3 Hanukoglu I (2017). "Conservation of the Enzyme-Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase-A Ubiquitous Enzyme". Journal of Molecular Evolution. 85 (5): 205–218. Bibcode:2017JMolE..85..205H. doi:10.1007/s00239-017-9821-9. PMID   29177972. S2CID   7120148.
  8. ↑ Hanukoglu I (1996). "Electron transfer proteins of cytochrome P450 systems". Physiological Functions of Cytochrome P450 in Relation to Structure and Regulation (PDF). pp. 29–55. doi:10.1016/S1569-2558(08)60339-2. ISBN   9780762301133.{{cite book}}: |journal= ignored (help)
  9. ↑ Ziegler GA, Vonrhein C, Hanukoglu I, Schulz GE (Jun 1999). "The structure of adrenodoxin reductase of mitochondrial P450 systems: electron transfer for steroid biosynthesis". Journal of Molecular Biology. 289 (4): 981–90. doi:10.1006/jmbi.1999.2807. PMID   10369776.
  10. 1 2 Ziegler GA, Schulz GE (2000). "Crystal structures of adrenodoxin reductase in complex with NADP+ and NADPH suggesting a mechanism for the electron transfer of an enzyme family". Biochemistry. 39 (36): 10986–95. doi:10.1021/bi000079k. PMID   10998235.
  11. ↑ Aliverti A, Pandini V, Pennati A, de Rosa M, Zanetti G (June 2008). "Structural and functional diversity of ferredoxin-NADP(+) reductases". Archives of Biochemistry and Biophysics. 474 (2): 283–91. doi:10.1016/j.abb.2008.02.014. hdl: 2434/41439 . PMID   18307973.
  12. ↑ Spaans SK, Weusthuis RA, van der Oost J, Kengen SW (2015). "NADPH-generating systems in bacteria and archaea". Frontiers in Microbiology. 6: 742. doi: 10.3389/fmicb.2015.00742 . PMC   4518329 . PMID   26284036.
  13. ↑ Lambeth JD, Kamin H (Jul 1976). "Adrenodoxin reductase. Properties of the complexes of reduced enzyme with NADP+ and NADPH". The Journal of Biological Chemistry. 251 (14): 4299–306. doi: 10.1016/S0021-9258(17)33296-9 . PMID   6475.
  14. ↑ Hanukoglu I, Jefcoate CR (Apr 1980). "Mitochondrial cytochrome P-450scc. Mechanism of electron transport by adrenodoxin" (PDF). The Journal of Biological Chemistry. 255 (7): 3057–61. doi: 10.1016/S0021-9258(19)85851-9 . PMID   6766943.
  15. 1 2 Hanukoglu I, Gutfinger T, Haniu M, Shively JE (Dec 1987). "Isolation of a cDNA for adrenodoxin reductase (ferredoxin-NADP+ reductase). Implications for mitochondrial cytochrome P-450 systems". European Journal of Biochemistry. 169 (3): 449–455. doi: 10.1111/j.1432-1033.1987.tb13632.x . PMID   3691502.
  16. ↑ Solish SB, Picado-Leonard J, Morel Y, Kuhn RW, Mohandas TK, Hanukoglu I, Miller WL (Oct 1988). "Human adrenodoxin reductase: two mRNAs encoded by a single gene on chromosome 17cen----q25 are expressed in steroidogenic tissues". Proceedings of the National Academy of Sciences of the United States of America. 85 (19): 7104–7108. Bibcode:1988PNAS...85.7104S. doi: 10.1073/pnas.85.19.7104 . PMC   282132 . PMID   2845396.
  17. ↑ Hanukoglu I, Hanukoglu Z (May 1986). "Stoichiometry of mitochondrial cytochromes P-450, adrenodoxin and adrenodoxin reductase in adrenal cortex and corpus luteum. Implications for membrane organization and gene regulation". European Journal of Biochemistry. 157 (1): 27–31. doi: 10.1111/j.1432-1033.1986.tb09633.x . PMID   3011431.
  18. ↑ Hanukoglu I, Suh BS, Himmelhoch S, Amsterdam A (October 1990). "Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells". The Journal of Cell Biology. 111 (4): 1373–81. doi:10.1083/jcb.111.4.1373. PMC   2116250 . PMID   2170421.
  19. 1 2 Hanukoglu I, Gutfinger T (Mar 1989). "cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases". European Journal of Biochemistry. 180 (2): 479–84. doi: 10.1111/j.1432-1033.1989.tb14671.x . PMID   2924777.
  20. ↑ Hanukoglu I (2015). "Proteopedia: Rossmann fold: A beta-alpha-beta fold at dinucleotide binding sites". Biochem Mol Biol Educ. 43 (3): 206–209. doi: 10.1002/bmb.20849 . PMID   25704928. S2CID   11857160.

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