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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{enzyme
{{PBB_Controls
| align =
| update_page = yes
| Name = Steroid 21-monooxygenase
| require_manual_inspection = no
| EC_number = 1.14.99.10
| update_protein_box = yes
| CAS_number = 9029-68-9
| update_summary = no
| IUBMB_EC_number = 1/14/99/10
| update_citations = yes
| GO_code = 0004509
}}
| image = 21-hydroxylase subunit.png
| width =
| caption =
| name=Steroid 21-Hydroxylase}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
'''Steroid 21-[[hydroxylase]],''' also called '''steroid 21-monooxygenase''', '''21α-hydroxylase''', '''P45021A2''', and, less commonly '''21β-hydroxylase''', is a [[cytochrome P450]] [[enzyme]] that is involved with the [[biosynthesis]] of the [[steroid hormone]]s [[aldosterone]] and [[cortisol]].<ref name="pmid13416221">{{cite journal | vauthors = Ryan KJ, Engel LL | title = Hydroxylation of steroids at carbon 21 | journal = The Journal of Biological Chemistry | volume = 225 | issue = 1 | pages = 103–14 | date = March 1957 | pmid = 13416221 | doi =  | url = http://www.jbc.org/content/225/1/103.full.pdf }}</ref> These syntheses take place in the [[adrenal cortex]].<ref name="Guengerich_2016">{{cite journal | vauthors = Guengerich FP, Waterman MR, Egli M | title = Recent Structural Insights into Cytochrome P450 Function | journal = Trends in Pharmacological Sciences | volume = 37 | issue = 8 | pages = 625–40 | date = August 2016 | pmid = 27267697 | pmc = 4961565 | doi = 10.1016/j.tips.2016.05.006 }}</ref> Specifically, 21-hydroxylase converts [[progesterone]] and [[17α-Hydroxyprogesterone|17α-hydroxyprogesterone]] into [[11-Deoxycorticosterone|11-deoxycorticosterone]] and [[11-Deoxycortisol|11-deoxycortisol]], respectively, by hydroxylating at the C21 position.<ref name="Pallan_2015">{{cite journal | vauthors = Pallan PS, Wang C, Lei L, Yoshimoto FK, Auchus RJ, Waterman MR, Guengerich FP, Egli M | title = Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: structure of the enzyme·progesterone substrate complex and rate-limiting c-h bond cleavage | journal = The Journal of Biological Chemistry | volume = 290 | issue = 21 | pages = 13128–43 | date = May 2015 | pmid = 25855791 | pmc = 4505568 | doi = 10.1074/jbc.M115.646307 }}</ref> The products of the conversions then continue through their appropriate pathways towards creation of aldosterone and cortisol. Like other cytochrome P450 enzymes, 21-hydroxylase participates in the [[Cytochrome P450|cytochrome P450 catalytic cycle]], and engages in one-electron transfer with [[NADPH]]-[[Cytochrome P450 reductase|P450 reductase]]. Its structure includes an essential iron [[heme]] group centered within the protein, also common to all P450 enzymes. Variations of the 21-hydroxylase enzyme can be found in all [[vertebrate]]s.<ref>{{cite journal | vauthors = Graham SE, Peterson JA | title = Sequence alignments, variabilities, and vagaries | journal = Methods in Enzymology | volume = 357 | pages = 15–28 | year = 2002 | pmid = 12424893 | doi = 10.1016/s0076-6879(02)57661-8 }}</ref> However, understanding of human 21-hydroxylase structure and function is of particular clinical value, as a failure of the enzyme to act appropriately results in [[congenital adrenal hyperplasia]]. The [[X-ray crystallography|x-ray crystal structure]] for human 21-hydroxylase, with bound progesterone, was realized and published in 2015, providing opportunity for further study.<ref name="Pallan_2015" /> The enzyme is notable for its [[Substrate (chemistry)|substrate specificity]] and relatively high [[Specificity constant|catalytic efficiency]].
{{GNF_Protein_box
| image =
| image_source = 
| PDB =  
| Name = Cytochrome P450, family 21, subfamily A, polypeptide 2
| HGNCid = 2600
| Symbol = CYP21A2
| AltSymbols =; CPS1; CA21H; CAH1; CYP21; CYP21B; MGC150536; MGC150537; P450c21B
| OMIM = 201910
| ECnumber =
| Homologene = 68063
| MGIid = 88591
  | GeneAtlas_image1 = PBB_GE_CYP21A2_214622_at_tn.png
| Function = {{GNF_GO|id=GO:0004497 |text = monooxygenase activity}} {{GNF_GO|id=GO:0004509 |text = steroid 21-monooxygenase activity}} {{GNF_GO|id=GO:0005496 |text = steroid binding}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0008289 |text = lipid binding}} {{GNF_GO|id=GO:0019825 |text = oxygen binding}} {{GNF_GO|id=GO:0020037 |text = heme binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0005792 |text = microsome}} {{GNF_GO|id=GO:0016020 |text = membrane}}  
| Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006700 |text = C21-steroid hormone biosynthetic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1589
    | Hs_Ensembl = ENSG00000168482
    | Hs_RefseqProtein = NP_000491
    | Hs_RefseqmRNA = NM_000500
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = c6_COX
    | Hs_GenLoc_start = 32101901
    | Hs_GenLoc_end = 32104612
    | Hs_Uniprot = P08686
    | Mm_EntrezGene = 13079
    | Mm_Ensembl = ENSMUSG00000024365
    | Mm_RefseqmRNA = NM_009995
    | Mm_RefseqProtein = NP_034125
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 34409836
    | Mm_GenLoc_end = 34412455
    | Mm_Uniprot = A0JP50
  }}
}}


{{SI}}
== Structure ==
{{Infobox_gene}}
[[File:Full Structure of 21-Hydroxylase.png|thumb|left|Full structure of Human 21-Hydroxylase, showing three identical subunits, each with a centralized heme group (magenta)]]
21-hydroxylase is a complex of three independent and identical [[Protein subunit|enzyme subunits]]. Each subunit in the human enzyme consists of 13 '''[[Alpha helix|􏰁􏰁]]'''[[Alpha helix|α-helices]] and 9 [[Beta sheet|ß-strands]]''',''' formed into a triangular prism-like [[Protein tertiary structure|tertiary structure]].<ref name="Pallan_2015" /> The iron(III) heme group that defines the [[active site]] resides in the center of each subunit. The human enzyme binds one substrate at a time.<ref name="Pallan_2015" /> In contrast, the well-characterized bovine enzyme can bind two substrates.<ref>{{cite journal | vauthors = Zhao B, Lei L, Kagawa N, Sundaramoorthy M, Banerjee S, Nagy LD, Guengerich FP, Waterman MR | title = Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants | journal = The Journal of Biological Chemistry | volume = 287 | issue = 13 | pages = 10613–22 | date = March 2012 | pmid = 22262854 | pmc = 3323056 | doi = 10.1074/jbc.M111.323501 }}</ref> The human and bovine enzyme share 80% [[Protein primary structure|amino acid sequence]] identity, but are structurally different, particularly in loop regions, and also evident in [[Protein secondary structure|secondary structure]] elements.<ref name="Pallan_2015" />


==Overview==
== Function ==
'''Steroid 21-[[hydroxylase]]''' (or '''steroid 21-monooxygenase''' or '''21α-Hydroxylase'''; {{EC number|1.14.99.10}}) is a [[cytochrome P450]] [[enzyme]] which is involved with the [[biosynthesis]] of the [[steroid hormone]]s [[aldosterone]] and [[cortisol]].  
This gene encodes a member of the [[cytochrome P450]] superfamily of enzymes. The [[cytochrome P450]] proteins are [[monooxygenase]]s which catalyze many reactions involved in drug metabolism and synthesis of [[cholesterol]], [[steroid]]s and other [[lipid]]s. This protein localizes to the [[endoplasmic reticulum]] and [[Hydroxylation|hydroxylates]] steroids at the 21 position. The 21-hydroxylase enzyme is one of three [[Microsome|microsomal]] [[steroid]]ogenic P450 enzymes, the others being [[17-hydroxylase]] and [[aromatase]].<ref>{{cite book | vauthors = Auchus RJ, Miller WL | date = 2015 | chapter = P450 enzymes in steroid processing | title = Cytochrome P450: Structure, Mechanism, and Biochemistry | edition = Fourth | pages = 851–879 | publisher = Springer International Publishing | doi = 10.1007/978-3-319-12108-6_12 }}</ref> 21-hydroxylase is an essential enzyme in the biosynthetic pathways that produce cortisol and aldosterone.


The [[CAS number]] is 9029-68-9.
== Reaction ==


21-Hydroxylase is encoded by the [[gene]] '''CYP21B'''.
21-Hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of two steroids: [[progesterone]] and [[17α-Hydroxyprogesterone|17α-hydroxyprogesterone.]]


==Reaction==
[[File:Progesterone Reaction with 21-Hydroxylase.png|Reaction scheme showing hydroxylation of progesterone]]
It [[catalyst|catalyses]] the [[hydroxylation]] of the [[carbon]] atom 21 in [[steroid]]s (adding an "–OH"), which is necessary with the formation of these [[hormone]]s.
[[File:17a-hydroxyprogesterone reaction with 21-hydroxylase.png|Reaction scheme showing hydroxylation of 17a-hydroxyprogesterone]]


<gallery>
== Mechanism ==
Image:Progesterone-2D-skeletal.png|[[Progesterone]]
21-Hydroxylase is a cytochrome P450 enzyme and follows the [[Cytochrome P450|P450 catalytic cycle]].
Image:Deoxycorticosterone.svg|[[11-deoxycorticosterone]]
Image:Steroid-nomenclature.png|Steroid numbering - #21 is near center top
</gallery>


==Pathway==
=== Kinetics ===
[[Image:Corticosteroid-biosynthetic-pathway-rat.png|thumb|center|373px|Corticosteroid biosynthetic pathway in rat]]
21-Hydroxylase is highly specific for hydroxylation of progesterone and 17-hydroxyprogesterone. No studies have reported sufficient binding of alternate substrates. In this way, it differs from the evolutionarily and functionally related P450 enzyme [[17-hydroxylase]], which has a large range of substrates.<ref name="Auchus_2003">{{cite journal | vauthors = Auchus RJ, Sampath Kumar A, Andrew Boswell C, Gupta MK, Bruce K, Rath NP, Covey DF | title = The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21 | journal = Archives of Biochemistry and Biophysics | volume = 409 | issue = 1 | pages = 134–44 | date = January 2003 | pmid = 12464252 | doi = 10.1016/s0003-9861(02)00491-5 }}</ref>


[[Image:Steroidogenesis.gif|thumb|center|600px|[[Steroidogenesis]], showing both reactions of 21-Hydroxylase at center top.]]
Earlier studies of the human enzyme expressed in [[yeast]] classified 17-hydroxyprogesterone as the best substrate for 21-hydroxylase.<ref name="Auchus_2003" /><ref>{{cite journal | vauthors = Lorence MC, Trant JM, Mason JI, Bhasker CR, Fujii-Kuriyama Y, Estabrook RW, Waterman MR | title = Expression of a full-length cDNA encoding bovine adrenal cytochrome P450C21 | journal = Archives of Biochemistry and Biophysics | volume = 273 | issue = 1 | pages = 79–88 | date = August 1989 | pmid = 2502949 | doi = 10.1016/0003-9861(89)90164-1 }}</ref><ref>{{cite journal | vauthors = Wu DA, Hu MC, Chung BC | title = Expression and functional study of wild-type and mutant human cytochrome P450c21 in Saccharomyces cerevisiae | journal = DNA and Cell Biology | volume = 10 | issue = 3 | pages = 201–9 | date = April 1991 | pmid = 1707279 | doi = 10.1089/dna.1991.10.201 }}</ref> However,  recent analysis of the purified human enzyme found a lower [[Michaelis–Menten kinetics|K<sub>M</sub>]] and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone.<ref name="Pallan_2015" />


==Clinical significance==
The 2015 analysis found the [[Specificity constant|catalytic efficiency]] of 21-hydroxylase for conversion of progesterone in humans to be approximately 1.3 x 10^7 M-1s-1 at 37&nbsp;°C. This makes it the most catalytically efficient P450 enzyme of those reported, as of 2015, and more catalytically efficient than the closely related [[Bovinae|bovine]] 21-hydroxylase enzyme.<ref name="Guengerich_2016" /> C-H bond breaking to create a primary carbon [[Radical (chemistry)|radical]] is thought to be the [[Rate-determining step|rate-limiting step]] in the hydroxylation.<ref name="Pallan_2015" />
A [[genetic defect|defect]] within the CYP21B gene causes a disturbance of the development of the enzyme, which leads to [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency]]. A related [[pseudogene]] is located near this gene; [[gene conversion]] events involving the functional gene and the pseudogene are thought account for many cases of steroid 21-hydroxylase deficiency.<ref>{{cite web | title = Entrez Gene: CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1589| accessdate = }}</ref>


==References==
== Pathway ==
{{reflist|2}}
{|
==Further reading==
|[[File:Steroidogenesis.svg|thumb|275px|Human [[steroidogenesis]], showing both reactions of 21-Hydroxylase at center top.]]
{{refbegin | 2}}
|[[File:Corticosteroid-biosynthetic-pathway-rat.png|thumb|250px|Corticosteroid biosynthetic pathway in the rat.]]
{{PBB_Further_reading
|}
| citations =
 
*{{cite journal | author=White PC, Tusie-Luna MT, New MI, Speiser PW |title=Mutations in steroid 21-hydroxylase (CYP21). |journal=Hum. Mutat. |volume=3 |issue= 4 |pages= 373-8 |year= 1994 |pmid= 8081391 |doi= 10.1002/humu.1380030408 }}
==  Clinical significance ==
*{{cite journal | author=Helmberg A |title=Twin genes and endocrine disease: CYP21 and CYP11B genes. |journal=Acta Endocrinol. |volume=129 |issue= 2 |pages= 97-108 |year= 1993 |pmid= 8372604 |doi= }}
 
*{{cite journal | author=de-Araujo M, Sanches MR, Suzuki LA, ''et al.'' |title=Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency. |journal=Braz. J. Med. Biol. Res. |volume=29 |issue= 1 |pages= 1-13 |year= 1996 |pmid= 8731325 |doi=  }}
A [[genetic defect|defect]] within the CYP21A2 gene causes a disturbance of the development of the enzyme, which leads to [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency]]. A related [[pseudogene]] is located near this gene; [[gene conversion]] events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency.<ref name="entrez2">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1589|title=Entrez Gene: CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2|accessdate=}}</ref> Both genes are located on [[Chromosome 6 (human)|chromosome 6]], in the [[major histocompatibility complex]], and the pseudogene, CYP21A1, retains 98% [[exon]]ic sequence identity with the functional gene.<ref name="pmid34864222">{{cite journal | vauthors = Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y | title = Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 9 | pages = 2841–5 | date = May 1986 | pmid = 3486422 | pmc = 323402 | doi = 10.1073/pnas.83.9.2841 | bibcode = 1986PNAS...83.2841H }}</ref><ref>{{cite journal | vauthors = White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, Strominger JL | title = Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 4 | pages = 1089–93 | date = February 1985 | pmid = 2983330 | pmc = 397199 | doi = 10.1073/pnas.82.4.1089 | bibcode = 1985PNAS...82.1089W }}</ref>
*{{cite journal | author=Yu CY |title=Molecular genetics of the human MHC complement gene cluster. |journal=Exp. Clin. Immunogenet. |volume=15 |issue= 4 |pages= 213-30 |year= 1999 |pmid= 10072631 |doi= }}
 
*{{cite journal | author=Forest MG, Tardy V, Nicolino M, ''et al.'' |title=21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease. |journal=Ann. Endocrinol. (Paris) |volume=66 |issue= 3 |pages= 225-32 |year= 2005 |pmid= 15988383 |doi= }}
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, and occurs in approximately 1 in 15000 births globally.<ref>{{cite journal | vauthors = New MI, Wilson RC | title = Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 22 | pages = 12790–7 | date = October 1999 | pmid = 10536001 | pmc = 23101 | doi=10.1073/pnas.96.22.12790| bibcode = 1999PNAS...9612790N }}</ref><ref name="pmid9521938">{{cite journal | vauthors = Therrell BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S | title = Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia | journal = Pediatrics | volume = 101 | issue = 4 Pt 1 | pages = 583–90 | year = 1998 | pmid = 9521938 | doi = 10.1073/pnas.96.22.12790 | pmc = 23101 | bibcode = 1999PNAS...9612790N }}</ref> There are multiple forms of CAH, broken down into classical and nonclassical forms based on the amount of function retained. The classical forms include salt-wasting (SW), and simple-viralizing (SV). [[Mutation]]s that interfere with the active site—the heme group or residues involved in substrate binding—result in a complete loss of enzymatic activity, the salt-wasting type.<ref>{{cite journal | vauthors = Pallan PS, Lei L, Wang C, Waterman MR, Guengerich FP, Egli M | title = Research Resource: Correlating Human Cytochrome P450 21A2 Crystal Structure and Phenotypes of Mutations in Congenital Adrenal Hyperplasia | journal = Molecular Endocrinology | volume = 29 | issue = 9 | pages = 1375–84 | date = September 2015 | pmid = 26172259 | pmc = 4552440 | doi = 10.1210/ME.2015-1127 }}</ref> Cortisol and aldosterone deficits are associated with life-threatening salt-loss (hence salt-wasting), as the steroids play roles in regulating [[sodium]] [[homeostasis]]. Retaining minimal enzyme activity, the simple-viralizing type is associated with mutations in conserved hydrophobic regions or near the transmembrane domain. Simple viralizing CAH patients maintain adequate sodium homeostasis, but exhibit other phenotypical symptoms shared by SW, including accelerated growth in childhood and ambiguous [[Sex organ|genitalia]] in female neonates. Nonclassical forms retain 20-60% of hydroxylase function—this form is associated with normal cortisol expression, but an excess of androgens post-puberty.<ref>{{cite journal | vauthors = Miller WL, Auchus RJ | title = The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders | journal = Endocrine Reviews | volume = 32 | issue = 1 | pages = 81–151 | date = February 2011 | pmid = 21051590 | pmc = 3365799 | doi = 10.1210/er.2010-0013 }}</ref><ref>{{cite journal | vauthors = Haider S, Islam B, D'Atri V, Sgobba M, Poojari C, Sun L, Yuen T, Zaidi M, New MI | title = Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 7 | pages = 2605–10 | date = February 2013 | pmid = 23359706 | pmc = 3574933 | doi = 10.1073/pnas.1221133110 | url = http://www.pnas.org/content/110/7/2605 | bibcode = 2013PNAS..110.2605H }}</ref>
}}
 
== See also ==
* [[Steroidogenic enzyme]]
* [[Cytochrome P450 oxidoreductase deficiency]]
 
== References ==
{{reflist|32em}}
 
== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = White PC, Tusie-Luna MT, New MI, Speiser PW | title = Mutations in steroid 21-hydroxylase (CYP21) | journal = Human Mutation | volume = 3 | issue = 4 | pages = 373–8 | year = 1994 | pmid = 8081391 | doi = 10.1002/humu.1380030408 }}
* {{cite journal | vauthors = Helmberg A | title = Twin genes and endocrine disease: CYP21 and CYP11B genes | journal = Acta Endocrinologica | volume = 129 | issue = 2 | pages = 97–108 | date = August 1993 | pmid = 8372604 | doi = 10.1530/acta.0.1290097 }}
* {{cite journal | vauthors = de-Araujo M, Sanches MR, Suzuki LA, Guerra G, Farah SB, de-Mello MP | title = Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency | journal = Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas | volume = 29 | issue = 1 | pages = 1–13 | date = January 1996 | pmid = 8731325 | doi =  }}
* {{cite journal | vauthors = Yu CY | title = Molecular genetics of the human MHC complement gene cluster | journal = Experimental and Clinical Immunogenetics | volume = 15 | issue = 4 | pages = 213–30 | year = 1999 | pmid = 10072631 | doi = 10.1159/000019075 }}
* {{cite journal | vauthors = Forest MG, Tardy V, Nicolino M, David M, Morel Y | title = 21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease | journal = Annales d'Endocrinologie | volume = 66 | issue = 3 | pages = 225–32 | date = June 2005 | pmid = 15988383 | doi = 10.1016/s0003-4266(05)81754-8 }}
{{refend}}
{{refend}}


== External links ==
== External links ==
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cah  GeneReviews/NCBI/NIH/UW entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia]
* [https://www.ncbi.nlm.nih.gov/omim/201910  OMIM entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia]
* [http://www.chups.jussieu.fr/polys/biochimie/MMbioch/MM_32_PICT.jpg Synthesis of Desoxycorticosterone from Progesterone through 21-Hydroxylase (Image)]
* [http://www.chups.jussieu.fr/polys/biochimie/MMbioch/MM_32_PICT.jpg Synthesis of Desoxycorticosterone from Progesterone through 21-Hydroxylase (Image)]
* {{MeshName|Steroid+21-Hydroxylase}}
* {{MeshName|Steroid+21-Hydroxylase}}
* {{UCSC gene info|CPS1}}
* {{UCSC gene info|CYP21A2}}


{{NLM content}}
{{Steroid hydroxylases}}
{{Cytochrome P450}}
{{Dioxygenases}}
{{Enzymes}}


{{Oxygenases}}
{{Portal bar|Metabolism|Molecular and Cellular Biology|border=no}}
{{Cytochrome P450}}


[[Category:Enzymes]]
[[Category:Enzymes]]
[[Category:EC 1.14.99]]
[[Category:Cytochrome P450]]
[[Category:Cytochrome P450]]
[[Category:Metabolism]]
[[Category:Metabolism]]
 
[[Category:Human proteins]]
{{WH}}
{{WS}}

Latest revision as of 10:35, 31 August 2018

Steroid 21-Hydroxylase
File:21-hydroxylase subunit.png
Identifiers
EC number1.14.99.10
CAS number9029-68-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Steroid 21-hydroxylase, also called steroid 21-monooxygenase, 21α-hydroxylase, P45021A2, and, less commonly 21β-hydroxylase, is a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.[1] These syntheses take place in the adrenal cortex.[2] Specifically, 21-hydroxylase converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively, by hydroxylating at the C21 position.[3] The products of the conversions then continue through their appropriate pathways towards creation of aldosterone and cortisol. Like other cytochrome P450 enzymes, 21-hydroxylase participates in the cytochrome P450 catalytic cycle, and engages in one-electron transfer with NADPH-P450 reductase. Its structure includes an essential iron heme group centered within the protein, also common to all P450 enzymes. Variations of the 21-hydroxylase enzyme can be found in all vertebrates.[4] However, understanding of human 21-hydroxylase structure and function is of particular clinical value, as a failure of the enzyme to act appropriately results in congenital adrenal hyperplasia. The x-ray crystal structure for human 21-hydroxylase, with bound progesterone, was realized and published in 2015, providing opportunity for further study.[3] The enzyme is notable for its substrate specificity and relatively high catalytic efficiency.

Structure

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

n/a

n/a

RefSeq (mRNA)

n/a

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
File:Full Structure of 21-Hydroxylase.png
Full structure of Human 21-Hydroxylase, showing three identical subunits, each with a centralized heme group (magenta)

21-hydroxylase is a complex of three independent and identical enzyme subunits. Each subunit in the human enzyme consists of 13 􏰁􏰁α-helices and 9 ß-strands, formed into a triangular prism-like tertiary structure.[3] The iron(III) heme group that defines the active site resides in the center of each subunit. The human enzyme binds one substrate at a time.[3] In contrast, the well-characterized bovine enzyme can bind two substrates.[5] The human and bovine enzyme share 80% amino acid sequence identity, but are structurally different, particularly in loop regions, and also evident in secondary structure elements.[3]

Function

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. The 21-hydroxylase enzyme is one of three microsomal steroidogenic P450 enzymes, the others being 17-hydroxylase and aromatase.[6] 21-hydroxylase is an essential enzyme in the biosynthetic pathways that produce cortisol and aldosterone.

Reaction

21-Hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of two steroids: progesterone and 17α-hydroxyprogesterone.

Reaction scheme showing hydroxylation of progesterone Reaction scheme showing hydroxylation of 17a-hydroxyprogesterone

Mechanism

21-Hydroxylase is a cytochrome P450 enzyme and follows the P450 catalytic cycle.

Kinetics

21-Hydroxylase is highly specific for hydroxylation of progesterone and 17-hydroxyprogesterone. No studies have reported sufficient binding of alternate substrates. In this way, it differs from the evolutionarily and functionally related P450 enzyme 17-hydroxylase, which has a large range of substrates.[7]

Earlier studies of the human enzyme expressed in yeast classified 17-hydroxyprogesterone as the best substrate for 21-hydroxylase.[7][8][9] However, recent analysis of the purified human enzyme found a lower KM and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone.[3]

The 2015 analysis found the catalytic efficiency of 21-hydroxylase for conversion of progesterone in humans to be approximately 1.3 x 10^7 M-1s-1 at 37 °C. This makes it the most catalytically efficient P450 enzyme of those reported, as of 2015, and more catalytically efficient than the closely related bovine 21-hydroxylase enzyme.[2] C-H bond breaking to create a primary carbon radical is thought to be the rate-limiting step in the hydroxylation.[3]

Pathway

Error creating thumbnail: File missing
Human steroidogenesis, showing both reactions of 21-Hydroxylase at center top.
Corticosteroid biosynthetic pathway in the rat.

Clinical significance

A defect within the CYP21A2 gene causes a disturbance of the development of the enzyme, which leads to congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency.[10] Both genes are located on chromosome 6, in the major histocompatibility complex, and the pseudogene, CYP21A1, retains 98% exonic sequence identity with the functional gene.[11][12]

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, and occurs in approximately 1 in 15000 births globally.[13][14] There are multiple forms of CAH, broken down into classical and nonclassical forms based on the amount of function retained. The classical forms include salt-wasting (SW), and simple-viralizing (SV). Mutations that interfere with the active site—the heme group or residues involved in substrate binding—result in a complete loss of enzymatic activity, the salt-wasting type.[15] Cortisol and aldosterone deficits are associated with life-threatening salt-loss (hence salt-wasting), as the steroids play roles in regulating sodium homeostasis. Retaining minimal enzyme activity, the simple-viralizing type is associated with mutations in conserved hydrophobic regions or near the transmembrane domain. Simple viralizing CAH patients maintain adequate sodium homeostasis, but exhibit other phenotypical symptoms shared by SW, including accelerated growth in childhood and ambiguous genitalia in female neonates. Nonclassical forms retain 20-60% of hydroxylase function—this form is associated with normal cortisol expression, but an excess of androgens post-puberty.[16][17]

See also

References

  1. ↑ Ryan KJ, Engel LL (March 1957). "Hydroxylation of steroids at carbon 21" (PDF). The Journal of Biological Chemistry. 225 (1): 103–14. PMID 13416221.
  2. ↑ 2.0 2.1 Guengerich FP, Waterman MR, Egli M (August 2016). "Recent Structural Insights into Cytochrome P450 Function". Trends in Pharmacological Sciences. 37 (8): 625–40. doi:10.1016/j.tips.2016.05.006. PMC 4961565. PMID 27267697.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Pallan PS, Wang C, Lei L, Yoshimoto FK, Auchus RJ, Waterman MR, Guengerich FP, Egli M (May 2015). "Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: structure of the enzyme·progesterone substrate complex and rate-limiting c-h bond cleavage". The Journal of Biological Chemistry. 290 (21): 13128–43. doi:10.1074/jbc.M115.646307. PMC 4505568. PMID 25855791.
  4. ↑ Graham SE, Peterson JA (2002). "Sequence alignments, variabilities, and vagaries". Methods in Enzymology. 357: 15–28. doi:10.1016/s0076-6879(02)57661-8. PMID 12424893.
  5. ↑ Zhao B, Lei L, Kagawa N, Sundaramoorthy M, Banerjee S, Nagy LD, Guengerich FP, Waterman MR (March 2012). "Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants". The Journal of Biological Chemistry. 287 (13): 10613–22. doi:10.1074/jbc.M111.323501. PMC 3323056. PMID 22262854.
  6. ↑ Auchus RJ, Miller WL (2015). "P450 enzymes in steroid processing". Cytochrome P450: Structure, Mechanism, and Biochemistry (Fourth ed.). Springer International Publishing. pp. 851–879. doi:10.1007/978-3-319-12108-6_12.
  7. ↑ 7.0 7.1 Auchus RJ, Sampath Kumar A, Andrew Boswell C, Gupta MK, Bruce K, Rath NP, Covey DF (January 2003). "The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21". Archives of Biochemistry and Biophysics. 409 (1): 134–44. doi:10.1016/s0003-9861(02)00491-5. PMID 12464252.
  8. ↑ Lorence MC, Trant JM, Mason JI, Bhasker CR, Fujii-Kuriyama Y, Estabrook RW, Waterman MR (August 1989). "Expression of a full-length cDNA encoding bovine adrenal cytochrome P450C21". Archives of Biochemistry and Biophysics. 273 (1): 79–88. doi:10.1016/0003-9861(89)90164-1. PMID 2502949.
  9. ↑ Wu DA, Hu MC, Chung BC (April 1991). "Expression and functional study of wild-type and mutant human cytochrome P450c21 in Saccharomyces cerevisiae". DNA and Cell Biology. 10 (3): 201–9. doi:10.1089/dna.1991.10.201. PMID 1707279.
  10. ↑ "Entrez Gene: CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2".
  11. ↑ Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y (May 1986). "Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene". Proceedings of the National Academy of Sciences of the United States of America. 83 (9): 2841–5. Bibcode:1986PNAS...83.2841H. doi:10.1073/pnas.83.9.2841. PMC 323402. PMID 3486422.
  12. ↑ White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, Strominger JL (February 1985). "Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man". Proceedings of the National Academy of Sciences of the United States of America. 82 (4): 1089–93. Bibcode:1985PNAS...82.1089W. doi:10.1073/pnas.82.4.1089. PMC 397199. PMID 2983330.
  13. ↑ New MI, Wilson RC (October 1999). "Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12790–7. Bibcode:1999PNAS...9612790N. doi:10.1073/pnas.96.22.12790. PMC 23101. PMID 10536001.
  14. ↑ Therrell BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S (1998). "Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia". Pediatrics. 101 (4 Pt 1): 583–90. Bibcode:1999PNAS...9612790N. doi:10.1073/pnas.96.22.12790. PMC 23101. PMID 9521938.
  15. ↑ Pallan PS, Lei L, Wang C, Waterman MR, Guengerich FP, Egli M (September 2015). "Research Resource: Correlating Human Cytochrome P450 21A2 Crystal Structure and Phenotypes of Mutations in Congenital Adrenal Hyperplasia". Molecular Endocrinology. 29 (9): 1375–84. doi:10.1210/ME.2015-1127. PMC 4552440. PMID 26172259.
  16. ↑ Miller WL, Auchus RJ (February 2011). "The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders". Endocrine Reviews. 32 (1): 81–151. doi:10.1210/er.2010-0013. PMC 3365799. PMID 21051590.
  17. ↑ Haider S, Islam B, D'Atri V, Sgobba M, Poojari C, Sun L, Yuen T, Zaidi M, New MI (February 2013). "Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia". Proceedings of the National Academy of Sciences of the United States of America. 110 (7): 2605–10. Bibcode:2013PNAS..110.2605H. doi:10.1073/pnas.1221133110. PMC 3574933. PMID 23359706.

Further reading

  • White PC, Tusie-Luna MT, New MI, Speiser PW (1994). "Mutations in steroid 21-hydroxylase (CYP21)". Human Mutation. 3 (4): 373–8. doi:10.1002/humu.1380030408. PMID 8081391.
  • Helmberg A (August 1993). "Twin genes and endocrine disease: CYP21 and CYP11B genes". Acta Endocrinologica. 129 (2): 97–108. doi:10.1530/acta.0.1290097. PMID 8372604.
  • de-Araujo M, Sanches MR, Suzuki LA, Guerra G, Farah SB, de-Mello MP (January 1996). "Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency". Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas. 29 (1): 1–13. PMID 8731325.
  • Yu CY (1999). "Molecular genetics of the human MHC complement gene cluster". Experimental and Clinical Immunogenetics. 15 (4): 213–30. doi:10.1159/000019075. PMID 10072631.
  • Forest MG, Tardy V, Nicolino M, David M, Morel Y (June 2005). "21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease". Annales d'Endocrinologie. 66 (3): 225–32. doi:10.1016/s0003-4266(05)81754-8. PMID 15988383.

External links

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