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Reviewed, UniProtKB/Swiss-Prot P08686 (CP21A_HUMAN)

Last modified July 22, 2008. Version 107. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    Cytochrome P450 21
    EC=1.14.99.10
Alternative name(s):
    Cytochrome P450 XXI
    Steroid 21-hydroxylase
    21-OHase
    P450-C21
    P-450c21
    P450-C21B
Gene names
Name: CYP21A2
Synonyms: CYP21, CYP21B
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length494 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Specifically catalyzes the 21-hydroxylation of steroids. Required for the adrenal synthesis of mineralocorticoids and glucocorticoids.

Catalytic activity

A steroid + AH(2) + O(2) = a 21-hydroxysteroid + A + H(2)O.

Cofactor

Heme group.

Subcellular location

Endoplasmic reticulum membrane; Peripheral membrane protein. Microsome membrane; Peripheral membrane protein.

Domain

The leucine-rich hydrophobic amino acid N-terminal region probably helps to anchor the protein to the microsomal membrane.

Involvement in disease

Defects in CYP21A2 are the cause of adrenal hyperplasia type 3 (AH3) [MIM:201910]. AH3 is a form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late onset (NC or LOAH), and 'cryptic' (asymptomatic).

Miscellaneous

The human genome contains 2 genes, C4A and C4B, for C4 complement component separated by approximately 10 kb. 3'to each of the C4 genes there is a steroid 21-hydroxylase gene. The gene 3'to C4A is a pseudogene.

Sequence similarities

Belongs to the cytochrome P450 family.

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Ontologies

Keywords

   Biological processSteroidogenesis
   Cellular componentEndoplasmic reticulum
Membrane
Microsome
   Coding sequence diversityPolymorphism
   DiseaseCongenital adrenal hyperplasia
Disease mutation
   LigandHeme
Iron
Lipid-binding
Metal-binding
Steroid-binding
   Molecular functionMonooxygenase
Oxidoreductase
   Technical term3D-structure

Gene Ontology (GO)

   Biological processsteroid biosynthetic process

Inferred from Experiment. Source: Reactome

   Molecular functionsteroid hydroxylase activity Ref.5

Traceable author statement. Source: ProtInc

Complete GO annotation...

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical view

Molecule processing

Chain1 – 494494Cytochrome P450 21

Regions

Region342 – 35817Steroid-binding By similarity

Sites

Metal binding4281Iron (heme axial ligand)

Natural variations

Natural variant91L → LL in allele CYP21A2*2.
Natural variant151A → T in AH3; salt wasting form; no significant difference in activity compared with the wild-type.
Natural variant301P → L in AH3; non-classic form; 50% activity; 10% of non-classic AH3 Texan patients.
Natural variant301P → Q in AH3; does not affect membrane binding; enzyme function abolished.
Natural variant621H → L in AH3.
Natural variant641G → E in AH3; no activity.
Natural variant901G → V in AH3.
Natural variant981K → R
Natural variant1021K → R in allele CYP21A2*3.
Natural variant1051P → L in AH3.
Natural variant1241R → H in AH3.
Natural variant1691C → Y in AH3.
Natural variant1721I → N in AH3; simple virilizing form; 1-2% activity.
Natural variant1781G → A in AH3.
Natural variant1831D → E in allele CYP21A2*4.
Natural variant1961Missing in AH3; moderate.
Natural variant2111V → L in AH3; non-classic form; pathogenicity uncertain.
Natural variant2361I → N in AH3; salt wasting form.
Natural variant2371V → E in AH3; salt wasting form.
Natural variant2391M → K in AH3; salt wasting form.
Natural variant2611L → P in AH3.
Natural variant2681S → T in allele CYP21A2*5. dbSNP rs6472.
Natural variant2811V → G in AH3; salt wasting form.
Natural variant2811V → L in AH3; non-classic form; 50% activity; most common variant; 59% of non-classic AH3 Texan patients; normal KM but 20% reduced Vmax. dbSNP rs6471.
Natural variant2831M → L in AH3.
Natural variant2911G → C in AH3.
Natural variant2911G → R in AH3.
Natural variant2911G → S in AH3; salt wasting form; less then 1% activity.
Natural variant3001L → F in AH3; salt wasting form.
Natural variant3011S → Y in AH3.
Natural variant3041V → M in hyperandrogenism; due to 21-hydroxylase deficiency; non-classic type; residual activity of 46% for conversion of 17-hydroxyprogesterone and 26% for conversion of progesterone compared with the normal enzyme.
Natural variant3171L → M in AH3.
Natural variant3391R → H in AH3; non-classic form; 50% activity.
Natural variant3411R → P in AH3.
Natural variant3411R → W in AH3; non-classic form; mild.
Natural variant3541R → C in AH3; salt wasting form.
Natural variant3541R → H in AH3.
Natural variant3561R → P in AH3; salt wasting form; 0.15% activity.
Natural variant3561R → Q in AH3; simple virilizing form; mild; 0.65% activity.
Natural variant3561R → W in AH3; salt wasting form.
Natural variant3621A → V in AH3; no activity.
Natural variant3631L → W in AH3.
Natural variant3651H → Y in AH3.
Natural variant3751G → S in hyperandrogenism; due to 21-hydroxylase deficiency; almost completely abolished enzyme activity.
Natural variant3801E → D in AH3; salt wasting form.
Natural variant4081R → C in AH3; should lead to complete impairment of enzymatic activity.
Natural variant4241G → S in AH3.
Natural variant4261R → H in AH3; exhibit only low enzyme activity toward 17-hydroxyprogesterone.
Natural variant4351R → C in AH3.
Natural variant4531P → S in AH3; non-classic form; 50% activity; 23% of non-classic AH3 Texan patients; almost completely abolished enzyme activity when associated with S-375. dbSNP rs6445.
Natural variant4791R → L in AH3.
Natural variant4821P → S in AH3; rediced enzyme activity to 70% of normal.
Natural variant4831R → P in AH3; moderate; 1-2% of activity.
Natural variant4831R → Q in AH3.
Natural variant4831R → W in AH3; salt wasting form.
Natural variant4931N → S in AH3; could be a polymorphism; allele CYP21A2*6. dbSNP rs6473.

Experimental info

Mutagenesis2681S → C, M or T: No loss of function
Mutagenesis2811V → I: Normal KM but 50% reduced Vmax
Mutagenesis2811V → T: Normal KM but 10% reduced Vmax
Mutagenesis4281C → M, S or T: Loss of activity and loss of P450 absorption
Sequence conflict3111P → L Ref.8
Sequence conflict3461N → I Ref.8
Sequence conflict4261R → P in AAB59440. Ref.2
Sequence conflict4371E → D in AAB59440. Ref.2

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Sequences

Sequence LengthMass (Da)Tools
P08686-1 [UniParc].

Last modified January 1, 1988. Version 1.
Checksum: 7E1FF83B59FBA136

FASTA49455,887
        10         20         30         40         50         60 
MLLLGLLLLP LLAGARLLWN WWKLRSLHLP PLAPGFLHLL QPDLPIYLLG LTQKFGPIYR 

        70         80         90        100        110        120 
LHLGLQDVVV LNSKRTIEEA MVKKWADFAG RPEPLTYKLV SKNYPDLSLG DYSLLWKAHK 

       130        140        150        160        170        180 
KLTRSALLLG IRDSMEPVVE QLTQEFCERM RAQPGTPVAI EEEFSLLTCS IICYLTFGDK 

       190        200        210        220        230        240 
IKDDNLMPAY YKCIQEVLKT WSHWSIQIVD VIPFLRFFPN PGLRRLKQAI EKRDHIVEMQ 

       250        260        270        280        290        300 
LRQHKESLVA GQWRDMMDYM LQGVAQPSME EGSGQLLEGH VHMAAVDLLI GGTETTANTL 

       310        320        330        340        350        360 
SWAVVFLLHH PEIQQRLQEE LDHELGPGAS SSRVPYKDRA RLPLLNATIA EVLRLRPVVP 

       370        380        390        400        410        420 
LALPHRTTRP SSISGYDIPE GTVIIPNLQG AHLDETVWER PHEFWPDRFL EPGKNSRALA 

       430        440        450        460        470        480 
FGCGARVCLG EPLARLELFV VLTRLLQAFT LLPSGDALPS LQPLPHCSVI LKMQPFQVRL 

       490 
QPRGMGAHSP GQNQ

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References

[1]"Structure of human steroid 21-hydroxylase genes."
White P.C., New M.I., Dupont B.
Proc. Natl. Acad. Sci. U.S.A. 83:5111-5115(1986) [PubMed: 3487786] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]"Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene."
Higashi Y., Yoshioka H., Yamane M., Gotoh O., Fujii-Kuriyama Y.
Proc. Natl. Acad. Sci. U.S.A. 83:2841-2845(1986) [PubMed: 3486422] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia."
Rodrigues N.R., Dunham I., Yu C.Y., Carroll M.C., Porter R.R., Campbell R.D.
EMBO J. 6:1653-1661(1987) [PubMed: 3038528] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT AH3 THR-268, VARIANT SER-493.
[4]"Nonsense mutation causing steroid 21-hydroxylase deficiency."
Globerman H., Amor M., Parker K.L., New M.I., White P.C.
J. Clin. Invest. 82:139-144(1988) [PubMed: 3267225] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-281, VARIANT LEU-9 INS.
[5]"R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions."
Helmberg A., Tusie-Luna M.-T., Tabarelli M., Kofler R., White P.C.
Mol. Endocrinol. 6:1318-1322(1992) [PubMed: 1406709] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-9 INS ARG-102 AND SER-493, VARIANTS AH3 HIS-339 AND SER-453.
Tissue: Peripheral blood.
[6]"A de novo pathological point mutation at the 21-hydroxylase locus: implications for gene conversion in the human genome."
Collier S., Tassabehji M., Sinnott P., Strachan T.
Nat. Genet. 3:260-265(1993) [PubMed: 8485582] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 109-185, VARIANT ASN-172.
[7]"Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man."
Carroll M.C., Campbell R.D., Porter R.R.
Proc. Natl. Acad. Sci. U.S.A. 82:521-525(1985) [PubMed: 3871526] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 149-182.
[8]"P450XXI (steroid 21-hydroxylase) gene deletions are not found in family studies of congenital adrenal hyperplasia."
Matteson K.J., Phillips J.A. III, Miller W.L., Chung B.C., Orlando P.J., Frisch H., Ferrandez A., Burr I.M.
Proc. Natl. Acad. Sci. U.S.A. 84:5858-5862(1987) [PubMed: 3497399] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 265-494, VARIANT LEU-281.
[9]"Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and Ser268 result in complete, partial, or no loss of enzymatic activity, respectively."
Wu D.A., Chung B.C.
J. Clin. Invest. 88:519-523(1991) [PubMed: 1864962] [Abstract]
Cited for: CHARACTERIZATION OF VARIANT AH3 LEU-281, MUTAGENESIS OF SER-268 AND CYS-428.
[10]"Molecular genetics of 21-hydroxylase deficient late-onset adrenal hyperplasia."
Gunn S.K., Sherman L.D., Therrell B.L., Owerbach D.I.
Semin. Reprod. Endocrinol. 11:347-352(1993)
Cited for: REVIEW ON AH3 VARIANTS.
[11]"Mutations in steroid 21-hydroxylase (CYP21)."
White P.C., Tusie-Luna M.-T., New M.I., Speiser P.W.
Hum. Mutat. 3:373-378(1994) [PubMed: 8081391] [Abstract]
Cited for: REVIEW ON AH3 VARIANTS.
[12]"Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1."
Speiser P.W., New M.I., White P.C.
N. Engl. J. Med. 319:19-23(1988) [PubMed: 3260007] [Abstract]
Cited for: VARIANTS AH3 LEU-211 AND LEU-281.
[13]"Mutation in the CYP21B gene (Ile-172-->Asn) causes steroid 21-hydroxylase deficiency."
Amor M., Parker K.L., Globerman H., New M.I., White P.C.
Proc. Natl. Acad. Sci. U.S.A. 85:1600-1604(1988) [PubMed: 3257825] [Abstract]
Cited for: VARIANT AH3 ASN-172.
[14]"A missense mutation at Ile172-->Asn or Arg356-->Trp causes steroid 21-hydroxylase deficiency."
Chiou S.-H., Hu M.-C., Chung B.-C.
J. Biol. Chem. 265:3549-3552(1990) [PubMed: 2303461] [Abstract]
Cited for: VARIANTS AH3 ASN-172 AND TRP-356, VARIANT LEU-9 INS.
[15]"Substitution of Ile-172 to Asn in the steroid 21-hydroxylase B (P450c21B) gene in a Finnish patient with the simple virilizing form of congenital adrenal hyperplasia."
Partanen J., Campbell R.D.
Hum. Genet. 87:716-720(1991) [PubMed: 1937474] [Abstract]
Cited for: VARIANT AH3 ASN-172.
[16]"A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic steroid 21-hydroxylase deficiency allele."
Tusie-Luna M.T., Speiser P.W., Dumic M., New M.I., White P.C.
Mol. Endocrinol. 5:685-692(1991) [PubMed: 2072928] [Abstract]
Cited for: VARIANT AH3 LEU-30, VARIANT THR-268.
[17]"Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency."
Speiser P.W., Dupont J., Zhu D., Serrat J., Buegeleisen M., Tusie-Luna M.-T., Lesser M., New M.I., White P.C.
J. Clin. Invest. 90:584-595(1992) [PubMed: 1644925] [Abstract]
Cited for: VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281 AND TRP-356.
[18]"Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency."
Owerbach D., Sherman L., Ballard A.L., Azziz R.
Mol. Endocrinol. 6:1211-1215(1992) [PubMed: 1406699] [Abstract]
Cited for: VARIANT AH3 SER-453.
[19]"Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations."
Wedell A., Ritzen E.M., Haglund-Stengler B., Luthman H.
Proc. Natl. Acad. Sci. U.S.A. 89:7232-7236(1992) [PubMed: 1496017] [Abstract]
Cited for: VARIANTS AH3 LEU-105; SER-291 AND SER-453.
[20]"Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations through the pseudogene."
Wedell A., Luthman H.
Hum. Genet. 91:236-240(1993) [PubMed: 8478006] [Abstract]
Cited for: VARIANT AH3 PRO-483.
[21]"Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency."
Barbat B., Bogyo A., Raux-Demay M.-C., Kuttenn F., Boue J., Simon-Bouy B., Serre J.-L., Boue A., Mornet E.
Hum. Mutat. 5:126-130(1995) [PubMed: 7749410] [Abstract]
Cited for: VARIANTS AH3 ASN-172; ASN-236; LEU-281 AND PRO-483, VARIANT SER-493.
[22]"E380D: a novel point mutation of CYP21 in an HLA-homozygous patient with salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency."
Kirby-Keyser L., Porter C.C., Donohoue P.A.
Hum. Mutat. 9:181-182(1997) [PubMed: 9067760] [Abstract]
Cited for: VARIANT AH3 ASP-380.
[23]"A cluster of missense mutations at Arg356 of human steroid 21-hydroxylase may impair redox partner interaction."
Lajic S., Levo A., Nikoshkov A., Lundberg Y., Partanen J., Wedell A.
Hum. Genet. 99:704-709(1997) [PubMed: 9187661] [Abstract]
Cited for: VARIANTS AH3 PRO-356 AND GLN-356.
[24]"Synergistic effect of partially inactivating mutations in steroid 21-hydroxylase deficiency."
Nikoshkov A., Lajic S., Holst M., Wedell A., Luthman H.
J. Clin. Endocrinol. Metab. 82:194-199(1997) [PubMed: 8989258] [Abstract]
Cited for: VARIANTS AH3 LEU-105 AND SER-453.
[25]"Mutation analysis in patients with congenital adrenal hyperplasia in the Spanish population: identification of putative novel steroid 21-hydroxylase deficiency alleles associated with the classic form of the disease."
Lobato M.N., Ord