21-Hydroxylase

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Steroid 21-hydroxylase
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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PMCarticles
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NCBIproteins

Steroid 21-hydroxylase is a

blood pressure regulation, sodium homeostasis and blood sugar control. The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively,[12][13] within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in the enzyme may cause congenital adrenal hyperplasia
.

Steroid 21-hydroxylase is a member of the

cofactor
to oxidize substrates.

In humans, the enzyme is localized in endoplasmic reticulum membranes of cells in adrenal cortex,[14][15] and is encoded by the CYP21A2 gene which is located near the CYP21A1P pseudogene that has high degree of sequence similarity. This similarity makes it difficult to analyze the gene at the molecular level, and sometimes leads to loss-of-function mutations of the gene due to intergenic exchange of DNA.

Gene

See also: RCCX
CYP21A2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSMUSG00000024365

UniProt

P08686
Q08AG9

P03940

RefSeq (mRNA)

NM_000500
NM_001128590

NM_009995

RefSeq (protein)

NP_034125

Location (UCSC)Chr 6: 32.04 – 32.04 MbChr 17: 35.02 – 35.02 Mb
PubMed search[18][19]
Wikidata
View/Edit HumanView/Edit Mouse
Evolution of the CYP21A locus in humans and mice.

Steroid 21-hydroxylase in humans is encoded by the CYP21A2 gene that may be accompanied by one or several copies of the nonfunctional pseudogene CYP21A1P,[20][21] this pseudogene shares 98% of the exonic informational identity with the actual functional gene.[22][23]

Pseudogenes are common in genomes, and they originate as artifacts during the duplication process. Though often thought of as "junk DNA", research has shown that retaining these faulty copies can have a beneficial role, often providing regulation of their parent genes.[24]

In the mouse genome, the Cyp21a2 is a pseudogene and the Cyp21a1 is a functional gene.[25] In the chicken and quail, there is only a single Cyp21 gene, which locus is located between complement component C4 and TNX gene, along with Cenpa.[26]

CYP21A2 in humans is located in

C4B, the Tenascin X gene TNXB and STK19.[28] MHC class III is the most gene-dense region of the human genome, containing many genes that have, as of 2023 - unknown functions or structures.[29][27]

Inside the

protein-coding, but if a module count is two or more, there is only one copy of each functional gene rest being non-coding pseudogenes with the exception of the C4 gene which always has active copies.[30][35]

Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene and the complexity of the RCCX locus, it is difficult to perform molecular diagnostics for CYP21A2. The pseudogene can have single-nucleotide polymorphisms (SNP) that are identical or similar to those in the functional gene, making it difficult to distinguish between them. The pseudogene can also recombine with the functional gene, creating hybrid genes that have features of both. This can result in false-positive or false-negative results when testing for SNPs in the CYP21A2.[37]

The whole genome sequencing technology relies on breaking the DNA into small fragments, sequencing them, and then assembling them back together based on their overlaps. However, because of the high homology and variability of the CYP21A2 and its pseudogene, the fragments cannot be mapped unambiguously to either copy of the gene. This can lead to errors or gaps in the assembly, or missing some variants that are present in the gene.[38][37]

duplications, which are frequent in the case of the CYP21A2.[39][40][38]

Southern blotting, a method used for detecting and quantifying a specific DNA sequence in DNA samples, also has limitations in analyzing CYP21A2. This method is time-consuming and requires a large amount of good-quality DNA, which makes it less applicable in routine diagnostic settings. This method comes with a radioactive biohazard, which poses safety concerns and makes it labor-intensive. Southern blotting is unable to detect the junction sites of chimeras. The CYP21A2 gene is prone to mismatch and rearrangement, producing different types of complex variations that include copy number variants, large gene conversions, small insertions/deletions, and single-nucleotide (SNP) variants. Southern blotting is not capable of detecting all these types of variants simultaneously. Besides that, southern blotting requires genetic analysis of the parents, which is not always feasible or practical.[38][41]

Therefore, to analyze the CYP21A2 gene accurately, a more specialized and sensitive method is needed, such as targeted long-read sequencing, which can sequence longer DNA fragments and capture more information about the gene structure and variation. However, this method is not widely available or affordable for clinical use.[42][43][44]

Protein

Steroid 21-hydroxylase, is a member of the cytochrome P450 family of monooxygenase enzymes, the protein has 494 amino acid residues with a molecular weight of 55,000. This enzyme is at most 28% homologous to other P-450 enzymes that have been studied.[45]

Structurally, the protein contains an evolutionarily conserved core of four

cofactor binding loop.[46] Each subunit in the human enzyme consists of a total of 13 α-helices and 9 β-strands that folds into a triangular prism-like tertiary structure.[12]

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.[12] In contrast, the well-characterized bovine enzyme can bind two substrates.[47] 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.[12]

Species

Variations of the steroid 21-hydroxylase can be found in all vertebrates.[48]

Cyp21 first emerged in

11β-hydroxylase enzyme responsible for converting 11-deoxycortisol to cortisol as observed in mammals. Instead, they rely on 11-deoxycortisol, a product of a reaction catalyzed by CYP21, as their primary glucocorticoid hormone with mineralocorticoid properties. This suggests the presence of a complex and highly specific corticosteroid signaling pathway that emerged at least half a billion years ago during early vertebrate evolution.[50]

In vertebrates, such as fish, amphibians, reptiles, birds, and mammals, Cyp21 participates in the biosynthesis of glucocorticoids and mineralocorticoids, therefore, Cyp21 is essential for the regulation of stress response, electrolyte balance and blood pressure, immune system, and metabolism in vertebrates.[51]

Cyp21 is relatively conserved among mammals, and shows some variations in its structure, expression, and regulation.[51] Rhesus macaques and orangutans possess two copies of Cyp21, while chimpanzees have three, still, a pseudogene (CYP21A1P) is only present in humans among primates.[52]

Tissue and subcellular distribution

Steroid 21-hydroxylase is localized in

17-hydroxylase and aromatase.[53]

Unlike other enzymes of the cytochrome P450 superfamily of enzymes that are expressed in multiple tissues, with most abundant expression in the liver, in adult humans steroid 21-hydroxylase, along with steroid 11β-hydroxylase and aldosterone synthase, is almost exclusively expressed in the adrenal gland.[54][55]

As of 2023, the main subcellular location for the encoded protein in human cells is not known, and is pending cell analysis.[56]

Function

Steroid numbering, C21 is in the side chain of C17

The enzyme, steroid 21-hydroxylase hydroxylates steroids at the C21 position.[13]Steroids are a group of naturally occurring and synthetically produced organic compounds, steroids all share a four ring primary structure. The enzyme catalyzes the chemical reaction in which the hydroxyl group (-OH) is added at the C21 position of the steroid biomolecule. This location is on a side chain of the D ring.

The enzyme is a member of the cytochrome P450 superfamily of monooxygenase enzymes. The cytochrome P450 enzymes catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids.

Steroid 21-hydroxylase is essential for the biosynthesis of cortisol and aldosterone.[57][58]

Mechanism

Reaction scheme showing hydroxylation of progesterone (top) and 17a-hydroxyprogesterone (bottom)
steroidogenesis, showing both reactions of 21-Hydroxylase at center top.
Corticosteroid biosynthetic pathway in the rat.

Steroid 21-hydroxylase is a cytochrome P450 enzyme that is notable for its substrate specificity and relatively high catalytic efficiency.[48]

Like other cytochrome P450 enzymes, steroid 21-hydroxylase participates in the

17-hydroxylase, which has a broad range of substrates.[59]

The chemical reaction in which steroid 21-hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of progesterone, 17α-hydroxyprogesterone and 21-desoxycortisone[60] was first described in 1952.[61]

Studies of the human enzyme expressed in yeast initially classified 17-hydroxyprogesterone as the preferred substrate for steroid 21-hydroxylase,[59][62][63] however, later analysis of the purified human enzyme found a lower KM and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone.[12]

The

bovine steroid 21-hydroxylase enzyme.[14] C-H bond breaking to create a primary carbon radical is thought to be the rate-limiting step in the hydroxylation.[12]

Clinical significance

Congenital adrenal hyperplasia

Main article: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

autosomal recessive disorder
. There are multiple forms of CAH, defined as classical and nonclassical forms based on the amount of enzyme function still present in the patient.

The classical forms occur in approximately 1 in 10000 to 1 in 20000 births globally,

neonates
.

The nonclassical form is the mildest condition, retaining about 20% to 50% of enzyme function.[58] This form is associated with mild and clinically silent cortisol impairment,[65] but an excess of androgens post-puberty.[66]

Non-classic congenital adrenal hyperplasia

Main article: Late onset congenital adrenal hyperplasia

Non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (NCCAH) is a milder and late-onset congenital adrenal hyperplasia. Its prevalence rate in different ethnic groups varies from 1 in 1000 to 1 in 50.[58] Some people affected by the condition have no relevant signs and symptoms, while others experience symptoms of hyperandrogenism.[58][65][66]

Women with NCCAH usually have normal female genitalia at birth. In later life, the signs and symptoms of the condition may include acne, hirsutism, male-pattern baldness, irregular menstruation, and infertility.[58][65][25]

Fewer studies have been published about males with NCCAH comparing to those about females, because males are generally asymptomatic.[25][58] Males, however, may present with acne[67][68] and early balding.[69][70]

While symptoms are usually diagnosed after puberty, children may present with premature adrenarche.[71]

Research on other conditions

There is ongoing research on how

autosomal dominant posterior polar cataract, suggesting that steroid 21-hydroxylase may be involved in the extra-adrenal biosynthesis of aldosterone and cortisol in the lens of the eye.[72]

History

In the 1950s and 1960s, steroidogenic pathways that included cholesterol conversion to progesterone through a complex pathway involving multiple steps were identified, and, among them, a pathway for cortisol synthesis showing specific enzymatic steps that included hydroxylation reactions at position 21 (21-hydroxylation) mediated by cytochrome P450 enzymes.[73] Cytochrome P450 enzymes were then described, and steroid 21-hydroxylation was associated with cytochrome P450.[74][73]

In the 1980s and 1990s, partial-length bovine Cyp21 cDNA clones were identified as related to human CYP21A2.[75][73] Researchers discovered mutations in the CYP21A2 gene associated with congenital adrenal hyperplasia (CAH).[73]

From the 1990s onward, specific mutations were correlated with different forms/severity levels of CAH. Genotype/phenotype correlations were investigated for improved diagnostic accuracy.[73]

See also

References

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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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