5α-Reductase
3-Oxo-5α-steroid 4-dehydrogenase | |||||||||
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KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Chr. 5 p15 | |||||||
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Chr. 2 p23 | |||||||
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5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are
.5α-Reductases catalyze the following generalized chemical reaction:
- a 3-oxo-5α-steroid + acceptor ⇌ a 3-oxo-Δ4-steroid + reduced acceptor
Where a 3-oxo-5α-steroid and acceptor are
- NADP+NADPH+ H+
where dihydrotestosterone is the 3-oxo-5α-steroid, NADP+ is the acceptor and testosterone is the 3-oxo-Δ4-steroid and NADPH the reduced acceptor.
Production and activity
The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries,
5α-Reductases act on 3-oxo (3-keto), Δ4,5 C19/C21 steroids as its substrates; "3-keto" refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ4,5'. The reaction involves a stereospecific and permanent break of the Δ4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.[8]
Distribution with age
5α-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the epithelium and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.[8]
After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin.
5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.[3][8]
In adulthood, 5α-R1-3 [clarification needed] is ubiquitously expressed.
Substrates
Specific substrates include
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[14]
Testosterone
5α-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:
The major difference is the Δ4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.
List of conversions
The following reactions are known to be catalyzed by 5α-reductase:[9]
- Cholestenone → 5α-Cholestanone
- Progesterone → 5α-Dihydroprogesterone
- 3α-Dihydroprogesterone → Allopregnanolone
- 3β-Dihydroprogesterone → Isopregnanolone
- 5α-Dihydrodeoxycorticosterone
- Corticosterone → 5α-Dihydrocorticosterone
- Aldosterone → 5α-Dihydroaldosterone
- 5α-Androstanedione
- 5α-Dihydrotestosterone
- Nandrolone → 5α-Dihydronandrolone
Structure
5α-Reductase is a membrane bound enzyme that catalyzes the
Inhibition
The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate.
Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably,
Additionally, it has been claimed that
Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and
Finasteride
Finasteride inhibits two 5α-reductase isoenzymes (II and III), while dutasteride inhibits all three.[2] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 till an IC50 of 360 nM.[21] Finasteride decreases mean serum level of DHT by 71% after 6 months,[22] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[2]
Dutasteride
Dutasteride inhibits 5α-reductase isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%).[23] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months.[24] A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%.[25] The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro[26] suggest that dutasteride may be a triple 5α reductase inhibitor.[8]
Congenital deficiencies
5α-Reductase 1
5α-Reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle.[29] In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.[6]
5α-Reductase 2
Impaired 5α-reductase 2 activity can result from mutations in the underlying SRD5A2 gene. The condition, known as 5α-reductase 2 deficiency, has a range of presentations as atypical appearances of the external genitalia in males. This is because 5α-reductase 2 catalyzes the transformation of testosterone to the potent androgen dihydrotestosterone, which is required for the proper masculinization of male genitalia.[30]
5α-Reductase 3
When
Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of asparagine residues on nascent protein in the endoplasmic reticulum.[32]
Nervous system
Affective disorders
Isolation rearing has been shown to lower protein expression of 5α-reductase isoenzymes 1 and 2 in
Hypothalamic–pituitary–adrenal axis dysfunction
An alternative mechanism of
Nomenclature
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-oxo-5α-steroid:acceptor Δ4-oxidoreductase. Other names in common use include:
- 5α-Reductase
- 3-Oxosteroid Δ4-dehydrogenase
- 3-Oxo-5α-steroid Δ4-dehydrogenase
- Steroid Δ4-5α-reductase
- Δ4-3-Keto steroid 5α-reductase
- Δ4-3-Oxo steroid reductase
- Δ4-3-Ketosteroid-5α-oxidoreductase
- Δ4-3-Oxosteroid-5α-reductase
- 3-Keto-Δ4-steroid-5α-reductase
- Testosterone 5α-reductase
- 4-Ene-3-ketosteroid-5α-oxidoreductase
- Δ4-5α-Dehydrogenase
- 3-Oxo-5α-steroid:(acceptor) Δ4-oxidoreductase
See also
- Steroidogenic enzyme
- Acne vulgaris
- Cholestenone 5α-reductase
- Hirsutism
- Lower urinary tract symptoms
- Polycystic ovarian syndrome
- List of steroid metabolism modulators
References
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Further reading
- Levy HR, Talalay P (August 1959). "Bacterial oxidation of steroids. II. Studies on the enzymatic mechanism of ring A dehydrogenation". The Journal of Biological Chemistry. 234 (8): 2014–21. PMID 13673006.
External links
- Testosterone+5-alpha-Reductase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)