5αあるふぁ-Reductase

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3-Oxo-5αあるふぁ-steroid 4-dehydrogenase
Bacterial SDR5A in complex with NADPH and monoolein PDB: 7C83​
Identifiers
EC no.1.3.1.22
CAS no.9036-43-5
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IntEnzIntEnz view
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MetaCycmetabolic pathway
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PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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NCBIproteins
Steroid-5αあるふぁ-reductase 1
Identifiers
SymbolSRD5A1
NCBI gene6715
HGNC11284
OMIM184753
RefSeqNM_001047
UniProtP18405
Other data
EC number1.3.1.22
LocusChr. 5 p15
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Steroid-5αあるふぁ-reductase 2
Human SRD5A2 in complex with NADPH and Finasteride PDB: 7BW1​
Identifiers
SymbolSRD5A2
NCBI gene6716
HGNC11285
OMIM607306
RefSeqNM_000348
UniProtP31213
Other data
EC number1.3.1.22
LocusChr. 2 p23
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StructuresSwiss-model
DomainsInterPro
Steroidogenesis, showing both actions of 5αあるふぁ-reductase at bottom center.

5αあるふぁ-Reductases, also known as 3-oxo-5αあるふぁ-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of 5αあるふぁ-reductase encoded by the genes SRD5A1, SRD5A2, and SRD5A3.

5αあるふぁ-Reductases catalyze the following generalized chemical reaction:

a 3-oxo-5αあるふぁ-steroid + acceptor ⇌ a 3-oxo-Δでるた4-steroid + reduced acceptor

Where a 3-oxo-5αあるふぁ-steroid and acceptor are substrates, and a corresponding 3-oxo-Δでるた4-steroid and the reduced acceptor are products. An instance of this generalized reaction that 5αあるふぁ-reductase type 2 catalyzes is:

dihydrotestosterone + NADP+ testosterone + NADPH + H+

where dihydrotestosterone is the 3-oxo-5αあるふぁ-steroid, NADP+ is the acceptor and testosterone is the 3-oxo-Δでるた4-steroid and NADPH the reduced acceptor.

Production and activity[edit]

The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries,[1] skin, seminal vesicles, prostate, epididymis and many organs,[2] including the nervous system.[3][4] There are three isoenzymes of 5αあるふぁ-reductase: steroid 5αあるふぁ-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3).[2][5][6][7]

5αあるふぁ-Reductases act on 3-oxo (3-keto), Δでるた4,5 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 'Δでるた4,5'. The reaction involves a stereospecific and permanent break of the Δでるた4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the αあるふぁ face at the fifth carbon, and a proton on the βべーた face at carbon 4.[8]

Distribution with age[edit]

5αあるふぁ-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5αあるふぁ-R2 is expressed in fetal prostates similar to adults. 5αあるふぁ-R1 is expressed mainly in the epithelium and 5αあるふぁ-R2 the stroma of the fetal prostate. Scientists looked for 5αあるふぁ-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あるふぁ-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5αあるふぁ-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5αあるふぁ-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5αあるふぁ-R2 is reexpressed in the skin and scalp.

5αあるふぁ-R1 and 5αあるふぁ-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. 5αあるふぁ-R1 and 5αあるふぁ-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あるふぁ-R1-3 [clarification needed] is ubiquitously expressed.

Substrates[edit]

Specific substrates include testosterone, progesterone, androstenedione,[9] epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5αあるふぁ-reduced steroids is unknown.[8] Beyond reducing testosterone to dihydrotestosterone, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effects on cerebral function achieved by enhancing GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.[10] 5αあるふぁ-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[11] Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5αあるふぁ-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.[3][4] 5αあるふぁ-dihydroaldosterone is a potent antinatriuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[12]

This is the mechanism of 5αあるふぁ-reductase on testosterone to convert it into DHT (dihydrotestosterone). 5αあるふぁ-Reductase works by using the reducing power of NADPH to perform a hydride shift on the double carbon bond in the ring causing enolate formation and subsequent tautamerization to form DHT.[13]

5αあるふぁ-DHP is a major hormone in circulation of normal cycling and pregnant women.[14]

Testosterone[edit]

5αあるふぁ-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:

The major difference is the Δでるた4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.

List of conversions[edit]

The following reactions are known to be catalyzed by 5αあるふぁ-reductase:[9]

Structure[edit]

A side view of 5AR with monoolein and NADPH in the hydrophobic pocket; a view of the 7 transmembrane domains from the top

5αあるふぁ-Reductase is a membrane bound enzyme that catalyzes the NADPH dependent reduction of double bonds in steroid substrates to increase potency.[15] The crystal structure of a homolog of 5αあるふぁ-reductase isoenzymes 1 and 2 has been found in Proteobacteria (proteobacteria 5αあるふぁ-reductase). This exists as a monomer with a seven alpha-helix transmembrane structure housing a hydrophobic pocket that holds cofactor NADPH and monoolein which occupies the steroid substrate binding pocket.[16] In insect cells monoolein is not found, but is subbed out for other androgens and inhibitors.[17] The integral seven transmembrane topology is likely conserved across species, with the N terminus in the endoplasmic reticulum lumen and the C terminus facing the cytosol. High conformational dynamics of the cytosolic region likely regulate NADPH/NADP+ exchange.[17] Sequence conservation across known crystal structures has corroborated high conservation in enzyme structure.[16]

Inhibition[edit]

Main article: 5αあるふぁ-Reductase inhibitor

The mechanism of 5αあるふぁ reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5αあるふぁ-Reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, pattern hair loss (androgenetic alopecia), and hormone replacement therapy for transgender women.

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あるふぁ-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5αあるふぁ-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea.[8] Riboflavin was also identified as a 5αあるふぁ-reductase inhibitor .[18]

Additionally, it has been claimed that alfatradiol works through this mechanism of activity (5αあるふぁ-reductase), as well as the Ganoderic acids in lingzhi mushroom, and the Saw Palmetto.

Inhibition of 5αあるふぁ-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and estradiol. Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive 17βべーた-hydroxysteroid dehydrogenase, oxidative 3αあるふぁ-hydroxysteroid dehydrogenase, and 3βべーた-hydroxysteroid dehydrogenase enzymes.[19]

Gynecomastia, erectile dysfunction, impaired cognitive function, fatigue, hypoglycemia, impaired liver function, constipation, and depression, are only a few of the possible side-effects of 5αあるふぁ-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.[20]

Finasteride[edit]

Finasteride inhibits two 5αあるふぁ-reductase isoenzymes (II and III), while dutasteride inhibits all three.[2] Finasteride potently inhibits 5αあるふぁ-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5αあるふぁ-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あるふぁ-R3 at a similar potency to 5αあるふぁ-R2 in transfected cell lines.[2]

Dutasteride[edit]

Dutasteride inhibits 5αあるふぁ-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あるふぁ-R3 in vitro[26] suggest that dutasteride may be a triple 5αあるふぁ reductase inhibitor.[8]

This is the mechanism of inhibition for Finasteride on 5αあるふぁ-reductase,[27] Finasteride works to inhibit 5αあるふぁ-reductase through competitive inhibition[28] which is why the mechanism shows the NADP+ getting attacked by the enolate formed rather than instant tautamerization occurring like in the case of 5αあるふぁ-reductase's work on testosterone. Finasteride does eventually get released from 5αあるふぁ-reductase enzyme-substrate complex which is why it is not considered a suicide inhibitor as the product eventually formed is dihydrofinasteride.

Congenital deficiencies[edit]

Main article: 5αあるふぁ-Reductase deficiency

5αあるふぁ-Reductase 1[edit]

5αあるふぁ-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あるふぁ-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あるふぁ-Reductase 2[edit]

Impaired 5αあるふぁ-reductase 2 activity can result from mutations in the underlying SRD5A2 gene. The condition, known as 5αあるふぁ-reductase 2 deficiency, has a range of presentations as atypical appearances of the external genitalia in males. This is because 5αあるふぁ-reductase 2 catalyzes the transformation of testosterone to the potent androgen dihydrotestosterone, which is required for the proper masculinization of male genitalia.[30]

5αあるふぁ-Reductase 3[edit]

When small interfering RNA is used to knock down the expression of 5αあるふぁ-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios.[31] It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.[8]

Congenital deficiency of 5αあるふぁ-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[edit]

Affective disorders[edit]

Isolation rearing has been shown to lower protein expression of 5αあるふぁ-reductase isoenzymes 1 and 2 in cortical and subcortical brain regions of rat models. However, the amount of 5αあるふぁ-reduced metabolite remained unaffected. This means isolation rearing likely leads to changes in the expression and activity of 5αあるふぁ-reductase in the brain, leading to dysregulation of dopamine neurotransmission, resulting in early chronic stress[33] Treatment with finasteride, a 5αあるふぁ-reductase inhibitor, has been shown to mimic the effects of SSRI's causing sexual dysfunction.[34] Research has shown that 5αあるふぁ-reductase is the rate-limiting enzyme in neurosteroid synthesis, specifically in the conversion of progesterone to allopregnanolone,[35] low levels of allopregnanolone has been tied to depression, anxiety and schizophrenia. Sleep deprivation can enhance 5αあるふぁ-reductase expression and activity in the prefrontal cortex, leading to mania-related symptoms in rats.[35] It is also contested whether the use of 5αあるふぁ-reductase inhibitors is associated with suicidal ideation and depression in patient populations who use them for benign prostatic hyperplasia.[36][37] These symptoms have been found during active use of inhibitors and in immediate followup.[36] However, it is unknown if these symptoms arise naturally from benign prostatic hyperplasia.[37]

Hypothalamic–pituitary–adrenal axis dysfunction[edit]

An alternative mechanism of cortisol regulation is regulated via 5αあるふぁ-reductase which catalyzes an A-ring reduction of cortisol, metabolizing the compound.[38] Type 1 and 2 of 5αあるふぁ-reductase are the principal enzymes involved in cortisol clearance through the liver.[39] Excess cortisol has been tied to non-alcoholic fatty liver disease (NAFLD),  but in-vitro studies have found that an over expression of 5αあるふぁ-reductase type 2 can suppress lipogenesis.[40] The key role of 5αあるふぁ-reductase in cortisol breakdown and fat buildup has elucidated some of the side effects of 5αあるふぁ-reductase inhibitors. In randomized studies on human volunteers it was found that 5αあるふぁ-reductase inhibition through the use of dutasteride and finasteride can lead to hepatic lipid accumulation in men.[41] In critical illness, overstimulation of cortisol as part of a stress response can lead to decreased clearance of cortisol through the liver via 5αあるふぁ-reductase and kidneys via 11βべーた-hydroxysteroid dehydrogenase type 2,[39] longterm elevation of cortisol can lead to Cushing's syndrome.

Nomenclature[edit]

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あるふぁ-steroid:acceptor Δでるた4-oxidoreductase. Other names in common use include:

  • 5αあるふぁ-Reductase
  • 3-Oxosteroid Δでるた4-dehydrogenase
  • 3-Oxo-5αあるふぁ-steroid Δでるた4-dehydrogenase
  • Steroid Δでるた4-5αあるふぁ-reductase
  • Δでるた4-3-Keto steroid 5αあるふぁ-reductase
  • Δでるた4-3-Oxo steroid reductase
  • Δでるた4-3-Ketosteroid-5αあるふぁ-oxidoreductase
  • Δでるた4-3-Oxosteroid-5αあるふぁ-reductase
  • 3-Keto-Δでるた4-steroid-5αあるふぁ-reductase
  • Testosterone 5αあるふぁ-reductase
  • 4-Ene-3-ketosteroid-5αあるふぁ-oxidoreductase
  • Δでるた4-5αあるふぁ-Dehydrogenase
  • 3-Oxo-5αあるふぁ-steroid:(acceptor) Δでるた4-oxidoreductase

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]

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