5α-Reductase

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

Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown. 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself. Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-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. :: ::: {Substrate} + {NADPH} + H+ -> {5\alpha-substrate} + NADP+ 5α-DHP is a major hormone in circulation of normal cycling and pregnant women. Testosterone 5α-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone: This removes the Δ4,5 double-bond on the A (leftmost) ring. List of conversions The following reactions are known to be catalyzed by 5α-reductase: • Cholestenone → 5α-Cholestanone • Progesterone → 5α-Dihydroprogesterone • 3α-Dihydroprogesterone → Allopregnanolone • 3β-Dihydroprogesterone → Isopregnanolone • Deoxycorticosterone → 5α-Dihydrodeoxycorticosterone • Corticosterone → 5α-Dihydrocorticosterone • Aldosterone → 5α-Dihydroaldosterone • Androstenedione → 5α-Androstanedione • Testosterone → 5α-Dihydrotestosterone • Nandrolone → 5α-Dihydronandrolone == Structure ==

5α-Reductase is a membrane bound enzyme that catalyzes the NADPH dependent reduction of double bonds in steroid substrates to increase potency. The crystal structure of a homolog of 5α-reductase isoenzymes 1 and 2 has been found in Proteobacteria (proteobacteria 5α-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. In insect cells monoolein is not found, but is subbed out for other androgens and inhibitors. 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. Sequence conservation across known crystal structures has corroborated high conservation in enzyme structure. In the 5α-reductase from Proteobacteria bacterium, PbSRD5A, NADPH is bound by an extensive hydrogen bonding network, including residues Arg34, which hydrogen bonds to the nicotinamide group, Arg170, which hydrogen bonds to the 2'-phosphate on the ribose group bound to nicotinamide, Asn192 and His230, which hydrogen bond to the nicotinamide nucleotide phosphate group, Tyr32 and Tyr193, which hydrogen bond to the adenine nucleotide phosphate group, and Asn159, Glu196, and Thr219, which hydrogen bond to the adenine group of NADPH. The steroid-binding pocket contains a motif of Gln, Glu, and Tyr residues, which form a triad of hydrogen-bonds, which coordinate the C3 ketone of steroids into close proximity to the nicotinamide of NADPH, which allows a hydride transfer and Δ4 double-bond reduction. These residues are Gln53, Glu54, and Tyr87 in PbSRD5A. ==Inhibition==

The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5α-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-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, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Additionally, it has been claimed that alfatradiol works through this mechanism of activity (5α-reductase), as well as the Ganoderic acids in lingzhi mushroom, and the Saw Palmetto. Inhibition of 5α-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-hydroxysteroid dehydrogenase, oxidative 3α-hydroxysteroid dehydrogenase, and 3β-hydroxysteroid dehydrogenase enzymes. 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-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported. Finasteride Finasteride inhibits two 5α-reductase isoenzymes (II and III), while dutasteride inhibits all three. Finasteride decreases mean serum level of DHT by 71% after 6 months, and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines. It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months. A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%. The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro suggest that dutasteride may be a triple 5α reductase inhibitor. Finasteride works to inhibit 5α-reductase through competitive inhibition 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-reductase's work on testosterone. Finasteride does eventually get released from 5α-reductase enzyme-substrate complex which is why it is not considered a suicide inhibitor as the product eventually formed is dihydrofinasteride. ==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. In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty. 5α-Reductase 3 When small interfering RNA is used to knock down the expression of 5α-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios. It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors. == Nervous system ==

Affective disorders Isolation rearing has been shown to lower protein expression of 5α-reductase isoenzymes 1 and 2 in cortical and subcortical brain regions of rat models. However, the amount of 5α-reduced metabolite remained unaffected. This means isolation rearing likely leads to changes in the expression and activity of 5α-reductase in the brain, leading to dysregulation of dopamine neurotransmission, resulting in early chronic stress Treatment with finasteride, a 5α-reductase inhibitor, has been shown to mimic the effects of SSRI's causing sexual dysfunction. Research has shown that 5α-reductase is the rate-limiting enzyme in neurosteroid synthesis, specifically in the conversion of progesterone to allopregnanolone, low levels of allopregnanolone has been tied to depression, anxiety and schizophrenia. Sleep deprivation can enhance 5α-reductase expression and activity in the prefrontal cortex, leading to mania-related symptoms in rats. These symptoms have been found during active use of inhibitors and in immediate followup. Type 1 and 2 of 5α-reductase are the principal enzymes involved in cortisol clearance through the liver. Excess cortisol has been tied to metabolic dysfunction–associated steatotic liver disease (MASLD), but in-vitro studies have found that an over expression of 5α-reductase type 2 can suppress lipogenesis. The key role of 5α-reductase in cortisol breakdown and fat buildup has elucidated some of the side effects of 5α-reductase inhibitors. In randomized studies on human volunteers it was found that 5α-reductase inhibition through the use of dutasteride and finasteride can lead to hepatic lipid accumulation in men. In critical illness, overstimulation of cortisol as part of a stress response can lead to decreased clearance of cortisol through the liver via 5α-reductase and kidneys via 11β-hydroxysteroid dehydrogenase type 2, longterm elevation of cortisol can lead to Cushing's syndrome. ==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 ==