5-alpha reductase is an enzyme that converts testosterone, the male sex hormone, into the more potent dihydrotestosterone: (Kegg Pathway)
the major difference is the Δ4,5 double-bond on the A ring.
There are 3 isoenzymes, steroid 5-alpha reductase 1, 2 and 3 (SRD5A1 , SRD5A2, SRD5A3).
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. Liver, brain, forehead skin and prostate (at a low level).
- Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain. 2001 Fulltext
- Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.
Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. Expressed in high levels in the prostate and many other androgen-sensitive tissues.
Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol. Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation. Acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism. Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT). Overexpressed in hormone-refractory prostate cancers (HRPC). Almost no or little expression in normal adult organs.
The enzyme is produced only in specific tissues of the male human body, namely the skin, seminal vesicles, prostate and epididymis.
Inhibition of 5-alpha reductase results in decreased production of DHT, increased levels of testosterone and possibly increased levels of estradiol. Gynecomastia is a possible side effect of 5-alpha reductase inhibition.
Both isoforms (1 and 2) of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively . Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission .
The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins.
- Cell signaling and Ligand transport
- Structural proteins
SRD5A2 deficiency leads to a form of intersexualism.
SRD5A3 Mutations in this gene are associated with congenital disorder of glycosylation type Iq.
Oxytocin and 5-alpha-reductase
Stimulatory effect of prolactin on luteinizing hormone-induced testicular 5 alpha-reductase activity in hypophysectomized adult rats, 1986
Morphine increases 5alpha-reductase enzyme activity in the central nervous system Rattus norvegicus (finasteride 5mg/kg, chronic finasteride administration effectively blocks the development of tolerance and dependence on morphine)
Finasteride, a 5alpha-reductase inhibitor, potentiates antinociceptive effects of morphine, prevents the development of morphine tolerance and attenuates abstinence behavior in the rat 2007
Inhibition by "Mitotane":
"Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement.
DNA methyltransferase 1 reduces expression of SRD5A2 in the aging adult prostate. 2016
We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression.
The ratio ET/AN in urinary steroids may be taken as an indirect measurement of the enzyme activity. 2012":http://www.ncbi.nlm.nih.gov/pubmed/2316
Less NADPH less DHT?
Risk Factors for Hypogonadism in Male Patients with Type 2 Diabetes. 2016
One clinical study found that patients with type 2 diabetes are prone to hypogonadism.
Diabetic neuropathic pain: a role for testosterone metabolites. 2014
- Diabetic neuropathy is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. In this study, we analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT), and 3α-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of the spinal cord and in the dorsal root ganglia of rats rendered diabetic by streptozotocin injection. Furthermore, the levels of DHT and 3α-diol were analyzed in the spinal cord. Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3α-diol treatments. In addition, 3α-diol treatment resulted in a significant increase in 3α-diol in the spinal cord compared with control values. Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action. Indeed, DHT counteracted the effect of diabetes on the mechanical nociceptive threshold, pre-and post-synaptic components, glutamate release, astrocyte immunoreactivity, and expression of interleukin-1β (IL1β), while 3α-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity, and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, IL1β, and translocator protein. These results indicate that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.
The role of 5alpha-reduction in steroid hormone physiology. 2001":https://www.ncbi.nlm.nih.gov/pubmed/11999320ù
A role for 5alpha-reduction in androgen physiology was first established with the recognition that dihydrotestosterone, the 5alpha-reduced metabolite of testosterone, is formed in many androgen target tissues, binds to the androgen receptor with greater affinity than testosterone, and plays an essential role in virilization of the urogenital sinus and urogenital tubercle during male development. Two 5alpha-reductases perform this reaction, and both isoenzymes utilize NADPH as cofactor and have broad specificity for steroids containing a delta4,3-keto configuration. 5alpha-Reduction, which is essentially irreversible, flattens the steroid molecule because of altered relation of the A and B rings, and stabilizes the hormone-receptor complex. Studies involving in vitro reporter gene assays and intact mice in which both isoenzymes are disrupted, indicate that the fundamental effect of dihydrotestosterone formation is to amplify hormonal signals that can be mediated by testosterone at higher concentrations. 5alpha-Reduction also plays a role in the action of other steroid hormones, including the plant growth hormone, brassinolide, the boar pheromones, androstanol and androstenol, progesterone (in some species), and, possibly, aldosterone and cortisol. The fact that the reaction is important in plants and animals implies a fundamental role in steroid hormone action.