5-alpha-reductase
Testosterone

Author: Francesca Prieri
Date: 10/04/2009

Description

DEFINITION

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).

DatabaseLink
WikigenesSRD5A1SRD5A2SRD5A3
GeneCards"SRD5A1":"SRD5A2":"SRD5A3":

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage

DatabasepO2Protein Synth.
SRD5A1high O2++
SRD5A2low O2+
SRD5A3low O2++

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis
post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization

SRD5A1

forehead skin

Brain

Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain. Fulltext J Clin Endocrinol Metab. 2001 Mar;86(3):1324-31.
Steckelbroeck S, Watzka M, Reichelt R, Hans VH, Stoffel-Wagner B, Heidrich DD, Schramm J, Bidlingmaier F, Klingmüller D.
**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.
biological function

  • Enzymes

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 .

Isoform 3

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

GENETIC DEFICIENCY

SRD5A2 deficiency leads to a form of intersexualism.

SRD5A3 Mutations in this gene are associated with congenital disorder of glycosylation type Iq.

REGULATION

Morphine increases 5alpha-reductase enzyme activity in the central nervous system Rattus norvegicus (finasteride 5mg/kg, chronic finasteride administration effectively blocks development of tolerance and dependence to 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 Finasteride

Enzyme deficiency can be mimicked by Finasteride

Papers Finasteride brain

Papers Finasteride epileptic

CNS Drug Rev. 2006 Spring;12(1):53-76.
A new look at the 5alpha-reductase inhibitor finasteride.

Finn DA, Beadles-Bohling AS, Beckley EH, Ford MM, Gililland KR, Gorin-Meyer RE, Wiren KM.

Department of Veterans Affairs Medical Research, Portland Alcohol Research Center, 97239, USA. finnd@ohsu.edu

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms 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. Consistent with their ability to enhance the action of GABA at GABA receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors . Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

Inhibition by "Mitotane":

"Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement.

Induction

Oxytocin

DIAGNOSTIC USE

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

Comments
2011-02-21T14:18:41 - Paolo Pescarmona

Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells., 2010

  • Elevated levels of 5α-reduced androgens have been shown to be associated with hyperandrogenism and hyperinsulinemia, the leading causes of ovulatory dysfunction in women. 5α-Dihydrotestosterone reduces ovarian granulosa cell proliferation by inhibiting FSH-mediated mitogenic signaling pathways. The present study examined the effect of insulin on 5α-reductase, the enzyme that catalyses the conversion of androgens to their 5α-derivatives. Granulosa cells isolated from immature rat ovaries were cultured in serum-free, phenol red-free DMEM-F12 media and treated with different doses of insulin (0, 0.1, 1.0, and 10.0 μg/ml) for different time intervals up to 12 h. The expression of 5α-reductase type 1 mRNA, the predominant isoform found in granulosa cells, showed a significant (P<0.05) increase in response to the insulin treatment up to 12 h compared with control. The catalytic activity of 5α-reductase enzyme was also stimulated in a dose-depended manner (P<0.05). Inhibiting the Akt-dependent signaling pathway abolished the insulin-mediated increase in 5α-reductase mRNA expression, whereas inhibition of the ERK-dependent pathway had no effect. The dose-dependent increase in 5α-reductase mRNA expression as well as catalytic activity seen in response to insulin treatment was also demonstrated in the human granulosa cell line (KGN). In addition to increased mRNA expression, a dose-dependent increase in 5α-reductase protein expression in response to insulin was also seen in KGN cells, which corroborated well with that of mRNA expression. These results suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells. The elevated levels of these metabolites, in turn, might adversely affect growth and proliferation of granulosa cells, thereby impairing follicle growth and ovulation.
2010-04-05T08:00:34 - Gianpiero Pescarmona

Metabolism of testosterone to 5-dihydro-testosterone

Metabolism of testosterone to 5-dihydrotestosterone is essential for initiation of the differentiation and development of the urogenital sinus into the prostate. Differentiation of male external genitalia (penis, scrotum and urethra) also strongly depends on the conversion of testosterone to 5-dihydrotestosterone in the urogenital tubercle, labioscrotal swellings and urogenital folds (9).
The irreversible conversion of testosterone to 5-dihydrotestosterone is catalyzed by the microsomal enzyme 5-alpha reductase. It converts testosterone into more potent Dihydrotestosterone (DTH).
There are two isoenzymes, steroid 5-alpha reductase 1 and 2 (SRD5A1 and SRD5A2):

  1. Enzyme 5-reductase type 2 (SRD5A2) is NADPH dependent (10) figure 3.
    • The cDNA of the gene for 5-reductase type 2 codes for a protein of 254 amino acid residues with a predicted molecular mass of 28,398 Dalton (11) .
      The NH2-terminal part of the protein contains a subdomain supposedly involved in testosterone binding, while the COOH-terminal region is involved in NADPH-binding (12) .
    • The gene is located on chromosome 2 at locus 2p23. Elucidation of the organization of the 5-reductase type 2 gene revealed 5 coding exons (11) .
    • The enzyme has a pH optimum at pH 5.5 in broken cell preparations, but may function optimally in the native state in intact cells at neutral pH and has an apparent Km for testosterone of 4-50 nM. The apparent Km for NADPH is 3-10 <61549>M. High expression of 5-reductase type 2 is observed in prostate tissue.
    • Mutations and deletions in the 5-reductase type 2 gene have been found to be the molecular basis for the syndrome of 5-Reductase type 2 deficiency (12) .
  2. The 5-reductase type 1 (SRD5A1) isozyme, also catalyzing the conversion of testosterone to 5-dihydrotestosterone, differs from the type 2 isozyme in its amino acid composition, kinetics, biochemical properties, substrate specificity, tissue distribution and pH optimum (10, 13 ).
    • The type 1 enzyme is not involved in androgen dependent male sexual differentiation.
    • The 5-reductase type 1 cDNA codes for a protein of 259 amino acid residues with a predicted molecular mass of 29,462 Dalton (13) . The gene is located on chromosome 5 at locus 5p15 (10).
    • The apparent Km for testosterone is 1-5 mM and for NADPH 3-10 mM. The expression of 5-reductase type 1 in prostate tissue is relatively low.
    • Male mice with a disruption of the 5-reductase type 1 gene have a normal phenotype and are fertile. However, female mice with a null allele, have a severe parturition defect, suggesting a role of 5-reduced androgens synthesized by the type 1 isozyme normal female physiology (14) .

The difference in pH optima between 5-reductase type 1 and type 2 enzymes can be used diagnostically for the differential assessment of the individual isoenzymes in genital skin fibroblasts of patients with the syndrome of 5-reductase deficiency ( 12 , 10).

Figure 3. Metabolism of Testosterone to 5a-Dihydrotestosterone by the enzyme 5a-Reductase type 2 (SDR5A2).

BJU Int. 2010 Nov;106(10):1444-51. doi: 10.1111/j.1464-410X.2010.09714.x.
5-α-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review. 2010
Wilt TJ, Macdonald R, Hagerty K, Schellhammer P, Tacklind J, Somerfield MR, Kramer BS.

Minneapolis VA Center for Chronic Disease Outcomes Research, Minneapolis, MN 55417, USA. tim.wilt@va.gov
Abstract
OBJECTIVE: • To estimate the benefits and harms of 5-α-reductase inhibitors (5-α-RIs) in preventing prostate cancer.

MATERIALS AND METHODS: • We searched MEDLINE and the Cochrane Collaboration Library through June 2010 to identify randomized trials. • We included articles if they examined 5-α-RI vs control, were ≥ 1 year in duration and provided clinical outcomes. • Our primary outcome was prostate cancer period-prevalence 'for-cause'.

RESULTS: • Eight studies met inclusion criteria but only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events were designed to assess the impact of 5-α-RIs on prostate cancer period-prevalence. The mean age of enrolees was 64 years, 92% were White, and mean PSA level was 3.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected in placebo-controlled studies. • Compared with placebo, 5-α-RI resulted in a 25% relative risk (RR) reduction in prostate cancers detected for-cause [RR 0.75, 95% confidence interval (CI) 0.67-0.83; 1.4% absolute risk reduction (3.5% vs 4.9%)]. One BPH trial reported that the risk of prostate cancers detected for-cause was significantly reduced with dutasteride and combined dutasteride plus tamsulosin compared with tamsulosin monotherapy. • Six trials vs placebo assessed prostate cancers detected overall. There was a 26% RR reduction favouring 5-α-RI [RR 0.74, 95% CI 0.55-1.00; 2.9% absolute risk reduction (6.3% vs 9.2%)]. There were reductions across categories of age, race and family history of prostate cancer. • One placebo-controlled trial of men that investigators considered at greater risk for prostate cancer (based on age, elevated PSA level and having a previous suspicion of prostate cancer leading to a prostate biopsy) reported that dutasteride did not reduce prostate cancers detected for-cause based on needle-biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23%[RR 0.77, 95% CI 0.70-0.85; absolute reduction 16.1% vs 20.8%]. There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. • Incidences of erectile dysfunction, ejaculate volume, decreased libido, and gynaecomastia were greater with 5-α-RI vs placebo.

2010-01-20T12:13:03 - Gianpiero Pescarmona

Finasteride treatment and neuroactive steroid formation. 2009

  • Finasteride is the 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostate hyperplasia and androgenetic alopecia. The 5alpha-reductase is enzyme responsible for the reduction of testosterone to dihydrostestosterone, progesterone to dihydroprogesterone and deoxycorticosterone to dihydrodeoxycorticosterone, steroids modulating the action of gamma-aminobutyric acid on GABA receptors. These neuroactive steroids possess anticonvulsant, antidepressant and anxiolytic effects. The objective of the study was to determine the effect of finasteride therapy on a broad steroid spectrum in men with benign prostate hyperplasia. A group of 20 men with benign prostate hyperplasia was involved in the present study. Finasteride in the daily dose of 5 mg/day was administrated for 4 months. In all individuals, their hormonal profile of steroid hormones was determined before and after 4 months lasting finasteride treatment. Finasteride treatment resulted in a significant decrease all alpha-reduced and increase of most 5beta-reduced metabolites of testosterone and progesterone as well as in an increase of 7alpha-hydoxyderivatives, which are known as neuroactive steroids acting by modulation of GABAA and NMAD receptors in the brain. In the course of finasteride treatment the decrease of the concentration of circulating steroids with known inhibitory activity on GABA-ergic excitation in the brain is very probably an important factors contributing to the development of the symptoms of depression seen in some isolated cases of finasteride administration.
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