5-alpha reductase

5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer.

5α-reductases catalyze the following chemical reaction:

a 3-oxo-5α-steroid + acceptor $\rightleftharpoons$ a 3-oxo-Delta₄-steroid + reduced acceptor

Thus, the two substrates of these enzymes are an 3-oxo-5α-steroid and acceptor, whereas its two products are 3-oxo-Delta4-steroid and a reduced acceptor.

1 Function
2 Isoenzymes
3 Production and inhibition
4 Pharmacology
5 Nomenclature
6 References
7 Further reading
8 See also
9 External

Function

5α-reductases convert testosterone, the male sex hormone, into the more potent dihydrotestosterone:

Note the major difference — the Δ4,5 double-bond on the A (leftmost) ring. (The other differences between the diagrams are unrelated to chemical structure.)

These enzymes also participate in the creation of such neurosteroids as allopregnanolone and THDOC.

Isoenzymes

There are two isoenzymes, steroid 5α-reductase 1 and 2 (SRD5A1 and SRD5A2).^[1]^[2]

The second isoenzyme is deficient in 5α-reductase deficiency, which leads to a form of intersexualism.

Production and inhibition

The enzyme is produced only in numerous tissues in both males and females especially in tissues of the reproductive tract, testis and ovary,^[3] namely the skin, seminal vesicles, prostate and epididymis.

Inhibition of 5α-reductase results in decreased production of DHT, increased levels of testosterone, and, perhaps, increased levels of estradiol. Gynecomastia is a possible side-effect of 5α-reductase inhibition.

Pharmacology

Main article: 5-alpha-reductase inhibitor

5α-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, male pattern baldness, and hormone replacement therapy (male to female) for transgendered women. Both isoforms are also produced in the brain, where they serve to create the neurosteroid allopregnanolone (5AR type I) and convert T to DHT(5AR type II)(1). Finasteride inhibits the function of only one of the isoenzymes (type 2), whereas dutasteride inhibits both forms. Saw palmetto extract also inhibits both forms.

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 Delta4-oxidoreductase. Other names in common use include steroid

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
5α-reductase
testosterone 5α-reductase
4-ene-3-ketosteroid-5α-oxidoreductase
Δ4-5α-dehydrogenase
3-oxo-5α-steroid:(acceptor) Δ4-oxidoreductase.

References

^ Killian J, Pratis K, Clifton RJ, Stanton PG, Robertson DM, O'Donnell L (May 2003). "5alpha-reductase isoenzymes 1 and 2 in the rat testis during postnatal development". Biol. Reprod. 68 (5): 1711–8. doi:10.1095/biolreprod.102.009142. PMID 12606426. http://www.biolreprod.org/cgi/pmidlookup?view=long&pmid=12606426.
^ Thiele S, Hoppe U, Holterhus PM, Hiort O (June 2005). "Isoenzyme type 1 of 5alpha-reductase is abundantly transcribed in normal human genital skin fibroblasts and may play an important role in masculinization of 5alpha-reductase type 2 deficient males". Eur. J. Endocrinol. 152 (6): 875–80. doi:10.1530/eje.1.01927. PMID 15941927. http://eje-online.org/cgi/pmidlookup?view=long&pmid=15941927.
^ Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E (October 2008). "Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice". Neurochem. Res. 33 (10): 1990–2007. doi:10.1007/s11064-008-9718-5. ISBN 1106400897185. PMID 18473173.

External

MeSH Testosterone+5-alpha-Reductase

Oxidoreductases: CH-CH oxidoreductases (EC 1.3)

1.3.1: NAD/NADP acceptor	Enoyl-acyl carrier protein reductase/Enoyl ACP reductase · 7-Dehydrocholesterol reductase · Biliverdin reductase · 2,4 Dienoyl-CoA reductase

1.3.3: Oxygen acceptor	Dihydroorotate dehydrogenase · Coproporphyrinogen III oxidase · Protoporphyrinogen oxidase

1.3.5: Quinone	Succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD)

1.3.99: Other acceptors	Fumarate reductase · Butyryl CoA dehydrogenase · Acyl CoA dehydrogenase (ACADSB, ACADS) · 5α-reductase (SRD5A1, SRD5A2, SRD5A3) · Glutaryl-CoA dehydrogenase · Isovaleryl coenzyme A dehydrogenase

B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6

Metabolism: lipid metabolism · ketones/cholesterol synthesis enzymes/steroid metabolism

Mevalonate pathway

To HMG-CoA	Acetyl-Coenzyme A acetyltransferase · HMG-CoA synthase (regulated step)

Ketogenesis	HMG-CoA lyase · 3-hydroxybutyrate dehydrogenase · Thiophorase

To Mevalonic acid	HMG-CoA reductase

To DMAPP	Mevalonate kinase · Phosphomevalonate kinase · Pyrophosphomevalonate decarboxylase · Isopentenyl-diphosphate delta isomerase

Geranyl-	Dimethylallyltranstransferase · Geranyl pyrophosphate

To cholesterol

To lanosterol	Farnesyl-diphosphate farnesyltransferase · Squalene monooxygenase · Lanosterol synthase

7-Dehydrocholesterol path	Lanosterol 14α-demethylase · Sterol-C5-desaturase-like · 7-Dehydrocholesterol reductase

Desmosterol path	24-dehydrocholesterol reductase