5 alpha reductase and its role in male pattern

baldnessBy Chris Stewart

The Disease

-“an impairment of health or a condition of abnormal functioning”

What about androgenic alopecia?

Very high prevalence-50% over age 50….

How it happens

http://www.surviving-hairloss.com/DHT.html

How it’s classified

Norwood, O'tar T. (1975) Male Pattern Baldness: classification and Incidence. Southern medical journal, 68(11):1359-1365

Hamilton-Norwood scale

Why is it such a big deal?

• Loss of control• Loss of individuality, ability to express oneself• Sign of weakness• Unattractive

http://www.superstock.com/stock-photos-images/1439R-108011

Historically

• Scalping as a sign of prowess, trophy of war• In the military-removes external signs of

individuality• Neo-Nazis• Monks as a sign of commitment• Express individuality

http://www.dailymail.co.uk/news/article-518499/Buddhist-monk-cut-pieces-run-lawnmower-Milton-Keynes-temple.html

Treatments• All drugs were originally designed for

something else-Minoxidil(Rogaine): Originally for high blood pressure

-Finasteride(Proscar):Specific to SRD5A2-Dutasteride(Avodart):Non-Specific

Camille DeClementi; Keith L. Bailey, Spencer C. Goldstein, and Michael Scott Orser (December 2004). "Suspected

toxicosis after topical administration of minoxidil in 2 cats". Journal of Veterinary Emergency and Critical Care 14 (4): 287–292. doi:10.1111/j.1476-4431.2004.04014.x

TTTCTGCTCTGGGAAGGAAAGACAGGAAAGAGACCAAGGGATGTTAGGGTTCAGAGAAAGACTGTCCAGCCTCAGTAAAGTCTCACAGGGAAAGGGAAGAACGAACACATGTTAAATTGCCTACCATGCCCAATCGTTTAGTATCTATGGTCTCACTTAACTCTGTTGTAACCTTTTGAGAGATATTTATTATGTCCACTTTACAAAGAAACTGAGGCTGAGTAAGGTTATGGGACTGAAAGAAGACAATACAGCTGGTGCCCGCTAAGATGCAAATCTGAGCTTGTGAATCTCTGAGGTTTAAGACCTTTTAGCCGTTTTAAGTAGGCAGATATTCTATGCAAGAAGAGAACAGAGCCCATAAACAGAGAAAAGTTATCAAACGAAATCAAAACCTTGAAGGTTTTGCCTTATTTTGAGTAGAAGATTCCTAGGGTCAAAAGATCAAGGAAGTTTGGATTAGAAATTAGGATAAAGAATGCCTCTGGCATAATCTGTCTCGTAAAGAGAAAGTGATGCCTCATTTCGAGAGAAGAAGGTGTCAGAGACGGATTTCAAACTGTCTTTCTTAATTTCCTCTTATCCTCTGAATCTTCTTTATTGGTCAAGATTTAATATTTATGCAATCTTAACTGAATTCTCACTCTTTTTAAAAGGCAAATGTTGTCAAGTAATAAGAACTAAACTGTATCCTTTCAACAAATATTTACTAAAAGCCTGCTGTGAACAAGATTCTTTATTTTACACAGATTTTATTTTACTCAGATTTAGATGGTTTAATTTGCACAGAAAGAAGGATGTTGGATACAGGAGATAAGAGATTAGTTTTTTATTTCACTGATTTTTGAACAGACATTTGACAGAAATGTGATTTTTGTCAACAATTATTTTTATCTTCAAATTAACTACTGTATGTTGGCAACATAAGCAATATTTTTATGAGGTCATTTCATCTTAATGATTAGTGTTTTGTGACAATCATATTAATGTAATCTTTAGGCTTGTTTTTGAAATCAAAAGGCACTTTGCACAATACATTATGACCGGTGCATTTAAAAAAAAACCCAAAGGAGTAATTATGCATAAAACAAATATCTACATATTGTCCTTCTTCAGAGGAAATTTTAAAATATTAGTAAAGGACTTGGAGATTCATTCTGCCTGAGGGAAAATTGCCCACTGGAAGTACAACTCTTGAGCTACTTGTTCCTGAGGCATCGGGATCTGATGTTTGTCTTTCCTCTTTTTTGAATTCTTTCTTTGAAGCCACTGGAGTGTGTGATCTGTTATTATTTGAGTGCTTACAGGGTGTTACACTCTGTGTGCCAAACACTCTGAGTTAATAATTTACTCATCCTCATACCAACCCATTTAGGTAGGCACGCCCATTTTGCAGGTGGAAAACTGGAGCAAGAAAAGGTTAAATAACTTCCTTGCCCAAGGTCACACAATAACGAGGAATCAGAGTTCAAACCCAGGCAGTAGACTCCAGATCTCAGGCTCTTCAGGTATGATAATAAACTGTTGTATACTTGTTGGATAAATGCGACCTCATTCTTGCTTTTTAAAAACTATATTTATTCTTAAAATTATTATGTAAAAATTTTTTAAATTATAAAAACATTTTTTCCTAATGAAAAATGGAAAAATCCCAAAAGTAGAAAATACTCATAATTACATCTAAGTATATTAAATATTAATGTTTTAGAGAATTTCTATCAAATCTTTTTCCTTAGTAGATTTTCACACATGCTTGTTATGTTGAATATATGGTTTTTTAGTTCTGTTTAATTACCTAACATTTTATAGTATTTTCCAACATTATCACAGATTTCTTAATATCTGCTTATTTCATCTACTGTAAAAATAATAATTTACCTATATATTCATTTATAGTTGGACATTTAATTTGTCTTGGGGTGAGGCTAGGTTCATTGAAGCTGTGATGTACATTTTTTGCATCTAAATTCTTTTCAAAGGTTAGATCTATTTTCTTAGGATTTCCAGAAGTGGTTCAAAGGTTATGAACATTCTTTAGGGTCTTGATATAATCATACATATCTGTTTCGAGGCTTAAGGAGTCATTTGGCTTGATACTGAGGGTGCATTAAGGAACAAGCATCAGGCTGTCTTGGCTTTATCTCGTGCTGTGTGTTGCTAAGACAGAGAATAAGACGGAGAGACAGGGAGAAAGGATGGCTCAGGTTTGGCTCAGACTCTTTTGCAAAATGTCCATTGGGGACTGTTCAAAGCAGCAATATGTCCCATCAAATAGAAGTTAAAACTCATTGTACTTTTCTCAATACAAGGATGGCACACAAGAATGTAGATTCCACAGGGTCAAAGGTTTTTGTCTCACTTTTATGGCTGTATCCCCATTGTATACAAAGAGCTGGTACATAGTTGGTACTCACTAGAATTTGTTGAATGCATGAATGAACTCTACTTACAACAACCGTACAGACAGAATTGTAGGAGAGCTAGCAATTACTTGGGAATCATAATTGCTGAGATTGCATAGTTAGGTCAATTCAGATAACTTTCCTCTCTTCAGAATCTATTGTTGTGGCTGTTTGGATTCTTTAGCCACATGGAAATGACTGCTGCCTAAGCACATTGCCTAATCCCACTGCCAAAGGCATTTGAAGTCAAGAGTTATCTCACCTCTTTTTTTTTTTTTTTTTTTTAATGTTTTTTTTTTTATTATACTCTAAGTTTTAGGGTACATGTGCACATTGTGCAGGTTAGTTACATATGTATACATGTGCCATGCTGGTGCGCTGCACCCACTAACGTGTCATCTAGCATTAGGTATATCTCCCAATGCTATAAGAAAAACCAACACAGAGACCACCACAGTTCCCAGAGTGTGATATTCCCCTTCCTGTGTCCATGTGATCTCATTGTTCAATTCCCACCTATGAGTGAGAATATGCGGTGTTTGGTTTTTTGTTCTTGCGATAGTTTACTGAGAATGATGGTTTCCAATTTCATCCATGTCCCTACAAAGGACATGAACTCATCATTTTTTATGGCTGCATAGTATTCCATGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATTGTTGGACATTTGGGTTGGTTCCAAGTCTTTGCTATTGTGAATAGTGCCACAATAAACATATGTGTGCATGTGTCTTTATAGCAGCATGATTTATAGTCCTTTGGGTATATACCCAGTATTGGGATGGCTGGGTCAAATGGTATTTCTAGTTCTAGATCCCTGAGGAATCGCCACACTGACTTCCAC

The Gene

3-oxo-5 alpha-steroid 4-dehydrogenase 2 or SRD5A2

Type 2 isoform:• 58,587 b.p. on chromosome 2• Accession#:NC_000002.10/GI:89161199• 50% homologous with type 1 isoformhttp://www.genecards.org/cgi-bin/carddisp.pl?gene=SRD5A2&search=SRD5A2

MotifsWKVnRRRnVWK• W=A/T, K=G/T, V=G/A/C, and R is a

purine(A/G)

Highly mutated in prostate cancer

Named “Themis” after the Greek goddess of prophecy.

Markridakis, N.M., Caldas Ferraz, L.F., and Reichardt, J.K. 2009. Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. Hum Mutat. 30(1):39-48

The Protein

• 254 Amino Acids• Accession #: NP_000339.2/GI:39812447• Active at a slightly acidic pH

http://pfam.sanger.ac.uk/clan?id=Steroid_dh

http://www.expasy.ch/cgi-bin/prosite/sequence_logo.cgi?ac=PS50244

http://smart.embl-heidelberg.de/smart/show_motifs.pl

Structure

TMHMM predicted 6 transmembrane helices-

-37%

hydrophobichttp://www.cbs.dtu.dk/services/TMHMM/

GO:0016021=Integral to cell membrane

http://amigo.geneontology.org/cgi-bin/amigo/gp-assoc.cgi?gp=UniProtKB:P31213&session_id=8271amigo1240360044

http://www.treefam.org/cgi-bin/treeview.pl?ac=TF314668&stype=clean&misc=aln&highlight=SRD5A2_HUMAN

SRD5A1

Function

-Conversion of testosterone to dihydrotestosterone(DHT)-Knockout leads to male pseduohermaphroditism

http://www.brenda-enzymes.org/php/result_flat.php4?ecno=1.3.99.5

http://www.genome.jp/dbget-bin/show_pathway?mmu00150+78925

Function in Plants-DET-2 gene homolog in Arabidopsis-Essential in Brassinosteroid synthesis

Li, J., Biswas, M.G., Chao, A., Russell, D.W., and Chory, J. (1997) Conservation of function between mammalian and plant steroid 5 alpha reductases. Proc. Natl. Acad. Sci. 94:3554-3559

InteractionsAro: Aromatase

HSD: hydroxy-steroid dehydrogenase

UGT:UDP- glucuronosyltransferase

http://string.embl.de/newstring_cgi/show_network_section.pl

http://www.endotext.org/Pediatrics/pediatrics7/pediatrics7.html

UDP- glucuronosyltransferase (UGT)

-Addition of glucuronic acid alters solubility

-Assists excretion of toxins, drugs, hormones, etc..

-Did you know?

http://www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/c14.html

Do you think your outlook on life would change if you found out you

were going to be bald in the future?

Genetic Testing-250$ for a cheek swab-Test for Androgen receptor variant

Also available for women-Based on CAG repeat score

http://www.hairdx.com/

Current Pursuits

• Wnt signalling in abrasions– Cells return to embryonic responsive stateIto, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. 2007.

Nature. 447:316-320, doi:10.1038/nature05766

• Hair CloningCooley, J. Follicular cell implantation: an update on “hair follicle cloning” 2004. Facial Plastic Surgery Clinics of North America. 12:2(219-224), doi:10.1016/j.fsc.2004.01.003

Questions?