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5 alpha reductase and its role in male pattern baldness

5 alpha reductase and its role in male pattern baldness. By 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.

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5 alpha reductase and its role in male pattern baldness

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  1. 5 alpha reductaseand its role in male pattern baldness By Chris Stewart

  2. The Disease -“an impairment of health or a condition of abnormal functioning” What about androgenic alopecia? Very high prevalence -50% over age 50….

  3. How it happens http://www.surviving-hairloss.com/DHT.html

  4. How it’s classified Hamilton-Norwood scale Norwood, O'tar T. (1975) Male Pattern Baldness: classification and Incidence. Southern medical journal, 68(11):1359-1365

  5. 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

  6. 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

  7. 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 Care14 (4): 287–292. doi:10.1111/j.1476-4431.2004.04014.x

  8. The Gene TTTCTGCTCTGGGAAGGAAAGACAGGAAAGAGACCAAGGGATGTTAGGGTTCAGAGAAAGACTGTCCAGCCTCAGTAAAGTCTCACAGGGAAAGGGAAGAACGAACACATGTTAAATTGCCTACCATGCCCAATCGTTTAGTATCTATGGTCTCACTTAACTCTGTTGTAACCTTTTGAGAGATATTTATTATGTCCACTTTACAAAGAAACTGAGGCTGAGTAAGGTTATGGGACTGAAAGAAGACAATACAGCTGGTGCCCGCTAAGATGCAAATCTGAGCTTGTGAATCTCTGAGGTTTAAGACCTTTTAGCCGTTTTAAGTAGGCAGATATTCTATGCAAGAAGAGAACAGAGCCCATAAACAGAGAAAAGTTATCAAACGAAATCAAAACCTTGAAGGTTTTGCCTTATTTTGAGTAGAAGATTCCTAGGGTCAAAAGATCAAGGAAGTTTGGATTAGAAATTAGGATAAAGAATGCCTCTGGCATAATCTGTCTCGTAAAGAGAAAGTGATGCCTCATTTCGAGAGAAGAAGGTGTCAGAGACGGATTTCAAACTGTCTTTCTTAATTTCCTCTTATCCTCTGAATCTTCTTTATTGGTCAAGATTTAATATTTATGCAATCTTAACTGAATTCTCACTCTTTTTAAAAGGCAAATGTTGTCAAGTAATAAGAACTAAACTGTATCCTTTCAACAAATATTTACTAAAAGCCTGCTGTGAACAAGATTCTTTATTTTACACAGATTTTATTTTACTCAGATTTAGATGGTTTAATTTGCACAGAAAGAAGGATGTTGGATACAGGAGATAAGAGATTAGTTTTTTATTTCACTGATTTTTGAACAGACATTTGACAGAAATGTGATTTTTGTCAACAATTATTTTTATCTTCAAATTAACTACTGTATGTTGGCAACATAAGCAATATTTTTATGAGGTCATTTCATCTTAATGATTAGTGTTTTGTGACAATCATATTAATGTAATCTTTAGGCTTGTTTTTGAAATCAAAAGGCACTTTGCACAATACATTATGACCGGTGCATTTAAAAAAAAACCCAAAGGAGTAATTATGCATAAAACAAATATCTACATATTGTCCTTCTTCAGAGGAAATTTTAAAATATTAGTAAAGGACTTGGAGATTCATTCTGCCTGAGGGAAAATTGCCCACTGGAAGTACAACTCTTGAGCTACTTGTTCCTGAGGCATCGGGATCTGATGTTTGTCTTTCCTCTTTTTTGAATTCTTTCTTTGAAGCCACTGGAGTGTGTGATCTGTTATTATTTGAGTGCTTACAGGGTGTTACACTCTGTGTGCCAAACACTCTGAGTTAATAATTTACTCATCCTCATACCAACCCATTTAGGTAGGCACGCCCATTTTGCAGGTGGAAAACTGGAGCAAGAAAAGGTTAAATAACTTCCTTGCCCAAGGTCACACAATAACGAGGAATCAGAGTTCAAACCCAGGCAGTAGACTCCAGATCTCAGGCTCTTCAGGTATGATAATAAACTGTTGTATACTTGTTGGATAAATGCGACCTCATTCTTGCTTTTTAAAAACTATATTTATTCTTAAAATTATTATGTAAAAATTTTTTAAATTATAAAAACATTTTTTCCTAATGAAAAATGGAAAAATCCCAAAAGTAGAAAATACTCATAATTACATCTAAGTATATTAAATATTAATGTTTTAGAGAATTTCTATCAAATCTTTTTCCTTAGTAGATTTTCACACATGCTTGTTATGTTGAATATATGGTTTTTTAGTTCTGTTTAATTACCTAACATTTTATAGTATTTTCCAACATTATCACAGATTTCTTAATATCTGCTTATTTCATCTACTGTAAAAATAATAATTTACCTATATATTCATTTATAGTTGGACATTTAATTTGTCTTGGGGTGAGGCTAGGTTCATTGAAGCTGTGATGTACATTTTTTGCATCTAAATTCTTTTCAAAGGTTAGATCTATTTTCTTAGGATTTCCAGAAGTGGTTCAAAGGTTATGAACATTCTTTAGGGTCTTGATATAATCATACATATCTGTTTCGAGGCTTAAGGAGTCATTTGGCTTGATACTGAGGGTGCATTAAGGAACAAGCATCAGGCTGTCTTGGCTTTATCTCGTGCTGTGTGTTGCTAAGACAGAGAATAAGACGGAGAGACAGGGAGAAAGGATGGCTCAGGTTTGGCTCAGACTCTTTTGCAAAATGTCCATTGGGGACTGTTCAAAGCAGCAATATGTCCCATCAAATAGAAGTTAAAACTCATTGTACTTTTCTCAATACAAGGATGGCACACAAGAATGTAGATTCCACAGGGTCAAAGGTTTTTGTCTCACTTTTATGGCTGTATCCCCATTGTATACAAAGAGCTGGTACATAGTTGGTACTCACTAGAATTTGTTGAATGCATGAATGAACTCTACTTACAACAACCGTACAGACAGAATTGTAGGAGAGCTAGCAATTACTTGGGAATCATAATTGCTGAGATTGCATAGTTAGGTCAATTCAGATAACTTTCCTCTCTTCAGAATCTATTGTTGTGGCTGTTTGGATTCTTTAGCCACATGGAAATGACTGCTGCCTAAGCACATTGCCTAATCCCACTGCCAAAGGCATTTGAAGTCAAGAGTTATCTCACCTCTTTTTTTTTTTTTTTTTTTTAATGTTTTTTTTTTTATTATACTCTAAGTTTTAGGGTACATGTGCACATTGTGCAGGTTAGTTACATATGTATACATGTGCCATGCTGGTGCGCTGCACCCACTAACGTGTCATCTAGCATTAGGTATATCTCCCAATGCTATAAGAAAAACCAACACAGAGACCACCACAGTTCCCAGAGTGTGATATTCCCCTTCCTGTGTCCATGTGATCTCATTGTTCAATTCCCACCTATGAGTGAGAATATGCGGTGTTTGGTTTTTTGTTCTTGCGATAGTTTACTGAGAATGATGGTTTCCAATTTCATCCATGTCCCTACAAAGGACATGAACTCATCATTTTTTATGGCTGCATAGTATTCCATGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATTGTTGGACATTTGGGTTGGTTCCAAGTCTTTGCTATTGTGAATAGTGCCACAATAAACATATGTGTGCATGTGTCTTTATAGCAGCATGATTTATAGTCCTTTGGGTATATACCCAGTATTGGGATGGCTGGGTCAAATGGTATTTCTAGTTCTAGATCCCTGAGGAATCGCCACACTGACTTCCAC 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 isoform • http://www.genecards.org/cgi-bin/carddisp.pl?gene=SRD5A2&search=SRD5A2

  9. Motifs WKVnRRRnVWK • 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

  10. 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

  11. Structure TMHMM predicted 6 transmembrane helices - -37% hydrophobic http://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

  12. SRD5A1 http://www.treefam.org/cgi-bin/treeview.pl?ac=TF314668&stype=clean&misc=aln&highlight=SRD5A2_HUMAN

  13. 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

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

  15. 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

  16. Interactions Aro: Aromatase HSD: hydroxy-steroid dehydrogenase UGT:UDP- glucuronosyltransferase http://string.embl.de/newstring_cgi/show_network_section.pl

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

  18. 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

  19. Do you think your outlook on life would change if you found out you were going to be bald in the future?

  20. 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/

  21. Current Pursuits • Wntsignalling in abrasions • Cells return to embryonic responsive state Ito, 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 Cloning Cooley, 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

  22. Questions?

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