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Biochemistry I, Barry University March 31, 2005 Steroid Chemistry & Endocrinology Kenneth L. Campbell Professor of B

Biochemistry I, Barry University March 31, 2005 Steroid Chemistry & Endocrinology Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston.

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Biochemistry I, Barry University March 31, 2005 Steroid Chemistry & Endocrinology Kenneth L. Campbell Professor of B

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  1. Biochemistry I, Barry University March 31, 2005 Steroid Chemistry & Endocrinology Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

  2. This presentation is made possible by a grant entitled“Shortcourses in Endocrinology at Minority Undergraduate Institutions”from the National Institute of General Medical Sciences (NIGMS) to The Minority Affairs Committee of the Endocrine Society

  3. Steroid Functions • Glucocorticoids & sex steroids support growth & development, especially in the embryo, gonads, brain, & pubertal animal • Glucocorticoids helps maintain glucose homeostasis & modulate stress responses • Mineralocorticoids help maintain sodium balance & blood pressure • Sex steroids regulate & maintain gametogenesis & reproductive function

  4. Steroid Health Problems • The broad spectrum of physiological functions steroids control  steroid over- or under- production are key features of many health problems: • Delayed or precocious growth or development • Diabetes • Abnormal immune response • High blood pressure or sodium imbalance • Female infertility, endometriosis, cystic ovaries, ovarian failure, hirsutism, early pregnancy loss, menopausal symptoms, osteoporosis, lactational failure • Male infertility, spermatogenic insufficiency, erectile dysfunction, prostatic hyperplasia • Reproductive cancers: breast, ovary, cervix, endometrium; testicular, prostate

  5. Regressing Corpus Luteum trc.ucdavis.edu/mjguinan/apc100/modules/Reproductive/mammal/images/testis10.jpg www.vet.ksu.edu/media/images/therio/ov-structures/02.jpg Preovulatory Follicle anatomy.med.unsw.edu.au/cbl/embryo/Notes/images/week1/ovary/ovary.gif Gonadal Anatomy

  6. http://www.urologyhealth.org/common/images/anatomy_AdrenalGland_coronal.jpghttp://www.urologyhealth.org/common/images/anatomy_AdrenalGland_coronal.jpg Sheep: http://arbl.cvmbs. colostate.edu/hbooks/pathphys/endocrine/adrenal/adrenal1.jpg & adrenal2.jpg Rhesus, Helly's fluid, H&E, 50 x: http:// www.vh.org/adult/provider/anatomy/ MicroscopicAnatomy/Images/Plate292.jpg Rhesus, Zenker's fluid, H&E, 612 x: http:// www.vh.org/adult/provider/anatomy/MicroscopicAnatomy/Images/Plate294.jpg Adrenal Anatomy

  7. LH, FSH, & ACTH Axes

  8. Cholesterol Metabolism: Uptake

  9. Chemistry of Steroid Hormones from University of Missouri - Rolla http://web.umr.edu/~nercal/teaching/chem363/chem363lec11chap26/

  10. Cholesterol Metabolism: De Novo Synthesis http://www.cellml.org/examples/images/metabolic_models/cholesterol_biosynthesis.gif

  11. Steroid Synthesis arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/basics/steroidogenesis.gif

  12. Gonadal Steroid Synthetic Paths Right & Center: Principle Paths in Leydig Cells, & Ovary

  13. Steroid Synthetic Paths: Adrenal Cortex http://www.med.unibs.it/~marchesi/adrenalsteroidsynthesis.jpg

  14. Cellular Locations of Steroid Synthesis

  15. Follicular 2-Cell Pathway

  16. www.antiaging.com/images/ testosterone_decline.gif

  17. Hormone Levels with Age www.dpcweb.com/documents/news&views/spring_02/the_aging_male.html

  18. Most steroids circulate in association with carrier proteins that increase their distribution volume & circulatory half-life. X-ray structure of SHBG with DHT: http://www.mdc-berlin.de/~crystal/ Structures/images/sex.jpg

  19. Steroid Hormone Transport Proteins

  20. But, it is only free steroid that can diffuse into target cells & bind to receptors that is bioactive.

  21. Transcriptional Mechanism of Steroids http://www.aw-bc.com/mathews/ch23/fi23p16.gif

  22. Steroid Receptors Bind HREs as Homo- or Heterodimers http://gibk26.bse.kyutech.ac.jp/jouhou/image/dna-protein/all/small_S1glu.gif

  23. Receptor Binding to HREs Can Bend DNA & Alter Transcription http://gibk26.bse.kyutech.ac.jp/jouhou/image/dna-protein/all/small_S1run.gif

  24. Enterohepatic Circulation involves Phase I & II enzymes in liver that increase hydrophilicity& water solubility.

  25. Direct Links to Other Endocrine Axes Also help control PRL, TSH, & GH

  26. Conclusions: Steroid metabolism is directly tied to many endocrine regulatory systems. While sex steroids are essential in maintaining species by controlling reproduction, they are dispensible.Corticoids are homeostatic, they control growth, development, immune function, carbohydrate metabolism, & ion balance.Endocrinologists will always be interested in steroids.

  27. Acknowledgements Gainj Project The Gainj People Rees Midgley Al Hermalin Lora Myers Jim Wood Pat Johnson Ila Maslar Diana Lai Sam Refetoff Peter Smouse Peter Heywood Michael Alpers Brian Davison Yan Ren Lynne Shinto Diane Drinkwater Darryl Holman Bettina Shell Turkana Project All Turkana Subjects Mike Little Paul Leslie Ben Campbell Dhanesh Dookhran Kathy Whiteman Alexandra Evindar William Lukas Sandra Gray Jeanine Quigley Christine Sekadde -Kigondu Leah Kirumbi Related Studies Kathy O’Connor Coralie Munro Susannah Barsom Ellie Brindle Cheryl Stroud Kai Orton Jodiann Thompson Yefim Proshchitskiy Yelena Filipova Matt Lopresti Oliver Schultheiss Cheryl Frederick Steve Monfort Malcolm Potts David McClelland (dec) Support from: NSF, Umass/Boston, Sandia National Labs, Hybritech, Quidel, Monoclonal Antibodies Inc. (*in the lab at UMB)

  28. Cellular Location: Cholesterol Synthesis Cholesterol de novo synthesis IIsoprenyl formation 2 NADPH 2 NADP HMG-CoAsynthase Thiolase HMG-CoAreductase 3-Hydroxy-3-methylglutaryl-CoA Acetoacetyl-CoA Science Slides: www.VisiScience.com Mevalonate Mevalonatekinase 3, 3-Dimethylalylpyrophosphate Isomerase ATP ADP Mevalonate-5-pyrophosphodecarboxylase Phosphomevalonatekinase ATP ATP ADP 5-Phosphomevalonate ADP 3-Isopentenylpyrophosphate 5-Pyrophosphomevalonate

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