1 Medical Biochemistry Sarah J. Breese McCoy, Ph.D. December 9, 2005.

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1 Medical Biochemistry Sarah J. Breese McCoy, Ph.D. December 9, 2005

2 Biochemistry of Hormones II: Steroid Hormones Overview/Clinical Correlations Chapter 22

3 Overview: Steroid Synthesis u All steroid hormones are made from pregnenolone. u Pregnenolone is made from cholesterol. u Cholesterol is made acetyl CoA (20%) or absorbed ready-made from diet (80%).

4 Overview: Steroid Synthesis

5 Cholesterol (C 27) Pregnenolone (C 21) Progesterone (C 21) Aldosterone (C 21) Cortisol (C 21) Androgens (C 19) Estrogens (C 18)

6 Overview: Steroid Synthesis

7 Clinical Correlate: Congenital Adrenal Hyperplasia u 21B hydroxylase deficiency u Adrenals cannot make enough glucocorticoids or mineralocorticoids. u Female fetuses are virilized. u Salt wasting or hypoglycemia can be fatal w/o treatment.

8 Overview: Steroid Mech. Action, Positive Transcriptional Effect u Enter cell u Bind to receptor; dimerize u Enter nucleus u Attach to DNA in promoter region, upstream of gene to be copied u Stimulate transcription of the gene u Translation of mRNA into protein u Protein (enzyme or receptor) affects cell metabolism

9

10 Clinical Correlate: Vitamin D u Vit D induces the synthesis of Ca- binding protein (calbindin 9K) in enterocytes, which aids in the absorption of Ca from the intestinal lumen.

11 Clinical Correlate: Vitamin D u Vit D deficiency in children leads to rickets, a calcium deficiency marked by malformed, soft bones.

12 Clinical Correlate: Aldosterone u Aldosterone from the adrenal cortex stimulates renal tubule cells to (1) make more Na+ channels, (2) make more Na+/K+ pumps, and (3) make more mitochondrial enzymes for ATP synthesis (to run the Na+/K+ pumps).

13 Clinical Correlate: Aldosterone

14 Clinical Correlate: T3/T4 u In muscle, liver, and kidney, T3 induces the synthesis of Na-K pumps and probably also ATPase, which break down ATP to release energy to run the pumps. u Thus, more ATP/O 2 are consumed and BMR.

15 Clinical Correlate: T3/T4 u In Graves Disease, the thyroid makes too much T3/T4. u Two of the symptoms related to the mechanism on the previous slide are heat intolerance and weight loss without dieting.

16 Overview: Steroid Mech. Action, Negative Transcriptional Effect u Enter cell u Bind to receptor; dimerize u Enter nucleus 1. Attach to DNA, displacing a positive transcription factor, stopping production of some protein, OR 2. Attach directly to positive transcription factor, blocking its binding to DNA

17 Overview: Steroid Mech. Action, Negative Transcriptional Effect

18 Clinical Correlate: Oral Contraception u Review: GnRH (hyp) FSH/LH (pit) ovulation (ovary) u Birth control pills contain steroids that suppress ovulation by preventing the hypothalamus from releasing GnRH. u GnRH production is the result of transcription/translation of the KISS-1 gene in the hyp neuron cell nucleus. u High, sustained levels of estrogens, progestins, or androgens serve as negative transcriptional factors for KISS-1 gene transcription. u Bottom line: No KISS-1 gene transcription no kisspeptin protein production no GnRH release no LH release no ovulation no pregnancy

19 Bottom Line for Medical Biochem u It is easier to diagnose and treat disease if you fully understand the relevant biochemistry. u Learning concepts is more important than memorizing details.