1. BIOC 460 DR. TISCHLER LECTURE 35 SYNTHESIS OF CHOLESTEROL & STEROIDS

2. OBJECTIVES 1.Cholesterol : a)physiological functions b)synthesis: i) key intermediates; ii) key coenzyme; iii) rate determining reaction iv) regulation 2.Bile acids: a)physiological functions b) synthesis: i) rate determining reaction; ii) 1 st reaction; iii) regulation

3. OBJECTIVES (cont.) 3.Steroid hormones: a) five general classes b) main human form c) synthesis of cortisol and aldosterone: i) where it occurs; ii) general pathways outline iii) intermediates common to both pathways iv) consequences of defective 21-hydroxylase d) pathway for synthesis of androgens in adrenal cortex and in testes, for estrogen in ovaries and in adipose tissue. 4.Disorders associated with vitamin D deficiency in children and in adults. 5.Disorder associated with estrogen loss in postmenopausal women.

4. CHOLESTEROL AND BILE ACIDS (SALTS) in tissues and plasma lipoproteins as free cholesterol or esterified synthesized from acetyl CoA and eliminated as bile acids precursor of all other steroids in the body product of animal metabolism - in foods of animal origin amphipathic lipid (hydrophobic and hydrophilic portions) essential structural component of membranes transported in the circulation in lipoproteins storage form is cholesterol ester found in most tissues.

5. The physiological roles of cholesterol include: a)an important lipid component of biological membranes, b)precursor of steroid hormones and c)source of bile acids. ROLES OF CHOLESTEROL AND BILE ACIDS (SALTS) Bile acids are polar derivatives of cholesterol and aid in: a)lipid digestion b)lipid absorption c)cholesterol excretion

6. Figure 1. Formation of hydroxymethylglutaryl CoA for the synthesis of cholesterol. CYTOPLASM MITOCHONDRIAL MATRIX Pyruvate Malate ME MDH NADH NAD + CO 2 NADP + Acetoacetyl CoA NADPH Cholesterol thiolase Hydroxymethyl glutaryl CoA HMG-S CoA AcCoA Citrate 2 Acetyl CoA CL ATP, CoA ADP+P i Oxaloacetate Citrate CS Oxaloacetate PC ATP, CO 2 ADP, P i Acetyl CoA Pyruvate

7. KEY CYTOPLASMIC REACTIONS ASSOCIATED WITH CHOLESTEROL SYNTHESIS citrate lyase: citrate + ATP + CoA  oxaloacetate + acetyl CoA + ADP + Pi thiolase: 2 acetyl CoA  acetoacetyl CoA + CoA HMG CoA synthase: acetoacetyl CoA + acetyl CoA  hydroxymethylglutaryl CoA (HMG CoA) + CoA

8. Hydroxymethylglutaryl CoA (HMG-CoA) MEVALONATE HMG CoA Reductase 2 NADPH2 NADP + + CoA Figure 2. The HMG CoA reductase reaction that is the rate-limiting step in cholesterol synthesis Inhibited by cholesterol and also mevalonate Statin drugs – competitive inhibitor of HMG-CoA

9. Mevalonate 3 ATP 3 ADP + P i + CO 2 Isoprenoid unit 2 Farnesyl diphosphate Squalene NADPHNADP + + PP i Squalene synthetase 3 Isoprenoid units several steps Farnesyl diphosphate + O 2 + NADPH Lanosterol CHOLESTEROL several steps + 3 O 2 + 4 NADPH Figure 3. The pathway for the conversion of mevalonate to cholesterol showing the requirement for NADPH.

10. Figure 4. The initial reaction, 7  -hydroxylase, in the conversion of cholesterol to bile acids. Cholesterol + NADPH + O 2 7-hydroxycholesterol + NADP + 7  -hydroxylase Rate-determining step Repressed (decreased synthesis) by bile salts Induced (increased synthesis) by cholesterol

11. Table 1. Functions of Hormones Derived from Cholesterol ProductFunctions Progesteroneprepares uterus lining for implantation of ovum Glucocorticoids (cortisol) (produced in adrenal cortex) (catabolic steroid) promote gluconeogenesis; favor breakdown of fat and protein (fuel mobilization); anti-inflammatory Mineralocorticoids (aldosterone) (produced in adrenal glands) maintains blood volume and blood pressure by increasing sodium reabsorption by kidney

12. Androgens (strongest = testosterone) (produced in testes primarily but weak androgens in adrenal cortex) (anabolic steroid) development of male secondary sex characteristics; prevents bone resorption Estrogen (produced in ovaries primarily but also in adipose cells of males and females) development of female secondary sex characteristics; prevents bone resorption Vitamin D (not a steroid hormone) (produced in the skin in response to UV light and processed to active form in kidney) intestinal calcium absorption; promotes bone formation; prevents phosphate loss by kidneys Table 1. Functions of Hormones Derived from Cholesterol (continued) ProductFunctions

13. Rickets in an adolescent is caused by exclusion from sunlight and dietary vitamin D Vitamin D deficiency in adults is osteomalacia Patient pictures cannot be displayed on the web

14. Osteoporosis post-menopausally in a patient can cause vertebral crush fractures Estrogen loss allows osteoclast (bone destroying) action to overshadow osteoblast (bone-forming) action Patient pictures cannot be displayed on the web

15. activated to turn on pathways Cholesterol Pregnenolone Progesterone 11-Deoxy- cortisone 21-hydroxylase Progesterone Aldosterone Figure 5. General pathways for the synthesis of aldosterone and cortisol in the adrenal cortex 11-Deoxy- cortisol Progesterone Cortisol 21-hydroxylase

16. Figure 6. Pathway for formation of androgens in the adrenal cortex. Beware of the hype about taking DHEA Defect of 21-hydroxylase forces pregnenolone to androgens instead of cortisol PregnenoloneDHEA Androstenedione “Andro”

17. CONGENITAL ADRENAL HYPERPLASIA: 21-OHase defect – most common CAH increased androstenedione; Patient pictures cannot be displayed on the web

18. Cholesterol Pregnenolone Progesterone Androstenedione Testosterone (pathway ends here in testes) Estradiol (pathway continues to here in ovaries) Estrone (produced in both male and female adipose cells) Figure 7. Pathways for the synthesis of testosterone (testes) and the estrogens estradiol (ovaries) and estrone (adipose cells)

19. AND NOW FOR A HUMOROUS INTERLUDE A 70-year old Tennessee man who enjoyed frequent intercourse inexplicably grew breasts reports the book “The Man Who Grew Two Breasts and Other True Tales of Medical Detection. It turns out his menopausal wife used LIBERAL doses of estrogen-laced vaginal cream for lubrication. Apparently he absorbed the powerful female hormone during sex and voila! Patient pictures cannot be displayed on the web