BIOC 460 DR. TISCHLER LECTURE 35

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BIOC 460 DR. TISCHLER LECTURE 35
 SYNTHESIS OF CHOLESTEROL STEROIDS
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OBJECTIVES

• Cholesterol
• physiological functions
• synthesis
• i) key intermediates ii) key coenzyme
• iii) rate determining reaction
• iv) regulation
• Bile acids
• physiological functions
• b) synthesis
• i) rate determining reaction ii) 1st reaction
• iii) regulation

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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.

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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.

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ROLES OF CHOLESTEROL AND BILE ACIDS (SALTS)

• The physiological roles of cholesterol include
• an important lipid component of biological
  membranes,
• precursor of steroid hormones and
• source of bile acids.

• Bile acids are polar derivatives of cholesterol
  and aid in
• lipid digestion
• lipid absorption
• cholesterol excretion

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CYTOPLASM
MITOCHONDRIAL MATRIX
Figure 1. Formation of hydroxymethylglutaryl CoA
for the synthesis of cholesterol.
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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
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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
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3 O2 4 NADPH
Figure 3. The pathway for the conversion of
mevalonate to cholesterol showing the requirement
for NADPH.
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Figure 4. The initial reaction, 7?-hydroxylase,
in the conversion of cholesterol to bile acids.

• Rate-determining step
• Repressed (decreased synthesis) by bile salts
• Induced (increased synthesis) by cholesterol

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Table 1. Functions of Hormones Derived from
Cholesterol
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Table 1. Functions of Hormones Derived from
Cholesterol (continued)
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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
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Osteoporosis post-menopausally in a patient can
cause vertebral crush fractures
Patient pictures cannot be displayed on the web
Estrogen loss allows osteoclast (bone destroying)
action to overshadow osteoblast (bone-forming)
action
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Figure 5. General pathways for the synthesis of
aldosterone and cortisol in the adrenal cortex
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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
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CONGENITAL ADRENAL HYPERPLASIA 21-OHase defect
most common CAH increased androstenedione
Patient pictures cannot be displayed on the web
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Pregnenolone
Progesterone
Cholesterol
Testosterone (pathway ends here in testes)
Progesterone
Androstenedione
Estrone (produced in both male and female adipose
cells)
Estradiol (pathway continues to here in ovaries)
Figure 7. Pathways for the synthesis of
testosterone (testes) and the estrogens estradiol
(ovaries) and estrone (adipose cells)
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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