Cholesterol, Alcohol,

Nucleotides
 1. Cholesterol and Steroid Hormones Ch 15.6

 2. Alcohol- not provided

 3. Nucleotide Ch 17

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 Cholesterol is not used as an energy
source. It was too valuable as a structural
precursor.
 It is synthesised to make:
 Bilesalts
 Steroid hormones (mineralocorticoids,
glucocorticoids, and sex hormones)
 Vitamin D
 Plasma membrane components

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 About 15% cholesterol is provided from
the diet.
 The rest (85%) is made from acetyl CoA in
the liver (and some in the GIT).
 Cholesterol is lost from the body when it is
catabolised and secreted in bile salts,
which are eventually excreted in faeces.

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 Cholesterol is a 27 carbon molecule
 It is synthesised from acetyl CoA (like
ketones) and the first 2 steps are similar to
ketone bodies formation (same enzyme).
 However, ketones are synthesised in the
mitochondria and cholesterol is synthesised in
the cytosol.
 In other words, it is the location of the
substrates that will determine which products
are synthesised.
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In 3 main stages
 Conversion of
1. Acetyl CoA (C2) to mevalonate (C6)
2. Mevalonate to squalene (C30)
3. Squalene to cholesterol (C27)

 This conversion occurs in the cytosol.

 This synthesis requires many different
enzymes and substrates (more than 20 steps
involved).
 It is energy dependent and needs oxygen and
NADPH.
 The 3rd step (squalene to cholesterol) requires
oxygen.
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 The formation of mevalonate is a committed
step (cannot go backwards) and uses the
enzyme:

“3-hydroxy-3–methylglutaryl CoA reductase” a.k.a.

“HMG CoA reductase”
 In ketones, the same enzyme is used to form acetoacetate.

Does this name sound familiar?

Does the word “statins” mean anything to you?

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 The endogenous synthesis of cholesterol
is affected by dietary cholesterol.

Dietary cholesterol suppresses the formation of

mevalonate (via the suppression of HMG
CoA reductase).

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 Cholesterol from diet is transported with TGs
in chylomicrons.
 Cells take up the TGs
 The chylomicron remnant (cholesterol rich) is taken
up by the liver.
 Lipids (TGs) synthesised endogenously (i.e. by
the liver) are carried by VLDLs.
 The TGs are taken up by cells as needed.
 The remnant (IDLs , i.e. cholesterol-rich) are taken
up by the liver.
 The liver converts the remnants (from
chylomicrons or IDLs) to LDLs (the major
carrier for cholesterol) which deliver
cholesterol to tissues.
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 Cells usually prefer obtaining their cholesterol from
the plasma rather than synthesising it themselves.

 To obtain cholesterol from LDLs, cells synthesise LDL

receptors.

 Cells regulate their cholesterol levels by:

 Controlling the HMG CoA reductase enzyme (I.e. the
synthesis of cholesterol)
 Synthesising LDLs receptors as they need them

 HDLs pick up cholesterol released into the plasma

from dying cells and from membranes undergoing
turnover and brings them back to the liver.
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 All have cholesterol as a precursor
 Contain 21 carbons, cf cholesterol (C27)
 Chlolesterol is metabolised to
Pregnenolone using NADPH and oxygen.
 ACTH (adrenocorticotropic hormone from the
anterior pituitary gland stimulates this
synthesis).
 The next step is the synthesis of
progesterone.
 From progesterone, different metabolites
are synthesised according to body needs.
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 STEROID SYNTHESIS

Cholesterol
C27

Pregnenolone
C21

Progestagens
(progesterone) C21

Corticosteroid Corticosteroid 17 alpha-

(corticosterone) C21 (cortisol) C21 Hydroxyprogesterone

Mineralocorticoid Androgens
(aldosterone) C21 (androstenedione) C19

Oestrone Testosterone
C18 C19

Oestradiol
C18

5 alpha
dihydrotestosterone
 STEROID SYNTHESIS

Cholesterol

Progesterone

Mineralocorticoid Corticosteroid Androgens

(aldosterone) C21 (cortisol) C21 C19

Oestrone Testosterone
C18 C19

Oestradiol
C18
 Has cholesterol as a precursor and the
amino acid glycine.
 Fibre binds bile salts; thus it indirectly
promotes the elimination of cholesterol.

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 Also has cholesterol as a precursor.
 7-dehydrocholesterol (pro-vitamin D)
changes into previtamin D with UV
lights and then spontaneously converts
into cholecalciferol.
 Cholecalciferol is activated to calcitriol
(1,25-Dihydroxycholecalciferol) (the
active vitamin D) in the liver and the
kidneys.
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 Alcohol is oxidised by the enzyme alcohol
dehydrogenase to acetaldehyde.
 This reaction requires NAD and the enzyme
requires zinc.
 Acetaldehyde is then oxidised to acetic acid
(acetate) + NAD and finally to acetyl CoA
 Acetyl CoA is used to produce energy or is
converted to lipids.

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 Nucleotides are precursors of DNA and RNA,
but also AMP, ATP, GDP, NAD, FAD, CoA,
etc.
 A nucleotide is a purine or pyrimidine
molecule + a pentose + phosphate.
• Purines:
• Two ring structures (C6 and C5)
• Adenine (A) or Guanine (G).
• Pyrimidines (C6):
• One ring structure
• Cytosine (C), Thymine (T) or Uracil (U)

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 The end product of purine catabolism in man is uric acid.
Other mammals have the enzyme urate oxidase and excrete the
more soluble allantoin as the end product. Man does not have
this enzyme so urate is the end product for us. Uric acid is
formed primarily in the liver and excreted by the kidney into
the urine.

 Gout is a group of pathological conditions associated with

markedly elevated levels of urate in the blood (3-7 mg/dl
normal). Hyperuricemia is not always symptomatic, but, in
certain individuals, something triggers the deposition of
sodium urate crystals in joints and tissues. In addition to the
extreme pain accompanying acute attacks, repeated attacks
lead to destruction of tissues and severe arthritic-like
malformations. The term gout should be restricted to
hyperuricemia with the presence of these tophaceous deposits.
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 Purines and pyrimidines are build from a
combination of amino acids linked together
with the help of folate and CO2.
 The base name changes with structure
 Adenine = Adenosine (e.g. ATP)
 Guanine = Guanosine (e.g. GMP)
 Uracil = Uridine
 Cytosine = Cytidine
 Thymine = Thymidine

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 The pentose which is a
ribonucleotide (ribose 5-
phosphate) is made from
 Glucose-6-phosphate (a metabolite
of glycolysis)
 Or glyceraldehyde 3-phosphate
 Or fructose 6-phosphate
 Plus NADPH, and ATP.

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