© 2002, 2003 by Changwon Kang
Chapter 26: Biosynthesis of Membrane Lipids and Steroids
A. Membrane components, triacylglycerols and steroids
(1) Three major components of membrane: phospholipids, sphingolipids and cholesterol.
(2) Triacylglycerol (TAG) molecules store excess energy for later use.
TAG
(3) Steroid hormones are made from cholesterol.
B. Phosphoglycerides (glycerol-based phospholipids)
(1) Chemically, they are derivatives of glycerol [CH2OH-CHOH-CH2OH].
Biochemically, they are derived from diacylglycerol 3-phosphate (= phosphatidate).
[Activated diacylglyceride + alcohol] or [Diacylglyceride + activated alcohol]
Glycerol 3-phosphate + 2 Acyl CoA
Glycerol phosphate acyltransferase
−O−CO−R (Triacylglycerol, TAG)
−OH (Diacylglycerol, DAG)
−OPO3−CMP
CTP
[Synthesis from CMP-activated diacylglyceride]
[From CDP-activated alcohols in mammals]
[HO-CH2-CH(COO−)-NH3+]
Serine
CDP-serine
ATP + CTP
(CDP-diacylglycerol)
Serine (amino acid)
CMP
Phosphatidyl serine
DAG
[HO-CH2-CH2-NH3+]
CO2
Ethanolamine
CDP-ethanolamine
Phosphatidyl ethanolamine
ATP + CTP
DAG
`
[HO-CH2-CH2-N(CH3)3+]
3 SAM (−CH3)
Choline
CDP-choline
Phosphatidyl choline
ATP + CTP
DAG
(2) Variety of phosphoglycerides
Inositol (sugar)
CMP
Phosphatidyl inositol
2 ATP
Kinases
Phosphatidyl inositol
4,5-bisphosphate (PIP2)
Phospholipase C
(p. 404)
DAG + IP3
(Inositol triphosphate)
• Variation on the fatty chains: saturated and unsaturated.
• Variation on the alcohol-derivative unit
1. an amino acid (eg. serine) 2. a sugar (eg. inositol)
3. ethanolamine 4. choline [N-trimethylethnolamine]
• Variation on the linkage at C-1: acyl and ether linkages.
(3) Glyceryl ether phospholipids contain an ether linkage (instead of acyl linkage) at C-1, and
derived from dihydroxyacetone phosphate (rather than from glycerol 3-phosphate).
1. Platelet-activating factor (PAF) is an ether phospholipid having acetyl group at C-2. This
induces blood platelet
aggregation, smooth muscle
contraction, and immune cell
activation.
2. Plasmalogens are
phospholipids having an α-β
unsaturated ether at C-1. An
example is phosphatidal
choline, an ether analogy of
phosphatidyl choline.
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© 2002, 2003 by Changwon Kang
C. Sphingolipids
(1) Chemically, derivatives of sphingosine [CH2OH-CH(NH3+)-CHOH-CH=CH-(CH2)12-CH3].
Biochemically, they are derived from N-acylsphingosine (= ceramide).
Palmitoyl CoA
+
Serine
NADPH + H+ + FAD
(2) Gangliosides are carbohydrate-rich sphingolipids
that contain acidic sugars, and abundant in the
nervous system. They are synthesized by the ordered,
step-by-step addition of sugar residues to ceramide by
specific glycosyltransferases, and degraded by removing
sugar units in an ordered manner inside lysosomes.
Disorders in degradation result in neurological diseases
(e.g. Tay-Sachs disease is caused by the absence of the
enzyme that degrades ganglioside GM2 into GM3).
Phosphorylcholine group
Variation on sugar unit
1. Glucose (cerebroside)
2. Galactose
3. Oligosaccharides
(gangliosides)
Ganglioside GM1
(GalNAc=N-acetylgalactosamine)
(NAM=N-acetylneuraminate)
D. Cholesterol
(1) Key properties
• It is abundant in eukaryotic membranes and modulates
the fluidity of animal cell membranes. (It is absent from
most prokaryotes.)
• It is the precursor of steroid hormones (5 classes).
(2) Biosynthesis from acetyl CoA in the cytosol.
Cleaved in mitochondria and converted into ketone bodies
Acetyl CoA
HMG CoA (3-hydroxy-3-methylglutaryl CoA)
Acetoacetyl CoA
Reduced in cytosol by HMG CoA reductase into mevalonate
C5
3 ATP
cyclization in liver
Isopentenyl PP
C10
C15
Squalene
Cholesterol
Bile salts
Pi + CO2
C5
Geranyl Farnesyl
C30
3 CH3
C27
[Cholesterol carbon numbering]
• Bile salts are effective detergents having both polar and non-polar groups and solubilize lipids.
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© 2002, 2003 by Changwon Kang
(3) Regulation of the biosynthesis must be tightly controlled.
ο Cholesterol is obtained from diets and synthesized in the liver and the intestine.
ο It is essential in eukaryotic plasma membranes for cell growth and viability, but too much of it
causes diseases and death. Excess cholesterol in blood causes formation of plaques in arteries.
• The HMG CoA reductase is regulated in the liver and the intestine
① Transcription level: the reductase gene has a sterol regulatory element (SRE).
200② Translation level: inhibition by non-sterol metabolites derived from mevalonate.
fold
changes ③ Protein degradation level: the membrane domain of the reductase
senses the level of derivatives of cholesterol and mevalonate.
④ Protein inactivation level: the reductase is switched off
by phosphorylation by an AMP-activated protein kinase.
• The uptake of LDL from plasma is controled in non-hepatic cells. The LDL receptor is under
feedback regulation in transcription level (the receptor gene has a sterol regulatory element).
(4) Cholesterol metabolism
• TAG, cholesterol and other lipids from diet are carried away from the intestine in large
chylomicrons (a VLDL). Chylomicrons are digested in muscles and others for fatty acid fuel
and fat synthesis. Chylomicron remnants are taken up by the liver.
• Excess TAG and cholesterol in the liver are exported into the blood in VLDL.
Remnants are taken up by the liver and excess is converted to LDL.
• LDL (carrying 1,500 molecules of cholesterol) in the blood is taken up in
non-hepatic cells by the LDL receptors on the plasma
membrane
endocytosis
fused with lysosomes
and hydrolyzed into amino acids and cholesterol, which is
used for membrane synthesis or re-esterified for storage.
• When LDL receptor is impaired in FH (familial hypercholesterolemia), blood level of LDL and
cholesterol are increased and deposited in tissues. Atherosclerotic plagues lead to heart attack.
Cure: ① inhibiting intestinal reabsorption of bile salts (positively charged polymers)
② blocking cholesterol synthesis (lovastatin is an inhibitor for the reductase.)
(5) Steroid hormones
Steroids are derived from pregnenolone (C21).
Steroids are hydroxylated at various carbons by
cytochrome P450 monooxygenases using
NADPH and activated oxygen.
① Progestagens (C21): progesterone prepares the lining of uterus
after pregnancy.
② Glucocorticoids (C21) promote gluconeogenesis,
glycogen formation, and degradation of fat and protein,
and inhibit inflammatory response (cortisol). They enable animals to respond to stress.
③ Mineralocorticoids (C21) increase blood pressure (aldosterone).
④ Androgens (C19) develop male secondary sex characteristics (testosterone in testis).
⑤ Estrogens (C18) develop female secondary sex characteristics (estrone in ovary).
• Vitamin D is derived from cholesterol by the ring-splitting activity of light.
• Isopentenyl pyrophosphate (C5) is a precursor of various extended carbon skeletons of
biomolecules, such as terpenes (C10 & C15), vitamin K2 (C30), coenzyme Q10 (C50), phytol side
chain (C20) of chlorophyll, and carotenoids (C40). Its attachment confers hydrophobic character.
Abstracted from Biochemistry (5th Ed) by Berg, Tymoczko & Stryer
Copyright  2002, 2003 by Prof. Changwon Kang at KAIST
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