Lipids
• Terpenes: isoprene units, classification, variations • Isopentenyl pyrophosphate biosynthesis from acetate general reactivity • C-C bond formation in terpene biosynthesis carbocation intermediate, extension, synthesis higher terpenes, synthesis cyclic structures • Cholesterol configuration, structure, biosynthesis, intermediate for: vitamin D, bile acids, corticosteroids, sex hormones • Carotenoids Steroids
C D
A B
H
H H HO cholesterol
From diet, but can also synthesize from… acetate!!
Terpenes: The Isoprene Rule
Terpenes and terpenoids are the most important constituents in essential oils
Terpenes are built from C5 isoprene units
CH3 C CH2 = H2C C H Isoprene (2-methyl-1,3-butadiene)
Isoprene units are linked head-to-tail tail
head
Terpenes are repeating isoprene units
Classified according to the number of isoprene units they contain
Class # Isoprene units # C atoms
Monoterpene 2 10 Sesquiterpene 3 15 Diterpene 4 20 Sesterpene 5 25 Triterpene 6 30 Tetraterpene 8 40
Terpenes may be substituted, cyclic, or linked tail-to-tail
Limonene Menthol (from lemon or orange oil) (from peppermint)
OH
Selinene Vitamin A (from celery oil)
tail
tail Squalene (from shark liver oil) Isopentenyl pyrophosphate
Isoprenoid compounds are synthesized from acetate!!
Early steps are analogous to fatty acid biosynthesis except no ACP
O O O + SCoA -O SCoA
Acetyl Malonyl coenzyme A coenzyme A
O O + CO2
SCoA + CoASH
Acetoacetyl coenzyme A O O O + SCoA SCoA Acetoacetyl Acetyl coenzyme A coenzyme A
OH O
SCoA OH + CoASH
O 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
Enzymatic reduction
OH O OH OH HO OH HO O Mevalonic acid Isopentenyl pyrophosphate: The biological isoprene unit
O Enzymatic O phosphorylation O O - - O OPOPOH O OH 2-O PO HO 3 OHOH Mevalonate
3- - PO4 - CO2
CH3 O O H2C CCH2CH2OPOPOH OPP OHOH Isopentenyl pyrophosphate
Enz-H isopentenyl diphosphate isomerase
OPP OPP H H + Enz-H Enz Dimethylallyl Carbocation intermediate pyrophosphate Structurally similar but different chemical reactivity
Isopentenyl Dimethylallyl pyrophosphate pyrophosphate (reactive C=C) (reactive allylic C)
E+ Nu
OPP OPP
good leaving group
C-C in Terpene Biosynthesis
10-C cation is the same whether 1 step or 2 steps
+ OPP OPP
OPP + OPP pyrophosphate ion
- [ OPP] OPP
OPP
OPP 10-C intermediate undergoes typical carbocation reactions
OPP H H
Enz-
OPP Geranyl pyrophosphate (allylic pyrophosphate)
H2O
OH Geraniol (monoterpene in rose oil) OPP Geranyl pyrophosphate
Enz OPP
OPP 15-C carbocation
[deprotonation]
H2O
OH Geranyl Farnesol geraniol
Higher terpenes formed from coupling of terpenes via another mechanism, not successive addition of C5 units
2 OPP Farnesyl pyrophosphate
Triterpene C30 (tail to tail coupling)
Steroids t. n a io c t . a z iz n r E e m o intramolecular is OPP attack OPP
"E" "Z"
- H+
Limonene OH 3o carbocation
H2O
- H+ +
-pinene -pinene bicyclic carbocation
figure 26.6 capture by H2O and rearrangement
Summary
Terpene and steroid biosynthetic paths
Monoterpenes Geranyl pyrophosphate (C10) (C10-pyrophosphate)
3-methyl-3-butenyl pyrophosphate
Sesquiterpenes Farnesyl pyrophosphate Squalene (C15) (C15-pyrophosphate) (C30)
3-methyl-3-butenyl pyrophosphate
Diterpenes C20-Pyrophosphate Lanosterol (C20)
Tetraterpenes Cholesterol (C40) (a steroid) Steroids: Cholesterol
C D
A B
CH3 CH3 R C D AB 5 H H 5 series (trans)
CH3 CH3 R C D B H 5 H A 5 series (cis) • The most abundant steroid in humans • All other steroids arise from cholesterol
H
H H HO Cholesterol
• The average adult has >200g • It is in almost all body tissues • Animals acquire cholesterol from their diet, but can synthesize all they need from acetate Synthesis from acetate
Squalene
O2, NADH monooxygenase
O
epoxide ring opening
carbocation reactions * p. 1133
H
H H HO Cholesterol Cholesterol is a precursor to other lipids
Steroids
Reactions Vitamin D
Cholesterol
Sex hormones Bile acids
Corticosteroids
Vitamin D
From enzymatic oxidation of cholesterol to 7-dehydrocholesterol
Present in skin and converted to vitamin D by sunlight
Important in Ca2+ absorption
sunlight
HH HO 7-Dehydrocholesterol HH HO
Vitamin D3 Bile Acids Bile salts: amide derivatives Bottom face polar; top face non-polar Emulsify fats by forming micelles where fats on inside and bile salts on outside
FAT salts O H O X 2 OH
H
H H HO H OH
X = OH; Cholic Acid X = NHCH2CH2SO3Na; Sodium taurocholate (bile salt)
Micelle fig. from Mol. Cell. Biol.
Corticosteroids
Many physiological effects, ie. maintain electrolyte balance; regulate carb, lipid, protein metabolism; mediate allergic and inflammatory response Cortisol most abundant Cortisone – antiinflammatory drug
OH O
HO OH H OH H H O O O OH Cortisol H
H H O Cortisone
Sex hormones
Regulate biological processes
• Male – androgens (testes) • Female – estrogens (ovaries) • Pregnancy – progestins
O
Cholesterol H
H H O Progesterone
OH OH
H H
H H H H O HO Testosterone Estradiol
Carotenoids Tetraterpenes; conjugated π-system
Color: flowers, fruit, plants, insects, animal
Tail-to-tail linkage between 2-C20 units
100 million tons carotenoids bio- synthesized from acetate per year
Lycopene (tomatoes)
H
H -Carotene (carrots)