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Lipids

: units, classification, variations • Isopentenyl from acetate general reactivity • C-C bond formation in biosynthesis carbocation intermediate, extension, synthesis higher terpenes, synthesis cyclic structures • configuration, structure, biosynthesis, intermediate for: vitamin D, bile acids, corticosteroids, sex

C D

A B

H

H H HO cholesterol

From diet, but can also synthesize from… acetate!!

Terpenes: The Isoprene Rule

Terpenes and 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-)

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 3 15 4 20 Sesterpene 5 25 6 30 8 40

Terpenes may be substituted, cyclic, or linked tail-to-tail

OH () OH

Limonene (from or oil) (from )

OH

Selinene (from celery oil)

tail

tail (from ) 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 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 (allylic pyrophosphate)

H2O

OH ( in rose oil) OPP Geranyl pyrophosphate

Enz OPP

OPP 15-C carbocation

[deprotonation]

OPP

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 bicyclic carbocation

figure 26.6 capture by H2O and rearrangement

Summary

Terpene and 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 (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 • 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

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, , protein ; 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 – (testes) • Female – estrogens (ovaries) • Pregnancy – progestins

O

Cholesterol H

H H O

OH OH

H H

H H H H O HO Estradiol

Carotenoids ; conjugated π-system

Color: flowers, fruit, , insects,

Tail-to-tail linkage between 2-C20 units

100 million tons carotenoids bio- synthesized from acetate per year

Lycopene (tomatoes)

H

H - (carrots)