Lipids

• Terpenes: isoprene units, classification,variations

• Isopentenyl

pyrophosphatebiosynthesis from acetategeneral reactivity

• C-C bond formation in terpene

biosynthesiscarbocation intermediate, extension,synthesis higher terpenes, synthesiscyclic structures

• Cholesterolconfiguration, structure, biosynthesis,intermediate for: vitamin D, bile acids,

corticosteroids, sex hormones• Carotenoids

Steroids

A B

C D

HO

H

H

H

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

Isoprene units are linked head-to-tail

tail

head

Isoprene(2-methyl-1,3-butadiene)

H2CC

CH3

CH

CH2 =

Terpenes

are repeating isoprene units

Classified according to the number of isoprene units they contain

Class # Isoprene units # C atoms

Monoterpene Sesquiterpene Diterpene Sesterpene Triterpene Tetraterpene

234568

101520253040

OHFarnesol

(terpenoid)

Terpenes

may be substituted, cyclic, orlinked tail-to-tail

Squalene(from shark liver oil)

tail

tail

Selinene(from celery oil)

Limonene(from lemon or orange oil)

OH

Menthol(from peppermint)

OH

Vitamin A

Isopentenyl pyrophosphate

Isoprenoid compounds are synthesized from acetate!!

Early steps are analogous to fatty acid biosynthesis except no ACP

SCoA

O

Acetyl coenzyme A

+-O

O

SCoA

O

Malonylcoenzyme A

O

SCoA

O

Acetoacetylcoenzyme A

+ CO2

+ CoASH

O

SCoA

O

Acetoacetylcoenzyme A

+SCoA

O

Acetylcoenzyme A

OH

SCoA

O

O

OH

3-Hydroxy-3-methylglutarylcoenzyme A (HMG CoA)

+ CoASH

Enzymaticreduction

OH

OH

O

OH

Mevalonic acid

HO OH

O

HO

Isopentenyl pyrophosphate:The biological isoprene unit

Mevalonate

-O OH

O

HO

Enzymaticphosphorylation

-O OPOPOH

O

2-O3PO

- PO43-

- CO2

OPPCCH2CH2OPOPOHH2C

CH3 O

OH

O

OH

Isopentenyl pyrophosphate

isopentenyl diphosphate isomeraseEnz-H

H HOPP

Enz

Carbocation intermediate

OPP

+ Enz-H

Dimethylallylpyrophosphate

O

OH

O

OH

Structurally similar but different chemical reactivity

OPP OPP

Dimethylallylpyrophosphate

(reactive allylic C)

Isopentenylpyrophosphate(reactive C=C)

Nu

good leaving group

E+

OPPOPP+

OPP + OPPpyrophosphate ion

OPP

- [ OPP]

OPP

OPP

C-C in Terpene Biosynthesis

10-C cation

is the same whether 1 step or 2 steps

10-C intermediate undergoestypical carbocation reactions

OPPH H

Enz-

OPP

Geranyl pyrophosphate(allylic pyrophosphate)

H2O

OHGeraniol

(monoterpene in rose oil)

OPP

Geranyl pyrophosphate

OPPEnz

OPP

15-C carbocation

[deprotonation]

OPPFarnesyl pyrophosphate

H2O

OHFarnesol

Geranylgeraniol

Higher terpenes

formed from couplingof terpenes

via another mechanism, not successive addition of C5

units

OPPFarnesyl pyrophosphate

2

Triterpene C30

(tail to tail coupling)

Steroids

OPP

"E" "Z"

OPP

Enz. c

at.

isom

eriz

atio

n

3o carbocation

- H+

H2O

LimoneneOH

bicyclic carbocation

- H+

-pinene -pinene

+

intramolecularattack

figure 26.6capture by H2O and

rearrangement

Summary

Terpene

and steroid biosynthetic paths

Geranyl pyrophosphate(C10-pyrophosphate)

Farnesyl pyrophosphate(C15-pyrophosphate)

C20-Pyrophosphate

Tetraterpenes(C40)

3-methyl-3-butenylpyrophosphate

3-methyl-3-butenylpyrophosphate

Squalene(C30)

Lanosterol

Cholesterol(a steroid)

Monoterpenes(C10)

Sesquiterpenes(C15)

Diterpenes(C20)

Steroids: Cholesterol

A B

C D

CH3

CH3

HH

R

A BC D

5 series (trans)

5

CH3

CH3

H

R

BC D

5H

5 series (cis)

A

HO

H

H

H

Cholesterol

• The most abundant steroid in humans• All other steroids arise from cholesterol

• The average adult has >200g • It is in almost all body tissues• Animals acquire cholesterol from their

diet, but can synthesize all they needfrom acetate

Synthesis from acetate

Squalene

O2, NADHmonooxygenase

O

epoxide ring opening

carbocation reactions* p. 1133

HO

H

H

H

Cholesterol

Cholesterol

Steroids

Bile acids

Vitamin D

Sex hormones

Corticosteroids

Reactions

Cholesterol is a precursor to other lipids

Vitamin D

From enzymatic oxidation of cholesterol to 7-dehydrocholesterol

Present in skin and converted to vitamin D by sunlight

Important in Ca2+

absorption

HO

H H

7-Dehydrocholesterol

HO

H H

sunlight

Vitamin D3

Bile Acids

Bile salts: amide derivativesBottom face polar; top face non-polarEmulsify fats by forming micelles where

fats on inside and bile salts on outside

FAT

salts

H2 O

Micelle fig. from Mol. Cell. Biol.

O

H

H

H

X = OH; Cholic AcidX = NHCH2CH2SO3Na; Sodium taurocholate (bile salt)

HOH OH

OHX

Corticosteroids

Many physiological effects, ie. maintainelectrolyte balance; regulate carb, lipid,protein metabolism; mediate allergic and inflammatory response

Cortisol

most abundantCortisone –

antiinflammatory

drug

H

H

H

Cortisol

O

O

HO OH

OH

H

H

H

Cortisone

O

O

OH

OH

O

Sex hormones

Regulate biological processes

•

Male –

androgens

(testes)•

Female –

estrogens

(ovaries) •

Pregnancy –

progestins

OH

H

H

H

Testosterone

O

OH

H

H

H

Estradiol

HO

H

H

H

ProgesteroneO

O

Cholesterol

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)