199

392

Chapter 27. Biomolecules: Lipids

Naturally occurring compounds that are typically of low molecular weight and are hydrophobic (soluble in organic solvent).

• fatty acids and waxes• essential oils• many vitamins• hormones (non-peptide)• components of cell membranes (non-peptide)

393

27.1: Waxes, fats and oilsFatty acids: refers to long, straight-chain saturated and

unsaturated acids, typically from C12 - C20. saturated fatty acids:

CH3(CH2)nCO2H n=10, lauric acidn=12, myristic acidn=14, palmitic acidn=16, steric acid

unsaturated fatty acidC18, oleic acid

polyunsaturated fatty acids (PUFA)

C18, linolenic acid (18:3)C18, linoleic acid (18:4)C20, arachidonic acid (20:4)

CO2H

CO2H

CO2H

CO2H3

6

6

200

394

Fatty acid amides (FAA):

Waxes: esters of long chain fatty acids (C16 - C36) with long chain alcohols (C24 - C36)

CH3(CH2)nCO2–(CH2)nCH3

Fats and Oils: Triacylglcerols (triglycerides), fatty acid (C12 - C20) esters of glycerol, HOH2C-CH(OH)-CH2OH.

HO OH

OH

glycerol

fatty acids

H2C

HC

O

O

H2C O

C

C

C R1

O

R2

O

R3

O

O

H

HOH

tetrahydrocannabinolArachidonic Acid (C20)

O

NH

OH

395

27.2 Soapsodium & potassium salts of fatty acid produced from thesaponification (base hydrolysis) of animal fats (glycerides)

H2C

HC

O

O

H2C O

C

C

C Rn

O

Rn

O

Rn

O

NaOH

H2C

HC

OH

OH

H2C OH

Rn C O

O

Na+3

Soaps have a hydrophilic, polar “head group” (carboxylate salt)and a hydrophobic, non-polar “tail.”

In aqueous solution they form a micelle structure in which the soap molecules orient so that the the hydrophobic tail cluster in the middle of the micelle where their interaction with water is minimized; the polar carboxylate groups are on the solvent exposed outside of the micelle.

201

396

Micelle:

dodecylphosphocholine (DPC)

polar headgroup

hydrophobic tail

O

O

Steric acid

OP

O

O O

N

397

27.3 Phospholipids: diesters of phosphoric acid (H3PO4)

Glycerophospholipids: structurally related to a triglycerideglycerol backbone and two C12 - C20 fatty acid ester

H2C O

H2C O P

C Rsaturated

O

O

O

COCunsaturatedR

O

H

O

CH2CH2N(CH3)3

Phosphatidylcholine (lechtins)(L-configuration)

Phosphatidylethanolamine (cephalins)(L-configuration)

H2C O

H2C O P

C Rsaturated

O

O

O

COCunsaturatedR

O

H

O

CH2CH2NH3

202

398

Nonpolar tails aggregate in the center of a bilayerIonic head is exposed to solventCell membranes are on the order of 50 Å (5 nm) thick

Sphingomyelins:

Glycerophospholipids are important components of cell membranes

CHOH

H2C O P O

O

HC

O

CH2CH2N(CH3)3

CH(CH2)12CH3HC

HN C

O

(CH2)nCH3

CHOH

H2C OH

HC

CH(CH2)12CH3HC

NH2

sphingosine sphingomyelin

399

27.4 Prostaglandins (eicosanoids): C20 compounds derived from arachidonic acid and related fatty acids

hormone: (Greek, horman, to set in motion) chemical messenger from one cell to another, that acts as a signalfor a biochemical event.

HO

HOOH

CO2H

Prostaglandin F2!

O

HOOH

CO2H

Prostaglandin E2

HOOH

O

CO2H

Prostaglandin I2

(Prostacyclin)

Arachidonic acid

CO2H

O

O

OH

CO2H

prostaglandin H(PGH) synthase, 2 O2

HO

OOH

CO2H

Prostaglandin D2

prostacyclin (PGI)synthase

prostaglandinendoperoxide

reductase

prostaglandinendoperoxide E

isomerase

phospholipid

prostaglandinendoperoxide D

isomerase

Prostaglandin H2 (PGH2)

203

400

Prostaglandin biosynthesisO

O

OOH

Arachidonic acid

PGG2

CO2HCO2H

O

O

OH

CO2H

prostaglandin H synthase

cyclooxygenase(COX-1 or COX-2)

PGH2

Tyr385

O

CO2H

HH

CO2H CO2H

O

O

CO2H

OO

CO2H

O

O

O

O

CO2HO2 thene•, H+

PGG2

401

cell membrane

Tyr-385

Ser-530

Structure of COX-2

CO2H

O

O

acetylsalicylic acid

HN

O

NH

OH

Ser-530COX

+

HN

O

NH

O

O

covalently modifiedenzyme

204

402

Aracidonic acid

CO2H

C5H11

OCO2HLipoxygenase

Leukotriene A4

Heme, O2

C5H11

HO

CO2H

S

NH2HN

O

CO2H

Leukotriene D4

Thromboxanes: named for their role in thrombosis, the formation of a clot inside a blood vessel

O

CO2H

OH

O

Thromboxane A2

PGH2

thromboxanesynthase

O

CO2H

OH

HO

OH

Thromboxane B2

Leukotrienes”

403

COX-1 is a constitutive enzyme that is expressed in virtuallyall mammalian cells

COX-2 is an inducible enzyme that is expressed as a results of a biochemical response; expressed in phagocytes (macrophages) as part of an inflammation response.

NSAIDs: non-steroidal anti-inflammatory drugsAspirin, ibuprofren, and naproxen are non-selective

inhibitors of COX

Celebrex, vioxx, and brextra are selective inhibitorsof COX-2 (Coxibs)

OAc

CO2H

CO2H CO2H

H3CO

NN

SNH2

OO

CH3

F3C O

SNH2

OO

O

O

N

SNH2

OO

205

404

27.5 Terpenoids (isoprenoids): C10, C15 and C20 plant essential oilsRuzicka isoprene rule: terpenoids are derived from“isoprene units” (C5)

O

O

Camphour (+)-Carvone (caraway seeds)(-)-Carvone (spearmint)

(+)-limonene (oranges)(-)-limonene (lemons)

!-pinene "-pinene

CO2H

Chryanthemic acids

OH

Grandisol

CH3H3C

H3CCH3

patchouli alcohol(patchouli oil)

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

405

The precursor to C10 terpenoids (monoterpenes) is geraniolpyrophosphate (diphosphate), which consists of two C5 “isoprene units” that are joined “head-to-tail”

OPP

head - tail head - tail

head tail P

O

O

O P O

O

O

PP =

C15 sesquiterpenoids are derived from farnesyl pyrophosphate, which consists of three C5 “isoprene units” that are joined “head-to-tail”

OPP

C20 diterpenoids are derived from geranylgeranyl pyrophosphate, which consists of four C5 “isoprene units” that are joined “head-to-tail”

OPP

206

406

C25 sesterpenoids are derived from geranylfarnesyl pyrophosphate, which consists of five C5 “isoprene units” that are joined “head-to-tail”

C30 triterpenoids and steroids are derived from squalene, which consists of two C15 farnesyl units” that are joined “head-to-head”

C40 tetraterpenoids are derived from phytocene, which consists of two C20 geranylgeranyl units” that are joined “head-to-head”

OPP

407

Lycopene

!-carotene

HO

Lanosterol

CH3

CH3

CH3

H3C

H

cedrane

OO

HOH

CO2H

H OH

Gibberellic acid

207

408

27.6 Biosynthesis of TerpenoidsMevalonic acid is the biosynthetic precursor to the actual C5

“isoprene units,” which are isopentyl pyrophosphate (IPP, tail) and dimethylallyl pyrophosphate (DMAPP, head)

Mevalonate Pathway

N

N

N

NH2

N

O

OP

O

OH

O P O

OH

OH

O

HN

HN

O

HS

OHO

OH

PHO

O

O

CoAS =

Coenzyme A

C

O

H2C SCoA

HB:

H2C SCoAC

O

acetyl CoA

SCoA

OOClaisen

condensation

acetoacetyl CoA

C

O

H3C S-Cys-Enzyme

acetyl CoA

SCoA

OO

E-Cys-S

!-ketoacylthiolase

C

O

H3C SCoAEnzyme-Cys-SH

409

H2C SCoAC

O

SCoA

OO

SCoAHO2C

OHH3C O

3-Hydroxy-3-methylglutaric acid(HMG-CoA)

HMG-CoAreductase

2 NADPH OHHO2C

OHH3C

Mevalonic acid

C

O

H2C SCoA

HB:

acetyl CoAB H

aldolcondensation

HMG-CoAsynthase

acetoacetyl CoA

N

CONH2

R

HH

NADPH

R SCoA

O

N

CONH2

R

NADP+

H

N

CONH2

R

HH

NADPH

R H

O

N

CONH2

R

NADP+

H

H-B

RH

OH

H

OH

O N

HO

P

O

OH

OP

O

OH

O OH

O O O

PO32-

NH2

O

HH

N

N

N

N

H2N

NADPH

H

R

O

OO

O

R=H, compactinR=CH3, mevinolin (Lovastatin)

HMG-CoA reductase inhibitorsCholesterol lowering agents

208

410

Conversion of mevalonic acid to IPP and DMAPP

OHHO2C

OHH3C

Mevalonic acid

ATP AMP

O

OHH3C

P O

O-

O

P O-

O

O-

O

O

H

rearrangmentO P O

O-

O

P O-

O

O-H

dimethylallyl-PP(DMAPP)

isopentenyl-PP (IPP)

B:

H+

ATP ADP

O

OPO32-H3C

P O

O-

O

P O-

O

O-

O

O

H

O P O

O-

O

P O-

O

O-H H

B:

O

CH3

P O

O-

O

P O-

O

O-

O

O

H

- PO43-

Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PPelectrophilichead group

nucleophilictail group

electrophilichead group

nucleophilictail group

OPP

OPPH H

OPP

OPP B:DMAPP IPP

- OPP

Mg2+

OPP

OPP

H H

B:

OPP

farnesyl pyrophosphate (C15)

geranyl pyrophosphate (C10)

- OPP

Mg2+

411

OPP PPO

squalene synthase

Conversion of genanyl-PP to monoterpenesLimonene:

limoneneC=C bond actsas a nucleophile

OPP

OPPOPP

Linallyl-PP

OPP

- H+

Can notcyclize

H

:B

209

412

α-terpineol OPP

Linallyl-PP

OPP

OH

H2O

Problem 27.8a (hint)

Carbocation rearrangements:

H

H

1,2-hydrideshift

H2O

H

OH

terpinen-4-ol

!-pinene"-pinene

O

thujone

413

27.7 Steroids

Adenocortical: metabolic hormones (please read) Sex hormones: (please read)

androgens (male)

estrogens (female)

Synthetic steroids (please read)

Ring designationand numbering

H3C

HO

H

O

H

H

Estrone

H3C

HO

H

OH

H

H

Estradiol

H3C

HO

HH

H

O

Progesterone

H3C

HO

H

OH

H

HCCH

Ethynylestradiol

H3C

H3C

O

H

OH

H

H

Testosterone

H3C

H3C

HO

H

O

H

H

Androsterone

H3C

H3C

O

H

O

H

H

Androstenedione

H3C

H3C

O

H

OH

H

H

CH3

dianabol

H

210

414

27.8 Stereochemistry of steroidsstereochemistry of the ring fusion (two rings that share a

common C-C bond)decalin: two fused cyclohexanes (C10)

H

H

H

H

trans-decalin:

cis-decalin

H

H

H

H

415

The A-B ring fusion of steroids can be either cis or trans (most commonly trans)

The B–C and C–D ring fusions are usually transH3C

H3C

O

H

OH

H

H

H

Dihydrotestosterone

HO

CO2H

H

H H

H

H

H

OH

Cholic acid

HO

211

416

27.9 Cholesterol biosynthesis (figure 27.6, pages 1050-1052)part a: the cyclization

O

H A

HO HO

Squalene Oxide (C30H50O)Squalene (C30H50)

+

Squalene epoxidase

+

Squalenecyclase

HO

+

HO+

HO +

Heme , O2

Protosterol cation

417

Protosterol cation (C30H50O)

CH3

H3C

HO

CH3CH3

CH3H

H

H

+CH3

H3C

HO

CH3CH3

CH3H

H

H

H

+ H

1,2-hydrideshift

1,2-hydrideshift

CH3

H3C

HO

CH3CH3

CH3H

H

H+

H1,2-methyl

shiftCH3

H3C

HO

CH3

CH3H

H H3CH

H

+

CH3

H3C

HO

CH3

H

H H3CH

H

H3C+

- H+

B:

1,2-methylshift

CH3

H3C

HO

CH3

H

CH3

CH3

H

Lanosterol (C30H50O)

Cholesterol biosynthesis, part b: the 1,2-shifts

HO HO

Cholesterol (C27H46O)Lanosterol (C30H50O)

H

H H

H

H

H

H

H

H