199 Chapter 27. Biomolecules: Lipids Naturally Occurring Compounds That

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)

392

27.1: Waxes, fats and oils Fatty acids: refers to long, straight-chain saturated and unsaturated acids, typically from C12 - C20. saturated fatty acids:

CH3(CH2)nCO2H n=10, lauric acid n=12, myristic acid n=14, palmitic acid n=16, steric acid unsaturated fatty acid CO2H C18, oleic acid

polyunsaturated fatty acids (PUFA)

3 CO2H C18, linolenic acid (18:3) 6 CO2H C18, linoleic acid (18:4) 6 CO2H C20, arachidonic acid (20:4) 393

199 Fatty acid amides (FAA): O OH OH H N H H O

Arachidonic Acid (C20) tetrahydrocannabinol

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.

O fatty OH H2C O C R1 acids HO OH O HC O C R2 O glycerol H2C O C R3 394

27.2 Soap sodium & potassium salts of fatty acid produced from the saponification (base hydrolysis) of animal fats (glycerides) O

H2C O C Rn H2C OH O NaOH O 3 + HC O C Rn R C O Na HC OH O n

H2C O C Rn H2C OH

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.

395

200 Micelle:

O O

Steric acid

dodecylphosphocholine (DPC)

O O N P O O

polar head hydrophobic group tail

396

27.3 Phospholipids: diesters of phosphoric acid (H3PO4)

Glycerophospholipids: structurally related to a triglyceride

glycerol backbone and two C12 - C20 fatty acid ester O O H2C O C Rsaturated H2C O C Rsaturated O O unsaturatedR C O C H unsaturatedR C O C H O O H2C O P O CH2CH2NH3 H2C O P O CH2CH2N(CH3)3 O O

Phosphatidylcholine (lechtins) Phosphatidylethanolamine (cephalins) (L-configuration) (L-configuration) 397

201 Glycerophospholipids are important components of cell membranes

Nonpolar tails aggregate in the center of a bilayer Ionic head is exposed to solvent Cell membranes are on the order of 50 Å (5 nm) thick

Sphingomyelins: O H C OH 2 H2C O P O CH2CH2N(CH3)3 O O H HC NH 2 HC N C (CH2)nCH3 CHOH CHOH CH(CH ) CH HC 2 12 3 HC CH(CH2)12CH3 sphingosine sphingomyelin 398

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 signal for a biochemical event.

CO2H phospholipid

Arachidonic acid CO H prostaglandin H 2 (PGH) synthase, 2 O2 HO prostaglandin prostacyclin (PGI) O endoperoxide O CO2H synthase reductase CO2H O HO OH OH prostaglandin HO OH Prostaglandin F Prostaglandin H (PGH ) prostaglandin 2! endoperoxide D 2 2 endoperoxide E Prostaglandin I isomerase isomerase 2 (Prostacyclin)

HO O CO H CO2H 2

HO O OH OH Prostaglandin E Prostaglandin D2 2 399

202 Prostaglandin biosynthesis prostaglandin H CO2H synthase O O CO2H CO2H cyclooxygenase O O (COX-1 or COX-2) OOH OH Arachidonic acid PGH PGG2 2

Tyr385

O O O H H

CO2H CO2H CO2H

O O O O O2 then O + CO2H e•, H PGG2 O

400 CO2H CO2H

Structure of COX-2

cell membrane

CO2H OH H + N Tyr-385 O N H O O acetylsalicylic acid Ser-530 Ser-530 COX

O covalently modified H N enzyme N H O 401

203 Thromboxanes: named for their role in thrombosis, the formation of a clot inside a blood vessel OH thromboxane CO2H CO2H synthase O PGH2 O HO O OH OH

Thromboxane A2 Thromboxane B2

Leukotrienes”

O CO2H Lipoxygenase CO2H

C H Heme, O2 5 11

Aracidonic acid Leukotriene A4

CO2H

NH2 C5H11 H S N CO2H

O 402 Leukotriene D4

COX-1 is a constitutive enzyme that is expressed in virtually all 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 drugs Aspirin, ibuprofren, and naproxen are non-selective inhibitors of COX

CO2H CO2H CO2H OAc H3CO Celebrex, vioxx, and brextra are selective inhibitors of COX-2 (Coxibs)

O O O O O O S S S NH 2 NH2 NH2 N N F3C O O N O 403 CH3

204 27.5 Terpenoids (isoprenoids): C10, C15 and C20 plant essential oils Ruzicka isoprene rule: terpenoids are derived from

“isoprene units” (C5) isoprene (2-methyl-1,3-butadiene)

Camphour (+)-Carvone (caraway seeds) (+)-limonene (oranges) (-)-Carvone (spearmint) (-)-limonene (lemons)

H3C CH3 CH3 H3C

patchouli alcohol !-pinene "-pinene (patchouli oil)

CO2H

Chryanthemic acids Grandisol 404

The precursor to C10 terpenoids (monoterpenes) is geraniol pyrophosphate (diphosphate), which consists of two C5 “isoprene units” that are joined “head-to-tail” O O head tail PP = P O P O O O

OPP head - tail head - tail

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 405

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

OPP

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”

406

H C O 3 O H OH CH3

CH3 H HO CH H 3 CO2H HO cedrane Gibberellic acid Lanosterol

Lycopene

!-carotene

407

206 27.6 Biosynthesis of Terpenoids

Mevalonic acid is the biosynthetic precursor to the actual C5 “isoprene units,” which are isopentyl pyrophosphate (IPP, tail) and dimethylallyl pyrophosphate (DMAPP, head)

Mevalonate Pathway

O !-ketoacyl thiolase O H2C C SCoA C H H2C SCoA B: acetyl CoA Claisen O O condensation O O SCoA E-Cys-S SCoA acetoacetyl CoA O O Enzyme-Cys-SH H C C S-Cys Enzyme H3C C SCoA 3 - acetyl CoA

NH2 OH N H H O O N N N CoAS = HS O P O P O N N O O OH OH O OH Coenzyme A HO P O OH 408 O

HMG-CoA aldol HMG-CoA O O synthase O condensation H3C OH reductase H3C OH H C C SCoA 2 HO C HO2C C 2 SCoA 2 NADPH OH H H2C SCoA B: 3-Hydroxy-3-methylglutaric acid acetyl CoA Mevalonic acid (HMG-CoA) B H O O

SCoA acetoacetyl CoA

H-B O O OH

R SCoA R H R H H O

H H H H H H O O CONH2 CONH2 CONH2 CONH2 O N N N N H R R R R NADPH NADP+ NADPH NADP+ R

H R=H, compactin H O H2N N R=CH3, mevinolin (Lovastatin) O O

N N O O P O P O O N NH2 HMG-CoA reductase inhibitors N OH OH Cholesterol lowering agents O OH HO OH 2- PO3 NADPH 409

207 Conversion of mevalonic acid to IPP and DMAPP

ATP AMP ATP ADP OH O H3C 2- H3C O H3C OH OPO3 O O 3- O O - PO4 HO2C H H - OH O O P O P O- O O P O P O - - O- O- Mevalonic acid O O

H+ O CH O O O O 3 O O rearrangment O P O P O- - H - O P O P O O O P O P O - - H H O O H O- O- B: O- O- B: isopentenyl-PP dimethylallyl-PP (IPP) (DMAPP) Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP nucleophilic electrophilic tail group head group - OPP - OPP 2+ OPP 2+ Mg H H Mg OPP OPP B: DMAPP OPP IPP geranyl pyrophosphate (C10)

OPP H H OPP

electrophilic B: nucleophilic OPP farnesyl pyrophosphate (C15) 410 head group tail group

OPP PPO squalene synthase

Conversion of genanyl-PP to monoterpenes

Limonene: OPP OPP OPP

Can not Linallyl-PP cyclize

OPP - H+

H :B C=C bond acts limonene 411 as a nucleophile

208 OPP α-terpineol OPP H2O

Linallyl-PP

Problem 27.8a (hint)

"-pinene !-pinene

Carbocation rearrangements:

1,2-hydride H O shift 2 OH H H H terpinen-4-ol

412 thujone

27.7 Steroids Ring designation and numbering

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

OH H C OH H C O H C O H C 3 3 3 3 CH3

H3C H H3C H H3C H H3C H

H H H H H H H H O HO O O H Testosterone Androsterone Androstenedione dianabol estrogens (female)

O O OH H C OH H3C H3C H3C 3 C CH H H H H

H H H H H H H H HO HO HO HO Estrone Estradiol Progesterone Ethynylestradiol Synthetic steroids (please read) 413

209 27.8 Stereochemistry of steroids stereochemistry of the ring fusion (two rings that share a common C-C bond)

decalin: two fused cyclohexanes (C10) trans-decalin:

H H

cis-decalin

H H

414

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 trans

OH H3C

H3C H

H H O H Dihydrotestosterone

H HO CO2H H H

H H HO OH H Cholic acid

415

210 27.9 Cholesterol biosynthesis (figure 27.6, pages 1050-1052) part a: the cyclization

Squalene epoxidase O Heme , O2 Squalene (C H ) H A 30 50 Squalene Oxide (C30H50O)

Squalene cyclase + HO HO +

HO HO + +

HO +

Protosterol cation

416

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

CH3 H CH3 H CH CH 1,2-hydride 3 3 CH3 CH3 H shift HO + HO + H3C H H C H CH 3 H 3 CH3 H H

Protosterol cation (C30H50O)

H CH H CH 1,2-hydride 3 H 3 H H3C CH CH CH shift 3 3 1,2-methyl 3 shift HO HO H + H H C H C + 3 H 3 H CH3 CH3 B: CH3 H CH3 CH3 H H C 1,2-methyl 3 + CH3 shift CH3 - H HO HO H H H C CH3 H C + 3 H 3 H H3C Lanosterol (C30H50O)

H H

H H H

H H HO HO H H

Lanosterol (C H O) Cholesterol (C27H46O) 30 50 417

211