reginald h. garrett charles m. grisham

Reginald H. Garrett

Charles M. Grisham

Chapter 8

Lipids

What is the structure, chemistry, and

biological function of lipids?

Outline

• What are the structures and chemistry of fatty acids?

• What are the structures and chemistry of triacylglycerols?

• What are the structures and chemistry of glycerophospholipids?

• What are sphingolipids神經脂, and how are they important for higher animals?

• What are waxes, and how are they used?

• What are terpenes萜烯, and what is their relevance to biological systems?

• What are steroids, and what are their cellular functions?

• How do lipids and their metabolites act as biological signals?

• What can lipidomics tell us about cell, tissue, and organ physiology?

Classes of Lipids

All biological lipids are amphipathic

• Fatty acids

• Triacylglycerols

• Glycerophospholipids

• Sphingolipids

• Waxes

• Isoprene-based lipids (including steroids)異戊二烯

8.1 What Are the Structures and Chemistry

of Fatty acids?

Know the common names and structures for fatty

acids up to 20 carbons long

• Saturated

• Lauric acid (12 C)月桂酸

• Myristic acid (14 C)肉豆蔻酸

• Palmitic acid (16 C)棕櫚酸

• Stearic acid (18 C)硬脂酸

• Arachidic acid (20 C)花生酸

8.1 What Are the Structures and Chemistry

of Fatty acids?

• Unsaturated fatty acids

• Palmitoleic acid (16:1)棕櫚油酸

• Oleic acid (18:1)

• Linoleic acid (18:2)亞麻油酸

• -Linolenic acid (18:3)次亞麻油酸 n-3

• -Linolenic acid (18:3) n-6

• Arachidonic acid (20:4)花生四烯酸

◎

8.1 What Are the Structures and Chemistry

of Fatty acids?

8.1 What Are the Structures and Chemistry

of Fatty acids?

•Fatty acids are comprised of

alkyl chains terminated by

carboxylic acid groups.

•Shown here is palmitic acid, a

16-carbon saturated fatty acid.

•The term “saturated” indicates

that the acyl chain is fully

reduced, i.e., saturated with

hydrogens and electrons.

Figure 8.1

8.1 What Are the Structures and Chemistry

of Fatty acids?

Figure 8.1 The structures of typical saturated fatty acids.

8.1 What Are the Structures and Chemistry

of Fatty acids?

Figure 8.1 The structures of typical unsaturated fatty acids.

8.1 What Are the Structures and Chemistry

of Fatty acids?

Figure 8.1 The structures of typical unsaturated fatty acids.

8.1 What Are the Structures and Chemistry

of Fatty acids?

Structural consequences of unsaturation

• Saturated chains pack tightly and form more

rigid, organized aggregates (i.e., membranes)

• Unsaturated chains bend and pack in a less

ordered way, with greater potential for motion

Fats in the human diet vary widely in their

composition

Diets high in trans fatty acids raise plasma

LDL cholesterol levels

Figure 8.2 Structures

of elaidic acid and

vaccenic acid, two

trans fatty acids.

Trans fatty acids are

present at low levels in

dairy and meat

products from ruminant

animals. “Partially

hydrogenated” fats in

foods contain much

higher amounts.

反油酸

異油酸

8.2 What Are the Structures and Chemistry

of Triacylglycerols?

Triacylglycerols are also called triglycerides

• They are a major energy source for many

organisms

• Why?

• Most reduced form of carbon in nature

• No solvation needed

• Efficient packing

8.2 What Are the Structures and Chemistry

of Triacylglycerols?

Most of the fatty acids in

plants and animals exist in

the form of triacylglycerols.

If all three fatty acids are

the same, the molecule is

called a simple

triacylglycerol.

Figure 8.3 Triacylglycerols are formed from glycerol

and fatty acids.

8.2 What Are the Structures and Chemistry

of Triacylglycerols?

Mixed triacylglycerols

contain two or three

different fatty acids.

Figure 8.3 Triacylglycerols are formed from glycerol

and fatty acids.

Polar Bears Prefer Nonpolar Food

Polar Bears Prefer Nonpolar Food

Polar bears face an ironic dilemma. They are

surrounded by water they cannot use. Ice and

snow are too cold and seawater is too salty. They

produce all the water they need from metabolism

of fat: (CH2) + 1.5O2 → CO2 + H2O

Interestingly, adult polar bears consume only fat

(from seals they catch). By not consuming

protein (and merely recycling their own proteins

into new ones), they have no need to urinate or

defecate and go for months without doing so, thus

saving precious body water.

8.3 What Are the Structures and Chemistry

of Glycerophospholipids

• A 1,2-diacylglycerol that has a phosphate group esterified at carbon 3 of the glycerol backbone is a glycerophospholipid

Glycerophospholipids are phospholipids but not necessarily vice versa

• Know the names and structures in Figure 8.6

• Understand the prochirality of glycerol

• Remember that, if a phospholipid contains unsaturation, it is most likely at the 2-position

◎

8.3 What Are the Structures and Chemistry

of Glycerophospholipids

Figure 8.4 Phosphatidic acid, the parent compound for

glycerophospholipids.

Glycerophospholipids are essential components of cell

membranes and are also found in other parts of cells.

8.3 What Are the Structures and Chemistry

of Glycerophospholipids

Figure 8.6 The structure of phosphatidylcholine. The core of

the structure is shown here with a blue background. In the

rest of Figure 8.6, the core is displayed using this blue motif.

8.3 What Are the Structures and Chemistry

of Glycerophospholipids

Figure 8.6 Structures of several

glycerophospholipids and a space-

filling model of phosphatidylglycerol.

8.3 What Are the Structures and Chemistry

of Glycerophospholipids

Figure 8.6 Structures of several

glycerophospholipids and a space-

filling model of phosphatidylinositol.

肌醇

Phosphatides Exist in Many Varieties

Figure 8.7 A space-filling model

of 1-stearoyl-2-oleoyl-

phosphatidylcholine.

Unsaturated fatty acids are

found typically at the 2-

position of the glycerol

backbone. It is rare to find

unsaturated fatty acids at the

1-position.

Ether Glycerophospholipids Include PAF

and Plasmalogens

Ether glycerophospholipids possess an ether

linkage instead of an acyl group at the C-1

position of glycerol.

•See Figure 8.8

•

•Plasmalogens縮醛磷脂 are ether

glycerophospholipids in which the alkyl chain is

unsaturated

◎

Alzheimer's Disease/ Down syndrome

Ether Glycerophospholipids Include PAF

and Plasmalogens

Figure 8.9 The structure

of a choline plasmalogen.

Ether Glycerophospholipids Include PAF

and Plasmalogens

Figure 8.8 A 1-alkyl-2-acyl-

phosphatidylethanolamine (an

ether glycerophospholipid).

Ether Glycerophospholipids

•Platelet activating factor (PAF) is an ether

glycerophospholipid

•PAF is a potent biochemical signal molecule

•Note the short (acetate) fatty acyl chain at the

C-2 position in PAF

◎

Ether Glycerophospholipids Include PAF

and Plasmalogens

Figure 8.8 The structure of 1-alkyl-2-acetyl-

phosphatidylcholine (PAF).

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

• Sphingolipids represent another class of lipids

found frequently in biological membranes

• Sphingosine鞘氨醇, an 18-carbon alcohol,

forms the backbone of these lipids rather than

glycerol, sphingomyelin, 神經鞘磷脂

• A fatty acid joined to sphingosine in amide

linkage forms a ceramide神經醯胺• Glycosphingolipids are ceramides with one or

more sugars in beta-glycosidic linkage at the 1-

hydroxyl group

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

Figure 8.10 Sphingolipids are based

on the structure of sphingosine.

Sphingosine is an 18-carbon alcohol.

Fatty acids joined in amide linkage at

the highlighted nitrogen form

ceramides.

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

Figure 8.10 A ceramide is formed by

joining a fatty acid in amide linkage to

a sphingosine.

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

• Glycosphingolipids with one sugar are

cerebrosides腦苷脂

• Ceramides with 3 or more sugars, one of

which is a sialic acid唾液酸, are

gangliosides神經節苷脂.

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

Figure 8.10 A ceramide with

a phosphocholine head

group is a choline

sphingomyelin.

神經鞘脂質

多發性硬化症Multiple Sclerosis

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

Figure 8.10 A ceramide with a single

sugar is a cerebroside.

8.4 What Are Sphingolipids and How Are

They Important for Higher Animals?

Figure 8.10 Gangliosides are ceramides with three or more

sugars esterified, one of which is a sialic acid.

Gangliosides are

important

components of

muscle and

nerve

membranes.

◎

Tay–Sachs disease

8.5 What Are Waxes, and How Are They

Used?

Waxes are esters of long-chain alcohols with long-chain fatty acids

• Waxes are insoluble in water, due to their mostly hydrocarbon composition

• Animal skin and fur are wax-coated and are water-repellant

• Leaves of many plants and bird feathers are similarly water-repellant

• Carnauba wax, from a palm tree in Brazil, is a hard wax used for high-gloss finishes for automobiles, boats, floors, and shoes 棕梠蠟

• Lanolin is a wool wax used in cosmetics, such as Oil of Olay, named for its lanolin content

Triacontanol palmitate is the principal

component of beeswax.

8.5 What Are Waxes, and How Are They

Used?

Figure 8.11 Waxes consist of long-chain alcohols esterified to

long-chain fatty acids. Triacontanol palmitate is the principal

component of beeswax.

8.6 What Are Terpenes, and What is Their

Relevance to Biological Systems?

Terpenes are a class of lipids formed from combinations of isoprene units

• “Isoprene” is 2-methyl-1,3-butadiene

• Monoterpenes consist of two isoprene units

• Sesquiterpenes consist of three isoprenes

• A diterpene consists of four isoprene units

• All steroids (including cholesterol and the steroid hormones) are terpene-based molecules

8.6 What Are Terpenes, and What is Their

Relevance to Biological Systems?

•Note the two possible linkage modes:•“head-to-tail”•“tail-to-tail”

Figure 8.12 The structure of isoprene (2-methyl-1,3-butadiene)

and the structure of head-to-tail and tail-to-tail linkages.

Isoprene itself can be formed by distillation of natural rubber, a

linear head-to-tail polymer of isoprene units.

8.6 What Are Terpenes, and What is Their

Relevance to Biological Systems?

Figure 8.13 Many monoterpenes are readily recognized by

their characteristic flavors or odors (limonene in lemons;

citronellal in roses and perfumes; menthol used in cough drops.

8.6 What Are Terpenes, and What is Their

Relevance to Biological Systems?

Figure 8.13 The

diterpenes include retinal

(the visual pigment in

rhodopsin), and phytol

(found in chlorophyll.

Gibberellic acid is a plant

hormone.

植醇

phytanic acid

植烷酸 a-oxidation

8.6 What Are Terpenes, and What is Their

Relevance to Biological Systems?

Figure 8.13 The

triterpene

lanosterol is a

constituent of

wool fat and is

also a precursor

to cholesterol and

the other steroids.

Lycopene is a

carotenoid found

in ripe fruit,

especially

tomatoes.

◎

Long-chain polyisoprenoid molecules serve

several functions in various organisms

Figure 8.14 Dolichol phosphate is an initiation point for

synthesis of carbohydrate polymers in animals. In bacteria,

undecaprenol (aka bactoprenol) delivers sugars for synthesis

of cell wall components.

◎

Coumadin or Warfarin – Agent of Life and

Death

Coumadin is an oft-

prescribed anticoagulant

used by those as risk of

heart attacks. Warfarin is

a common rodent poison.

They are one and the

same molecule,

developed by Karl Paul

Link at the Wisconsin

Alumni Research

Foundation (WARF – thus

the latter name).

The key to both these uses is the action of

coumadin/warfarin as an antagonist of vitamin K in the body.

Coumadin or Warfarin – Agent of Life and

Death

• Vitamin K is required for

carboxylation of Glu residues on

proteins of the blood clotting

cascade.

• Vitamin K is oxidized in these

reactions and must be reductively

recycled.

• Coumadin/warfarin inhibits vitamin

K epoxide reductase, depleting the

cell’s supply of reduced vitamin K,

and thus inhibits the blood clotting

cascade.

◎

The Membranes of Archaea Are Rich in

Isoprene-Based Lipids

Archaea are found primarily in harsh environments, and are

ideally adapted to these stressful conditions. Isoprene-based

lipids such as caldarchaeol completely span the cell

membrane, providing exceptional membrane stability.

Figure 8.15 The structure of caldarchaeol, an isoprene-

based lipid found in archaea.

8.7 What Are Steroids, and What Are Their

Cellular Functions?

• Steroids are polyprenyl (isoprene-based)

molecules built on a core structure of three 6-

membered rings and one 5-membered ring, all

fused together

• Cholesterol is the most common steroid in

animals and precursor for all other steroids in

animals

• Steroid hormones serve many functions in

animals - including salt balance, metabolic

function and sexual function

8.7 What Are Steroids, and What Are Their

Cellular Functions?

Figure 8.16 The structure of

cholesterol, shown with steroid ring

designations and carbon numbering.

8.7 What Are Steroids, and What Are Their

Cellular Functions?

Figure 8.17 The structures of several important sterols

derived from cholesterol.

Cortisol provides control of carbohydrate, protein, and lipid

metabolism

Testosterone is the primary male sex steroid hormone

Estradiol is the primary female sex steroid hormone

Progesterone is a precursor of testosterone and estradiol

8.7 What Are Steroids, and What Are Their

Cellular Functions?

Figure 8.17 The structures of several important sterols

derived from cholesterol.

The bile acids, including cholic acid and deoxycholic acid,

are detergent molecules secreted in bile from the

gallbladder that assist in the absorption of dietary lipids in

the intestine.

◎

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

• Glycerophospholipids and sphingolipids play

important roles as chemical signals in and on cells

• Lipid signals act locally, either within the cell where

they are made or on nearby cells

• These signals typically initiate a cascade of reactions

with multiple effects

• The lifetimes of these signals are usually very short

• The creation and breakdown of lipid signals is

carefully regulated and timed

• Some of the reactions that produce these signals are

shown on the next slide

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

Figure 8.18 Phospholipases

A1 and A2 cleave fatty acids

from a glycerophospholipid,

producing lysophospholipids.

Phospholipases C and D

hydrolyze on either side of the

phosphate in the polar head

group.

◎

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

A diamondback rattlesnake

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

The Indian cobra

Phospholipases are

components of the

venoms of many

poisonous snakes.

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

• Glycerophospholipid breakdown produces a variety

of signal products

• Arachidonic acid

• Lysophosphatidic acid

• Diacylglycerol

• Inositol phosphates, including inositol-1,4,5-trisP

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

Figure 8.19 Modification and breakdown of

glycerophospholipids produce a variety of signals and

regulatory effects.

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

Figure 8.19 Detail◎

8.8 How Do Lipids and Their Metabolites

Act as Biological Signals?

Figure 8.19 Detail

Plant Sterols and Stanols – Natural

Cholesterol Fighters

Dietary guidelines for optimal health call for reducing

cholesterol intake. Eating plant sterols and stanols can play

a role. These cholesterol mimics bind to cholesterol

receptors on intestinal cells and block absorption of

cholesterol itself. (Plant sterols and stanols are not

themselves absorbed.)

(Note: Stanols are fully reduced sterols.)◎

Plant Sterols and Stanols – Natural

Cholesterol Fighters

Raisio Group, a Finnish company, has developed Benecol, a

stanol ester spread (available in many U.S. supermarkets) that

can lower LDL cholesterol by up to 14% if consumed daily (see

graph on next slide)

◎

Plant Sterols and Stanols – Natural

Cholesterol Fighters

Serum cholesterol

before and after

consumption of Benecol.

Green circles: 0g/day

Red squares: 2.6g/day

Blue triangles: 1.8g/day

17β-Hydroxysteroid Dehydrogenase 3

Deficiency

Deficiency of 17β-Hydroxysteroid Dehydrogenase 3 reduces

production of testosterone and can result in development of

male pseudohermaphroditism◎

Sphingolipids can be modified or broken

down to produce chemical signals

Sphingosine can be

phosphorylated to produce

sphingosine-1-phosphate (S1P)

inside cells.

Figure 8.20 Structures of

sphingosine-1-phosphate

(S1P) and fumonisin B1

Sphingolipids can be modified or broken

down to produce chemical signals

S1P may either exert a

variety of intracellular

effects or may be

excreted from the cell,

where it can bind to

membrane receptor

proteins, either on

adjacent cells or on the

cell from which it was

released.

Fumonisin inhibits sphingolipid biosynthesis

Fumonisin is a common fungal contaminant of corn and

corn-based products that inhibits sphingolipid biosynthesis.

Fumonisin can trigger esophageal cancer in humans and

leukoencephalomalacia, a fatal disease in horses.

8.9 What Can Lipidomics Tell Us about

Cell, Tissue, and Organ Physiology?• Many human diseases involve the disruption of lipid

metabolic enzymes and pathways.

• New techniques have made possible the global

analysis of lipids and their interacting protein partners

in organs, cells, and organelles – an approach termed

lipidomics

• Typical cells contain over a thousand different lipids

• Complete understanding of lipid function will require

the determination of which lipids are present and in

what concentrations

• Cellular lipidomics provides a framework for

understanding the myriad roles of lipids