Lipid Nomenclature & Structure

Student Edition 9/19/13 version

Pharm. 304 Biochemistry

Fall 2014

Dr. Brad Chazotte 213 Maddox Hall

chazotte@campbell.edu

Web Site: http://campbell.edu/faculty/chazotte

Original material only ©2008-14 B. Chazotte

Goals

To know the basic chemical and physical properties of lipids.

To be familiar with the basic roles of lipids in energy storage, structure, and cell signaling.

To know the basic aspects of lipid nomenclature including fatty acids.

To be familiar with the general structures of the various lipid molecule classes: fatty acids, glycerophospholipids, sphingolipids, cerebrosides, gangliosides, sterols (cholesterol), and eicosanoids

Lipids

Some Biological Functions:

• In biological membranes in the form of bilayers.

• As energy stores using the form of hydrocarbon chains.

• In intra- and intercellular signaling events that utilize lipid molecules.

Some Lipid Properties:

• Lipids are not polymeric in contrast to proteins, nucleic acids and polysaccarharides.

• One of the key (classifying) properties of lipids is that they are largely hydrophobic and only sparingly soluble in water.

• Lipids tend to aggregate and this is a key property for their structural role in biological membranes.

A Definition: Substances of biological origin that are soluble in organic solvents.

Horton et al 2012 Fig 9.2

Contain phosphate

Related to isoprene

Contain sphingosine & carbohydrates

An Overview

Note: The cell’s ER membrane synthesizes nearly all the major classes of lipids required for the production of new cell membranes.

Fatty Acid NomenclatureSystematic Name: derived from the parent hydrocarbon chain by substituting “oic” for the final “e”, e.g. Hexadecanoic acid for hexadecane.

Numbering: Fatty acids are numbered starting with the carboxyl terminus as C1.

Stryer 2007 Fig 12.2

Letters: Carbons 2 & 3 are often referred to as α and β, while the methyl carbon at the most distal end is referred to as ωDouble Bonds: their position represented by the symbol, Δ, e.g. Δ9 – a double bond between carbons 9 & 10.

Alternative Double Bond Nomenclature: Count from the distal end, ω-carbon, to the double bond, e.g. ω-3 fatty acids.

Voet, Voet, & Pratt 2013 Figure 9-1

Fatty Acids: Details & Structures Fatty acids: carboxylic acids with long

hydrocarbon chains. Weak acids: pka~4.5

Animals: C16 & C18 most common; those <C14 or >C20 are uncommon lengths.

Two major fatty acid classifications:

• Saturated – no double bonds, e.g. stearic acid, molecule is fully reduced.

• Unsaturated – one or more double bonds, e.g. oleic acid & linoleic acid, respectively.

• Most fatty acids have an even number of carbons. – (Synthesis is by 2-C units.)

• Double bonds have the cis configuration.

• They are ionized at physiological pH.

Voet, Voet, & Pratt 2013 Table 9-1

Common Biological Fatty Acids Table

Lehninger 2005 Figure 10.1a-d

Stearic Oleic

Lipid packing & melting points

The length and degree of unsaturation of fatty acids:

• largely determine fatty acid’s physical properties, e.g. poor solubility in water, and the compounds that contain the fatty acids.

• strongly influence melting points (due to lipid packing).

Fatty Acid Composition of Three Food Fats

Lehninger 2005 Figure 10.4

Some Common Types of Storage and Membrane Lipids

Lehninger 2005 Figure 10.6

Lipid type

block structure of molecule

Pink – backbone

Yellow - long chain alkyl groups

Blue - Polar headgroup

Fatty acids - R-COOH (R=hydrocarbon chain) are components of triacylglycerols, glycerophospholipids, sphingolipidsPhospholipids - contain phosphate moietiesGlycosphingolipids - contain both sphingosine and carbohydrate groups Isoprenoids - (related to the 5 carbon isoprene) include steroids, lipid vitamins and terpenes

Glycerol & Triacylglycerol Structures

Adipocytes

Animal triacylglycerol synthesis and storage cells

Voet, Voet, & Pratt 2013 p.244 Voet, Voet, & Pratt 2013 p.244Voet, Voet, & Pratt 2013 Fig. 9.2

Glycerophospholipid Structures & Classes

Horton et al 2012 Fig 9.2

Net charge pH 7

-1 0 0-1

-1

-1

-2

PAPEPCPS

PI

PG

CL

Voet, Voet, & Pratt 2013 Fig 9.3; Table 9.2

A glycerophospholipid Structure: 1-stearoyl-2-oleoyl-3-phosphatidylcholine

“tail”

“headgroup”

Voet, Voet, & Pratt 2013 Fig 9.4

Phospholipase Function

Phospholipases must be able to access lipids in a non-aqueous environment.

Phospholipases can act in intracellular and extracellular signaling pathways.

Voet, Voet, & Pratt 2013 Fig 9.5 & 9.6

Plasmalogen Structure

,-unsaturated ether

Voet et al 2008 Fig. 9.3

• Ethanolamine, choline, and serine are the most common headgroups.

• ,-unsaturated ether linkage in the cis configuration (as opposed to an ester linkage in glycerophospholipids).

• Functions not well known.

Horton et al 2012 Fig 9.2Voet, Voet, & Pratt 2013 p.247

Sphingolipids

• Are major membrane components

• Most sphingolipids are derivatives of the C18 amino alcohol – sphingosine (w/ trans configuration of double bond).

• N-acyl fatty acid derivatives of sphingosine called ceramides.

• Ceramides are the parent compounds of the more abundant sphingolipids

Ceramide: when fatty acid at C-2 is attached via an amide linkage.

Subclasses (differ in their head groups; all ceramide are derivatives):

1. Sphingomyelins [phosphocholine or phosphoethanolamine]

2. Neutral (uncharged) glycolipids [single sugar residue]

3. Gangliosides [w/ oligoaccharide and ≥ 1 sialic acid residue]

Voet, Voet, & Pratt 2013 p.248

A Sphingomyelin Structure

Horton et al 2012 Fig 9.2Voet, Voet, & Pratt 2013 Figure 9-7a,b

CerebrosidesCeramides with a single sugar residue as a headgroup

Since they lack phosphate groups they are nonionic (in contrast to phospholipids)

They can also be classified as glycosphingolipids.

Galactocerebrosides and glucocerebrosides are the most prevalent

Berg, Tymoczko & Stryer 2012 Chap 12. p 350 Horton et al 2012 Fig 9.2

Gangliosides

Horton et al 2012 Fig 9.2

• Most complex of glycosphingolipids.

• Based on ceramide with attached oligosaccharides w/ at least 1 sialic acid (N-acetylneuraminic acid) residue.

• Primarily components of cell surface membranes – physiologically & medically significant.

Voet, Voet, & Pratt 2013 Figure 9-9a,b

Cholesterol Structure

Steroid Parent Molecule

Polar group

• Rigid ring structure

• Amphipathic molecule

• Metabolic precursor of steroid hormones in mammals

Voet, Voet, & Pratt 2013 Figure 9.10Horton et al 2012 Fig 9.2

Steroid Hormones

Representative Hormones

Classified by their Evoked Physiological Response

Glucocorticoids: affect carbohydrate, protein & lipid metabolism; also wide variety of vital functions, e.g. inflamatory rx and stress. E.g., cortisol

Mineralocortocoids: regulate salt and water excretion by kidneys. E.g., aldosterone

Androgens & Estrogens: affect sexual development & function. E.g. Tostesterone & -estradiol

- carry messages between tissues

Voet, Voet, & Pratt 2013 Figure 9.11

Vitamin D Structure/Conversions

Vitamin D involved in Ca2+ metabolism (promotes intestinal absorption). Deficiency gives rise to ricketts

Sterol-derived hormone

Precursor converted by UV light

Voet, Voet, & Pratt 2013 p. 251

Isoprenoids

Not structural membrane components.

Constructed from 5-carbon units based on the isoprene carbon skeleton.

Plant kingdom is rich in isoprenoid compounds some of which are needed by animals, e.g. vitamin D, -carotene used to make vitamin A.

Voet, Voet, & Pratt 2013 p. 252, 253

Ubiquinone: An Isoprenoid

Found in the mitochondrial inner membrane and is involved in mitochondrial electron transport.

The mammalian ubiquinone has 10 isoprenoid units in its “tail”.

Voet, Voet, & Pratt 2013 p. 252

Vitamins K & E Structures

Voet, Voet, & Pratt 2013 p. 253

EicosanoidsProstaglandins

Prostacyclins

Thromboxanes

Leukotrienes

Lipoxins

• Arachidonic acid most important precursor in humans.

• Act locally near cellular site of production (not transported in blood). Paracrine hormones

• Act at low concentrations, e.g. nM.

• Tend to decompose in seconds to minutes (limits effective range).

• Involved in the production of pain & fever.

• Involved in the regulation of blood pressure, blood coagulation and reproduction

All C20 compounds

Voet, Voet, & Pratt 2013 Fig. 9.12

Eicosanoid Classes Prostaglandins ► 5-C ring from arachidonic acid. Two groups originally defined PGE (ether soluble) and PGF each containing numerous subtypes, e.g. PGE1, PGE2. Act in many tissue by regulating cAMP synthesis.

Prostacyclins

Thromboxanes ► 6-membered ring containing an ether. Produced by platelets. Act in blood clot formation and blood flow reduction at clot site. NSAIDS inhibit

cyclooxygenase (COX) involved in thromboxane synthesis.

Leukotrienes ► contain 3 conjugated double bonds. Powerful biological signals, e.g. leukotriene A4 smooth muscle contraction in lung airways. Overproduction can cause asthmatic attacks.

Lipoxins ► are trihydroxy-eicosatetraenoic acids, derived from arachidonic acid with the four double bonds in conjugation, which have distinctive anti-inflammatory properties, i.e. they are involved in the resolution phase of inflammation like the resolvins.

Roles of Selected Eicosanoids

• Prostaglandin E2 - can cause constriction of blood vessels

• Thromboxane A2 - involved in blood clot formation

• Leukotriene D4 - mediator of smooth-muscle contraction and bronchial constriction seen in asthmatics

Eicosanoids Generated from Arachidonic Acid Cleavage

Lehninger 2005 Figure 10.18b

NonSteroidal AntiInflammatory Drugs (e.g. aspirin, ibuprofen, meclofenamate) inhibit the enzyme, prostaglandin synthetase ( cyclooxygenase, COX) which catalyzes an early step in the pathway from which arachidonate to prostaglandins and thromboxanes.

Inherited Human Diseases: Abnormal Membrane Lipid Accumulation

Lehninger 2005 Box 10.2 Figure 1 Lehninger 2005 Box 10.2 Figure 2

Tay-Sachs: portion of infant human brain cell showing lysosomes with abnormal ganglioside deposits.

Phosphatidylinositols in Cellular Regulation

Lehninger 2005 Figure 10.17; Voet et al, 2008 Figure 13.24

(IP3)

Signaling steps:

• Initial removal of a phospholipid headgroup by phospholipase C

• Produces IP3 (soluble) & DAG (membrane)

• IP3 triggers Ca2+ from ER

• Higher [DAG] & [Ca2+] cytosol activate protein kinase C (PKC)

• PKC phosphorylates specific target protein

• Protein activity modified; metabolism modified

(DAG)

(PKC)

(PIP2)

PI

END OF LECTURES