1. 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/chazottehttp://campbell.edu/faculty/chazotte Original material only ©2008-14 B. Chazotte

2. 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

3. 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.

4. Fatty Acid Nomenclature Systematic 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 C 1. 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 ω Double Bonds: their position represented by the symbol, Δ, e.g. Δ 9 – 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.

5. Voet, Voet, & Pratt 2013 Figure 9-1 Fatty Acids: Details & Structures Fatty acids: carboxylic acids with long hydrocarbon chains. Weak acids: pk a ~4.5 Animals: C 16 & C 18 most common; those C 20 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.

6. Voet, Voet, & Pratt 2013 Table 9-1 Common Biological Fatty Acids Table Lehninger 2005 Figure 10.1a-d StearicOleic 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).

7. Fatty Acid Composition of Three Food Fats Lehninger 2005 Figure 10.4

8. 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, sphingolipids Phospholipids - contain phosphate moieties Glycosphingolipids - contain both sphingosine and carbohydrate groups Isoprenoids - (related to the 5 carbon isoprene) include steroids, lipid vitamins and terpenes

9. Glycerol & Triacylglycerol Structures Adipocytes Animal triacylglycerol synthesis and storage cells Voet, Voet, & Pratt 2013 p.244 Voet, Voet, & Pratt 2013 Fig. 9.2

10. Glycerophospholipid Structures & Classes Horton et al 2012 Fig 9.2 Net charge pH 7 0 0-2 PAPEPCPSPIPGCL Voet, Voet, & Pratt 2013 Fig 9.3; Table 9.2

11. A glycerophospholipid Structure: 1-stearoyl-2-oleoyl-3-phosphatidylcholine “tail” “headgroup” Voet, Voet, & Pratt 2013 Fig 9.4

12. 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

13. 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 9.2 Voet, Voet, & Pratt 2013 p.247

14. Sphingolipids Are major membrane components Most sphingolipids are derivatives of the C 18 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 Subclasses (differ in their head groups; all ceramide are derivatives): 1. 1.Sphingomyelins [phosphocholine or phosphoethanolamine] 2. 2.Neutral (uncharged) glycolipids [single sugar residue] 3. 3.Gangliosides [w/ oligoaccharide and ≥ 1 sialic acid residue] Voet, Voet, & Pratt 2013 p.248

15. A Sphingomyelin Structure Horton et al 2012 Fig 9.2 Voet, Voet, & Pratt 2013 Figure 9-7a,b

16. Cerebrosides Ceramides 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 350Horton et al 2012 Fig 9.2

17. Gangliosides 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

18. Cholesterol Structure Steroid Parent Molecule Polar group Rigid ring structure Amphipathic molecule Metabolic precursor of steroid hormones in mammals Voet, Voet, & Pratt 2013 Figure 9.10 Horton et al 2012 Fig 9.2

19. 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 r x 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

20. Vitamin D Structure/Conversions Vitamin D involved in Ca 2+ metabolism (promotes intestinal absorption). Deficiency gives rise to ricketts Sterol-derived hormone Precursor converted by UV light Voet, Voet, & Pratt 2013 p. 251

21. 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

22. 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

23. Vitamins K & E Structures Voet, Voet, & Pratt 2013 p. 253

24. Eicosanoids Prostaglandins 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 C 20 compounds Voet, Voet, & Pratt 2013 Fig. 9.12

25. Eicosanoid Classes Prostaglandins ► 5-C ring from arachidonic acid. Two groups originally defined PGE (ether soluble) and PGF each containing numerous subtypes, e.g. PGE 1, PGE 2. 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 A 4 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. reso

26. Roles of Selected Eicosanoids Prostaglandin E 2 - can cause constriction of blood vessels Thromboxane A 2 - involved in blood clot formation Leukotriene D 4 - mediator of smooth-muscle contraction and bronchial constriction seen in asthmatics

27. 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.

28. 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.

29. Phosphatidylinositols in Cellular Regulation Lehninger 2005 Figure 10.17; Voet et al, 2008 Figure 13.24 (IP 3 ) Signaling steps: Initial removal of a phospholipid headgroup by phospholipase C Produces IP 3 (soluble) & DAG (membrane) IP 3 triggers Ca 2+ from ER Higher [DAG] & [Ca 2+ ] cytosol activate protein kinase C (PKC) PKC phosphorylates specific target protein Protein activity modified; metabolism modified (DAG) (PKC) (PIP 2 ) PI

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