Chapter 26: Lipids. Hydrophobic (non-polar, soluble in organic solvent), typically of low molecular compound or organic origin

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1 hapter 26: Lipids. ydrophobic (non-polar, soluble in organic solvent), typically of low molecular compound or organic origin fatty acids and waxes essential oils many vitamins hormones (non-peptide) components of cell membranes (non-peptide) Share a common biosynthesis that ultimately derives their carbon source from glucose (glycolysis) Glucose pyruvate lactate : Acetyl oenzyme A. AcSoA is a thioester. R=, oas R= acetyl, AcSoA R S P P P Pyruvate dehydrogenase: Multi-enzyme complex that converts pyruvate to AcSoA. 2 2 oas 2 P P 2 pyruvate AD thiamin diphosphate (vitamin B 1 ) Lipoic Acid Flavin adenine diphosphate (VitaminB 2 ) S-oA 2 P P 2 2 AcSoA AD

2 Acetyl oa is a thioester. Thioesters are more reactive toward nucleophilic acyl substitution than esters, but considerably less reactive than acid chlorides and anhydrides. S-oA u- u oas S-oA ( 3 ) 3 choline choline acetyltransferase Thioester enolize more readily than esters. The enol can react with electrophile to afford α-substitution products acetylcholine ( 3 ) 3 oas S-oA S-oA E E S-oA acetyl-oa carboxylase S-oA 3 biotin, ATP S-oA Malonyl oa : Fats, ils, and Fatty Acids. Fatty acids: refers to long, straight-chain saturated and unsaturated acids, typically from (Table 26.1, p. 1069). saturated fatty acids: 3 ( 2 ) n 2 n=10, lauric acid ( 12 ) n=12, myristic acid ( 14 ) n=14, palmitic acid ( 16 ) n=16, steric acid ( 18 ) unsaturated fatty acid 2 18, oleic acid 3 polyunsaturated fatty acids (PUFA) , linolenic acid (18:3) 18, linoleic acid (18:4) 20, arachidonic acid (20:4)

3 Fats and ils: Triglycerides (triaceylglycerols) are tri-esters of glycerol (1,2,3-trihydroxypropane) and fatty acids. glycerol fatty acids R 1 R 2 R 3 The R groups can be saturated or unsaturated, the same or different 2 2 R 1 R 2 R 3 when some of the R groups are unsaturated 2, catalyst 2 2 R 1 R 2 R 3 Partially hydrogenated: some cis double bond are isomerized to trans double bonds 2, catalyst 2 2 R 1 R 2 R 3 ydrogenated- only saturated fatty acids 284 Soaps: sodium & potassium salts of fatty acid produced from the saponification (base hydrolysis) of animal fats (glycerides) 2 2 R n R n R n a 3 R n a 2 2 Soaps have a hydrophilic, polar head group (carboxylate salt) and a hydrophobic, non-polar tail. Fatty acid amides (FAA): Anandamide an ethanolamine amide of arachidonic Acid ( 20 ) tetrahydrocannabinol

4 26.3: Fatty Acid Biosynthesis. Fatty acid biosynthesis is performed by a cluster of discrete enzymes in bacteria, and a very large multi-protein assembly in animals (fatty acid synthase, FAS). The fatty acid is attached to an acyl carrier protein (AP), while other proteins perform an iterative two-carbon chain extension reaction that will yield the fatty acid. 2 S P P R S R AcS-oA P ysteine of Ketosynthase (KS) oa-s R S R AcS-KS 286 FAS chain extension reaction: Ketosynthase (KR) S-oA Malonyl oa S Phosphopantetheine P Serine of AP oa-s - 2 KS-S KS-S

5 Ketoreductase: ADP (nicotinamide adenine diphosphate phosphate) is a nucleophilic hydride ( ) donor (reducing agent) 2 P P P ADP = Ketoreductase ADP Dehydratase (D): Dehydratase - 2 Enoyl Reductase (ER) ADP Enoyl Reductase 288 Iterative two-carbon chain extension KS-S (ysteine of Ketosynthase) S-KS AP-S S-oA Malonyl oa AP-S oa-s S-KS KS - 2 KR ADP D - 2 ER ADP KS S-KS KS - 2 KR ADP D - 2 ER ADP KS S-KS

6 Thioesterase TE 2 18 Fatty acid (steric acid) S-oA R R oa-s 26.4 Phospholipids. 2 2 R 1 SoA -2 2 P 3 2 P -2 3 R 2 SoA L-glycerol-3- phosphate R 2 R 2 2 R 1 2 P -2 3 phosphatidic acid R 3 2 R 1 2 P R 3 phosphoglycerodes 2 - P 4-3 R 2 R Diacylglycerol 2 R 1 R 3 SoA 2 R 1 R 3 Triacylglycerol 290 Glycerophospholipids are important components of cell membranes. onpolar tails aggregate in the center of a bilayer ionic head is exposed to solvent ell membranes are ~5 nm thick unsaturatedr 2 2 P R saturated 2 2 ( 3 ) 3 Phosphatidylcholine (lechtins) 26.6: Waxes. esters of long chain fatty acids ( ) with long chain alcohols ( ) 3 ( 2 ) n 2 ( 2 ) n

7 26.6: Prostaglandins. (eicosanoids) 20 compounds derived from arachidonic acid and related fatty acids hormone: (Greek, horman, to set in motion) chemical messengers from one cell to another, that acts as a signal for a biochemical event. phospholipid 2 Arachidonic acid Prostaglandin F 2! (PGF 2! ) 2 prostaglandin endoperoxide reductase prostaglandin endoperoxide D isomerase prostaglandin (PG) synthase, 2 2 Prostaglandin 2 (PG 2 ) 2 prostacyclin (PGI) synthase prostaglandin endoperoxide E isomerase 2 Prostaglandin I 2 (Prostacyclin) 2 2 Prostaglandin D 2 (PGE 2 ) Prostaglandin E 2 (PGE 2 ) 292 Prostaglandin biosynthesis 2 prostaglandin synthase 2 2 Arachidonic acid cyclooxygenase (X-1 or X-2) PGG 2 PG 2 X-2 cell membrane Tyr-385 Ser acetylsalicylic acid Ser-530 X covalently modified enzyme

8 X-1 is a constitutive enzyme that is expressed in virtually all mammalian cells X-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. SAIDs: non-steroidal anti-inflammatory drugs Aspirin, ibuprofren, and naproxen are non-selective inhibitors of X Ac 3 elebrex, vioxx, and brextra are selective inhibitors of X-2 (coxibs) S 2 S 2 S 2 F Thromboxanes: named for their role in thrombosis, the formation of a clot inside a blood vessel PG 2 thromboxane synthase Thromboxane A 2 Thromboxane B 2 Leukotrienes 2 Lipoxygenase 2 eme, Aracidonic acid Leukotriene A S 2 2 Leukotriene D

9 26.7: Terpenes: The Isoprene Rule. Isoprenoids- 10 (terpenes), 15 (sesquiterpenes) and 20 (diterpenes) plant; essential oils Ruzicka isoprene rule: terpenoids are derived from isoprene units ( 5 ) isoprene (2-methyl-1,3-butadiene) ()-arvone (caraway seeds) (-)-arvone (spearmint) ()-limonene (oranges) (-)-limonene (lemons) itral (lempon grass) amphour patchouli alcohol (patchouli oil)!-pinene "-pinene Grandisol 296 The precursor to 10 terpenoids (monoterpenes) is geraniol diphosphate (diphosphate), which consists of two 5 isoprene units that are joined head-to-tail head tail PP = P PP head - tail head - tail P 15 sesquiterpenoids are derived from farnesyl diphosphate, which consists of three 5 isoprene units that are joined head-to-tail 20 diterpenoids are derived from geranylgeranyl diphosphate, which consists of four 5 isoprene units that are joined head-to-tail PP PP

10 25 sesterpenoids are derived from geranylfarnesyl diphosphate, which consists of five 5 isoprene units that are joined head-to-tail 30 triterpenoids and steroids are derived from squalene, which consists of two 15 farnesyl units that are joined tail-to-tail PP 40 tetraterpenoids are derived from phytocene, which consists of two 20 geranylgeranyl units that are joined tail-to-tail cedrane Taxol Lanosterol !-carotene

11 26.8: Isopentyl Diphosphate: The Biological Isoprene Unit. Mevalonic acid is the biosynthetic precursor to the actual 5 isoprene units, which are isopentyl diphosphate (IPP, tail) and dimethylallyl diphosphate (DMAPP, head) 26.10: The Pathway from Acetate to Isopentenyl Diphosphate. Mevalonate Pathway B: 2 SoA acetyl oa acetoacetyl-oa acetyltransferase 2 SoA laisen condensation SoA Enzyme-ys-S 3 SoA 3 S-ys-Enzyme acetyl oa acetoacetyl oa B: 2 SoA acetyl oa MG-oA synthase B 2 SoA aldol condensation 3 2 SoA 3-ydroxy-3-methylglutaric acid (MG-oA) MG-oA reductase 2 ADP 3 2 Mevalonic acid SoA acetoacetyl oa 300 onversion of mevalonic acid to IPP and DMAPP ATP 3 2 Mevalonic acid AMP 3 P - P - - ATP ADP 3 P 3 2- P - P P 4 3- B: 3 P - P - - B: P - P - - rearrangment P - P - - isopentenyl-pp (IPP) dimethylallyl-pp (DMAPP) 26.9: arbon-arbon Bond Formation in Terpene Biosynthesis. onversion of IPP and DMAPP to geraniol-pp and farnesyl-pp electrophilic head group DMAPP PP - PP Mg 2 PP B: IPP PP nucleophilic tail group PP geranyl pyrophosphate ( 10 ) - PP Mg 2 PP PP electrophilic head group PP B: nucleophilic tail group farnesyl pyrophosphate ( 15 )

12 PP PP squalene synthase onversion of genanyl-pp to monoterpenes Limonene & α-terpineol PP PP PP - geranyl diphosphate neryl diphosphate = bond acts as a nucleophile 2 :B limonene α-terpineol : Steroids D A 8 B holesterol biosynthesis (mechanism 26.3, p. 1089) part a: the cyclization Squalene epoxidase eme, 2 holesterol ( ) Squalene ( ) A Squalene xide ( ) Squalene cyclase Protosterol cation

13 holesterol biosynthesis, part b: the 1,2-shifts Protosterol cation ( ) 1,2-hydride shift ,2-hydride shift ,2-methyl shift ,2-methyl shift B: Lanosterol ( ) Lanosterol ( ) holesterol ( ) : Vitamin D. (please read) sunlight 7-Dehydrocholesterol Vitamin D : Bile Acids. (please read) 26.14: orticosteroids. (please read) ortisone

14 26.15: Sex hormones. (please read) androgens (male) Testosterone Androsterone Androstenedione dianabol estrogens (female) Estrone Estradiol Progesterone Ethynylestradiol 26.16: arotenoids. (please read) derived from phytocene ( 40 ) Lycopene!-carotene