Biosynthesis of Fatty Acids & Lipids

ANABOLISM II: Biosynthesis of Fatty Acids & Lipids ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Biosynthesis Fatty Acid Synthesis Isoprene Biosynthesis Fat Catabolism Fatty Acid Degradation Ketone body Utilization ANABOLISM II: Biosynthesis of Fatty Acids & Lipids 1. Biosynthesis of fatty acids 2. Regulation of fatty acid degradation and synthesis 3. Assembly of fatty acids into triacylglycerol and phospholipids 4. Metabolism of isoprenes a. Ketone bodies and Isoprene biosynthesis b. Isoprene polymerization i. Cholesterol ii. iii. Steroids & other molecules Regulation iv. Role of cholesterol in human disease Cholesterol and Steroid Biosynthesis In mitochondria Liver as a fuel source: Ketone Bodies & Glucose Cholesterol and Steroid Biosynthesis Fates of Acetyl CoA (HMG-CoA) Amino acid (L) • Nearly all the remaining lipids have a chemical relationship, and their biosynthesis are built on, the 5-carbon isoprene unit • Isoprene is made through the intermediate, mevalonate, which is derived from HMG-CoA Amino acids 1. Oxidation to CO2 2. Lipid metabolism 1.Fatty acids 2.Ketone bodies & cholesterol 3. Amino acid metabolism Konrad Bloch 1912-2000 Nobel Prize 1964 Cholesterol and Steroid Biosynthesis 5’ Cholesterol: what is it, and what does it do? Do we need to be afraid? Cholesterol and Steroid Biosynthesis IN THE CYTOSOL Formation of Mevalonate from HMG-CoA • HMG-CoA (from 3 acetyl-CoAs) is reduced to form mevalonate. • HMG-CoA reductase is a common target of cholesterol-lowering drugs; called Statins Cholesterol and Steroid Biosynthesis Mevalonate to Activated Isoprenes • Two phosphates are transferred stepwise from ATP to mevalonate. • A third phosphate from ATP is added at the hydroxyl, followed by decarboxylation and elimination catalyzed by pyrophosphomevalonate decarboxylase creates a pyrophosphorylated 5-C product: D3-isopentyl pyrophosphate (IPP) (isoprene) • Isomerization to a second isoprene dimethylallylpyrophosphate (DMAPP) gives two activated isoprene compounds that act as precursors for all of the other lipids in this class IPP D 3-isopentyl Isopentyl-D-pyrophosphate isomerase pyrophosphate DMAPP Cholesterol and Steroid Biosynthesis DMAPP Joining Isoprenes IPP H EAD H EAD TAIL TAIL • The two isoprenes join head to tail, displacing one set of diphosphates, forming 10-carbon geranyl pyrophosphate (GPP). geranyl-pyrophosphate synthase (I (DMAPP) Carotenoids Gibberellins Tocopherols Chlorophylls Geranyl-PP synthase Mechanism Geranyl-pyrophosphate synthase Resonance stabilized carbonium ion Farnesyl-PP synthase Ionization by elim ination of PP i Isopentyl pyrophosphate (IPP) Squalene synthase Geranyl pyrophosphate (GPP) H+ deprotonation Cholesterol and Steroid Biosynthesis Formation of Squalene • Geranyl pyrophosphate (GPP) joins to another isopentenyl pyrophosphate. à forms 15-C farnesyl pyrophosphate (tail-to-tail) • Two farnesyl pyrophosphates (FPP) join tail to tail to form phosphate-free squalene. Cholesterol and Steroid Biosynthesis Synthesis of Cholesterol Conversion of Squalene to Four-Ring Steroid Nucleus • Squalene monooxygenase (squalene epoxidase) adds one oxygen to the end of the squalene chain. (2,3-oxidosqualene) à forms squalene 2,3-epoxide à A mixed-function oxidase • Here, pathways diverge in animal cells versus plant cells. • In plants, the epoxide cyclizes to other sterols, such as stigmasterol. • In fungi, it forms ergosterol. lanosterol synthase ⑤ ② ④① ③ ⑥ ⑦ • The cyclization product in animals is lanosterol, which converts to cholesterol. 1) C14-demethylation (5 rxns) 2) C14-reduction 3) C4-demethylation (10 rxns) 4) C8à7 isomerization 5) C24-reduction 6) C5-desaturation 7) C7-reduction Cholesterol and Steroid Biosynthesis Fates of Cholesterol After Synthesis •In vertebrates, most cholesterol is synthesized in the liver, then exported. -They are exported as bile acids, biliary cholesterol, or cholesteryl esters. -Bile is stored in the gall bladder and secreted into the small intestine after fatty meal. -Bile acids such as taurocholic acid emulsify fats. –They surround droplets of fat, increasing surface area for attack by lipases. •Other tissues convert cholesterol into steroid hormones and Vitamin D Vitamin D pre-VitD 3 7-dehydro-Chol ( Oxysterols) From degradation of Cys Lecithin-Cholesterol Acyl TransferaseCatalyzed Reaction Occurs in HDL (LCAT) •Adrenal gland-synthesized steroids: – mineralcorticoids • control electrolyte balance, reabsorption of Na+, Cl−, HCO3− from kidney – glucocorticoids • regulate gluconeogenesis, reduce inflammation •Gonad-synthesized steroids: Oxysterols are involved in transcriptional control, signaling – progesterone, in development, apoptosis, inflammation, and sterol transport testosterone, estrogens Steroid Biosynthesis Steroid Hormones Derived from Cholesterol • Takes place in mitochondria • The “side chain” on C-17 of the D ring is modified, then cleaved. C-20 C-22 • Two adjacent carbons are hydroxylated. • Desmolase cleaves • All three use mixedfunction oxidases, NADPH and cytochrome P450 Steroid Biosynthesis Steroid Hormones Derived from Cholesterol • Takes place in mitochondria • The “side chain” on C-17 of the D ring is modified, then cleaved. ox=C3O & iso=C4/5 C-11 C-17 C-21 C-21 C-11 C-17 –acetateC-20/21 –C-19 aromatase C-20 C-22 C-18 ox-C18O • Two adjacent carbons are hydroxylated. • Desmolase cleaves • All three use mixedfunction oxidases, NADPH and cytochrome P450 Cholesterol and Steroid Biosynthesis TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties Composition (wt %) Lipoprotein Density (g/ml) Protein PL Free cholesterol Cholesteryl esters Triacylglycerols Chylomicrons <1.006 2 (ApoB-48,-E,-CII) 9 1 3 85 VLDL 0.95–1.006 10 (ApoC-I,CII) 18 7 12 50 LDL 1.006–1.063 23 (ApoB-100) 20 8 37 10 HDL 1.063–1.210 55 (ApoA-I,-II) 24 2 15 4 Source: Data from D. Kritchevsky, Nutr. Int. 2:290, 1986. • Lipids are carried through the plasma on spherical particles. –surface is made of protein (called apolipoprotein*) and a phospholipid monolayer –interior contains cholesterol, TAGs, and cholesteryl esters, which are more nonpolar than cholesterol • Named based on position of sedimentation (density) in centrifuge • Composition varies between class of lipoprotein • Includes four major classes shown in Table *“apolipoprotein” refers to the protein part of a lipoprotein particle. Cholesterol and Steroid Biosynthesis Biological Roles and Characteristics of Lipoproteins TABLE 21-2 Apolipoprotein Apolipoproteins of the Human Plasma Lipoproteins Polypeptide molecular weight Lipoprotein association Function (if known) ApoA-I 28,100 HDL Activates LCAT; interacts with ABC transporter ApoA-II 17,400 HDL Inhibits LCAT ApoA-IV 44,500 Chylomicrons, HDL Activates LCAT; cholesterol transport/clearance ApoB-48 242,000 Chylomicrons Cholesterol transport/clearance ApoB-100 Binds to LDL receptor 512,000 VLDL, LDL ApoC-I 7,000 VLDL, HDL ApoC-II 9,000 Chylomicrons, VLDL, HDL Activates lipoprotein lipase ApoC-III 9,000 Chylomicrons, VLDL, HDL Inhibits lipoprotein lipase ApoD 32,500 HDL ApoE 34,200 Chylomicrons, VLDL, HDL Triggers clearance of VLDL and chylomicron remnants ApoH 50,000 Possibly VLDL, binds cardiolipin Roles in coagulation, lipid metabolism, apoptosis, inflammation Source: Information from D. E. Vance and J. E. Vance (eds), Biochemistry of Lipids and Membranes, 5th edn, Elsevier Science Publishing, 2008. Cholesterol and Steroid Biosynthesis Biological Roles of Lipoproteins in Trafficking Cholesterol and TAGs Receptor-Mediated Endocytosis IN: Exogenous (diet) ❶–❹ Pathway HDL Pathway 10 – 13 OUT: Endogenous Pathway Enterohepatic Pathway ❺–❾ 14 Cholesterol and Steroid Biosynthesis