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Section 7. Lipid Metabolism Fats: fatty acid biosynthesis 11/04/05 Oxidation of Fatty Acids Other Than Palmitate O CH2 CH CH CH CH CH CH CH CH CH2 C – O CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 Arachidonate (eicosatetraenoate) 20:4 all cis-5,8,11,14 • Any even number of saturated carbons does not require any additional enzymes. Products are as for palmitate. • An odd number of saturated carbons does not require any additional enzymes. Same products plus one propionyl CoA. • Unsaturated fatty acids require additional enzymes. Same products, but less energy, compared to O saturated fatty acid the same length. CH3 CH2 C SCoA • See table 12.1 for a list of common propionyl CoA fatty acids. 1 Double Bonds in Odd-Numbered Positions • As acetyl CoA’s are removed from an unsaturated fatty acid, double bonds move into or near the active sites of the oxidation cycle enzymes. • An odd-numbered double bond moves into the 3-position, which is not a substrate for the principal enzymes of the cycle. • An isomerase moves it to the 2position. • Moving the double bond is energy neutral, but one less FADH2 is made because one acyl CoA dehydrogenase step is 2 “skipped.” 16:1 cis-9 (p 610) Double Bonds in Even- Numbered Positions. • An even-numbered double bond moves to the 4-position. • Acyl CoA dehydrogenase oxidizes it producing FADH2 and the nonsubstrate dienoyl CoA. • The additional enzyme 2,4-dienoyl CoA reductase uses NADPH to produce a position double bond. • The additional enzyme cis 3-enoyl CoA isomerase (see above) moves the double bond from the 3- to the 2-position. • NADH is produced after hydration, and then acetyl CoA, as usual (not shown). • The net effect for the cycle is the equivalent of one less NADH. 3 O R CH CH CH2 CH2 C S CoA acyl CoA 4 FAD FADH2 acyl CoA dehydrogenase O R CH CH CH CH C S CoA 2,4-dienoyl CoA NADPH + H+ NADP+ 2,4-dienoyl CoA reductase O R CH2 CH CH CH2 C S CoA cis -enoyl CoA cis 3-enoyl CoA isomerase R CH2 CH2 CH O CH C S CoA Fig. 22.10 modified + 3 acetyl CoA + 3 FADH2 + 3 NADH Example: Linoleoyl CoA C18:2 cis-9,cis-12 + acetyl CoA + NADH (no FADH2) 4 Ketone Bodies CoA • O C 2 CH3 C S CoA acetyl CoA CH2 acetyl CoA + H2O CoA CH3 C O C O – 3-hydroxy-3-methyl glutaryl CoA acetyl CoA CH3 HO O CH NAD+ H+ + NADH CH3 O C CH2 C C – O O O CH3 C CH2 3-D-hydroxybutyrate 5 HO CH2 acetoacetyl CoA See fig. 22.19 • • CH2 CH3 The liver normally converts acetyl CoA to ketone bodies that are used by peripheral tissues. • CoA C S C S CoA O • O O O– CH3 + CO2 acetone acetoacetate Production is enhanced by low carbohydrate (diabetes, starvation) and/or low O2 (hypoventilation) General anesthesia: CO2 up, pH down, ketone bodies up. Volatile acetone formation is non-enzymatic. Acetoacetate Utilization • In peripheral tissues, the ketone body acetoacetate is activated, and converted back to acetyl CoA. • 3-hydroxybutyrate and acetoacetate are favored over glucose by the renal cortex and cardiac muscle. 6 Fig. 22.20 Summary of Fatty Acid Biosynthesis • When the cell energy level is high, rather than being used by the Krebs cycle, acetyl CoA is transferred from the mitochondrial matrix to the cytosol. • In the cytosol, acetyl CoA is converted to malonyl CoA, which is used by fatty acyl synthase (FAS) for the synthesis of palmitate. • Palmitate is transported to adipose tissue and used to synthesize triacylglycerol. • The palmitate synthetic reactions are reversals of the degradative reactions, but the enzymes, cofactors and locations are different. 7 Reactions on the right are catalyzed by FAS in the cytosol. Fig. 22.2 8 Compare degradation and synthesis structures. Citrate Shuttle Transfers Acetyls to Cytosol ATP + CO2 Fig. 22.25 9 +CO2 • High [ATP] inhibits the Krebs cycle; [citrate] increases. • Citrate translocase enables citrate and pyruvate to cross the mitochondrial inner membrane. CoA does not cross (remember acyl CoA / acyl carnitine). • NADPH is made at the expense of NADH in the cytosol. Activation by Acetyl CoA Carboxylase O – + ATP + HCO CH3 C S CoA 3 acetyl CoA O – C O O CH2 C S CoA + ADP + Pi malonyl CoA (p 617) • In the cytosol, acetyl CoA is carboxylated to make the activated precursor, malonyl CoA. • This is the committed step in fatty acid biosynthesis. • ATP provides energy. • Biotin is a cofactor. • Two sequential reactions occur in the active site. (p 618) biotin-Enz + ATP + HCO3- CO2~biotin-Enz + ADP + Pi CO2~biotin-Enz + acetyl CoA malonyl CoA + biotin-Enz 10 • ATP reacts first providing energy to bind and activate HCO3-. • Next acetyl CoA binds and the activated CO2- is transferred to the acetyl group. Biotin: a CO2 Carrier Figs. 24-10 and 24-11 (Stryer 4th) 11 Fatty Acid Synthase Reactions CE (KR) CE + Fig. 22.22 Condensation forms 4 carbon unit on acyl carrier protein (ACP). Reduction of ketone to hydroxyl by NADPH. 12 Fatty Acid Synthase Reactions, con’t (DH) (ER) Fig. 22.22 13 • Dehydration produces a double bond. • Reduction to a saturated 4 carbon fatty acid chain. FAS is a Dimer Fig. 22.23 14 • Malonyl transfer (MT), acetyl transfer (ATP and condensation (CE) on one subunit. • Reduction (KR), dehydration (DH), reduction (ER) and thiolysis (TE) on the other subunit. • The growing FA chain is passed between subunits by ACP. Acyl carrier protein (ACP) Fig. 22.21 • ACP has a long flexible chain, derived from pantothenic acid, to which the growing fatty acid is attached. 15 Condensation Fig. 22.24 16 • Both subunits of FAS are involved. • Condensation is catalyzed by CE on upper subunit. Reduction Fig. 22.24 17 • 2 NADPH are used. • Reduction (reduction, dehydration, reduction see slides 12 &13) occur on lower subunit of the dimer. Translocation and binding of a new malonyl CoA Fig. 22.24 18 < The 4 carbon chain is transferred to CE. ^ A new malonyl CoA binds ACP on other subunit. • The cycle (condendation, reduction, dehydration, reduction) repeats until 16 carbon palmitate is formed (not shown). • Palmitate is released by TE (see slide 14). Net Reaction for Palmitate Synthesis 8 acetyl CoA + 7 ATP + 14 NADPH + 6 H+ palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7Pi (p 622) For this reaction, there are 7 (for 7 ATP) + 35 (for 14 NADPH) = 42 ~P equivalents used. Compare to 26 obtained from the palmitate conversion to acetyl CoA by fatty acyl CoA synthetase and the -oxidation cycle. 19 Control of Fatty Acid Synthesis is at the Committed Step 20 • Fig. 24-18 Styer 4th Control of Acetyl CoA Carboxylase Activity Fig. 22.26 • Phosphorylation by kinase inhibits carboxylase (+AMP, -ATP). • Phosphatase activates carboxylase (+insulin, -glucagon, & epinephrine). • Citrate partially activates the inactive phosphorylated acetyl Co A carboxylase allosterically. • Palmitoyl CoA inhibits carboxylase and citrate translocase. 21 Web links Odd Chain Fatty Acids. The fate of propionyl CoA. Unsaturated Fatty Acid Oxidation. The role of isomerase. Next Topic: Membrane lipids.