Wk10RG
Monday, March 11, 2019 11:43 PM
B-oxidation of Lipids
• B-oxidation: fatty acids are converted into acetyl-CoA in 4-step process.
• Dietary fats are absorbed in the small intestine. In response to fats ingested. Fig. 17-1, pg. 650
• In small intestine, bile salts turn fat into micelles of bile salts+triacylglyercol -> intestinal lipases degrade triacylglycerol -> degraded products diffu
intestinal surface, then reconvert into triacylglycerol and packaged w/ cholesterol/apolipoproteins into chylomicrons. -> while in the bloodstream,
lipase (activated by apoC-II) converts triacylglycerol into fatty acids/glycerol.
• In muscle, fatty acids are oxidized for energy.
Week 10 • In adipose, fatty acids are re-esterified (back to triacylglycerols) for storage.
• Hormones trigger mobilization of stored triacylglycerols. Only happens in response to glucose blood levels.
• Hormones signal -> Stored triacylglycerols are mobilized (brought out of storage) and transported to tissues in which fatty acids can be oxidized.
○ Condition: cell in need of metabolic energy, Location: adipose tissue -> muscle tissue
• Low [blood glucose], or flight/fight response -> signals Glucagon -> adenyl cyclase in adipocyte plasma membrane -> produces cAMP, triggers p
phosphorylation of hormone-sensitive lipases/perilipin (and of acetyl-CoA carboxylase)-> lipases degrade triacylglycerol into fatty acids and glyc
pg. 652
• Fatty acids leave lipid droplet and travel in the bloodstream (bound to serum albumin) -> enter myocyte (specific fatty acid transporter); are oxidiz
and ATP -> energy used for muscle contraction.
• Fatty acids are activated and transported into mitochondria.
• Carnitine shuttle: 3 enzymatic rxns that allow large fatty acids (+14 carbon-FFAs) to enter mitochondrial matrix.
○ Why: fatty acid oxidation, Where: rxns start in outer mitochondrial membrane.
○ (1) esterification of CoA to fatty acid-> fatty acyl-CoA, (2) trans-esterification to carnitine, followed by passive transport into matrix, and (3)
esterification back to CoA. Fig. 17-6, pg. 654
○ "Passive transport" is aided by carnitine acyltransferase 1 and inner-membrane integral transporter.
○ Carnitine acyltransferase is inhibited by malonyl-CoA. INC in malonyl-CoA -> fatty acids into the mitochondria, DEC in fatty acid oxidation.
• The B-oxidation of saturated fatty acids has 4 basic steps.
1. Dehydrogenation of fatty acyl-CoA -> trans-delta2-enoyl-CoA, 7 FADH2 -> 10.5 ATP
a. Catalyzed by acyl-CoA dehydrogenase. New double bond is trans, not cis.
b. Flavoproteins steal fatty acyl-CoA electrons, donating them to ETF -> FAD for respiratory chain.
2. Water added to trans-delta2-enoyl-CoA -> L isomer B/3-hydroxyacyl-CoA.
a. Catalyzed by enol-CoA hydratase.
b. H2O adds across the a-B double bond (why its called beta-oxidation).
3. Dehydrogenation of L-B-hydroxyacyl-CoA -> B-ketoacyl-CoA, 7 NADH, 17.5 ATP
a. Catalyzed by B-hydroxyacyl-CoA dehydrogenase.
b. NADH formed donates its e- to NADH dehydrogenase, e- carrier in respiratory chain.
4. Thiolysis: Splits off carboxyl terminal of B-ketoacyl-CoA w/ help of CoA-SH. -> acCoA+Acyl group!
a. Catalyzed by thiolase.
• QUESTION When (16C) palmitate is oxidized, an acetyl-residue is removed in the form of acetyl-CoA (requires 2Cs) from carboxyl end of chain
acetyl-CoA molecules are made after all of palmitate is oxidized?
○ 8 acetyl-CoA
• Purpose of B-oxidation: to destabilize and break stable methylene bonds in fatty acids. Helps begin fatty acid oxidation.
• B-oxidation steps are repeated to yield acetyl-CoA and ATP.
• Oxidation of unsaturated fatty acids requires 2 additional reactions (*).
• Unsaturated fatty acids have one or more double bonds in the cis configuration; cannot be acted upon by enol-CoA hydratase.
• For monounsaturated fatty acids: isomerase
○ Oleate -> Oleoyl-CoA. Carnitine shuttle into mitochondria. Oxidation x3 -> 3 acetyl-CoA and cis-delta3-dodecenoyl-CoA.
○ *Isomerization of cis-delta3-dodecenoyl-CoA -> trans-enoyl-CoA.
• Catalyzed by enoyl-CoA isomerase.
○ ** trans-enoyl-CoA -> trans-delta3-dodecenoyl-CoA (L-3-hydroxyacyl-CoA).
• Can NOW be catalyzed by enoyl-CoA hydratase.
○ Intermediate acted upon by remaining enzymes of B-oxidation.
• For polyunsaturated fatty acids: reductase
• Linoleoyl-CoA. Oxidation x3 -> 3 acetyl-CoA and cis-delta3, cis-delta6
○ Coenzyme A ester is in wrong configuration. Cannot be acted upon by B-oxidation enzymes.
○ 2,4-dienoyl-CoA reductase AND enoyl-CoA isomerase -> 6 acetyl-CoA.
○ Total: 9 acetyl-CoA molecules! Produces 1 more than saturated fatty acids, and more than quadruple during pyruvate oxidation.
• B-oxidation and TCA: first 3 steps are similar to last 3 steps of TCA (starting w/ succinate dehydrogenase).
• Complete oxidation of odd-number of fatty acids requires 3 extra reactions.
• Same pathway, however the substrate for the last pass of B-oxidation sequence is a 5C-fatty acid chain (instead of 4C). Once oxidized/cleaved,
acetyl-CoA + propionyl-CoA.
Acetyl group is transferred from the Cys SH- group of KS enzyme -> acetyl+aceto- ○ Propionyl-CoA -> D-methylmalonyl-CoA -> L-methylmalonyl-CoA -> Succinyl-CoA! Can enter TCA.
group attaches to the -SH of ACP • Fatty acid oxidation is tightly regulated.
• Transferring of fatty acyl groups from cytosol to mitochondrial matrix is important point of regulation!
Monday, March 11, 2019 11:43 PM
B-oxidation of Lipids
• B-oxidation: fatty acids are converted into acetyl-CoA in 4-step process.
• Dietary fats are absorbed in the small intestine. In response to fats ingested. Fig. 17-1, pg. 650
• In small intestine, bile salts turn fat into micelles of bile salts+triacylglyercol -> intestinal lipases degrade triacylglycerol -> degraded products diffu
intestinal surface, then reconvert into triacylglycerol and packaged w/ cholesterol/apolipoproteins into chylomicrons. -> while in the bloodstream,
lipase (activated by apoC-II) converts triacylglycerol into fatty acids/glycerol.
• In muscle, fatty acids are oxidized for energy.
Week 10 • In adipose, fatty acids are re-esterified (back to triacylglycerols) for storage.
• Hormones trigger mobilization of stored triacylglycerols. Only happens in response to glucose blood levels.
• Hormones signal -> Stored triacylglycerols are mobilized (brought out of storage) and transported to tissues in which fatty acids can be oxidized.
○ Condition: cell in need of metabolic energy, Location: adipose tissue -> muscle tissue
• Low [blood glucose], or flight/fight response -> signals Glucagon -> adenyl cyclase in adipocyte plasma membrane -> produces cAMP, triggers p
phosphorylation of hormone-sensitive lipases/perilipin (and of acetyl-CoA carboxylase)-> lipases degrade triacylglycerol into fatty acids and glyc
pg. 652
• Fatty acids leave lipid droplet and travel in the bloodstream (bound to serum albumin) -> enter myocyte (specific fatty acid transporter); are oxidiz
and ATP -> energy used for muscle contraction.
• Fatty acids are activated and transported into mitochondria.
• Carnitine shuttle: 3 enzymatic rxns that allow large fatty acids (+14 carbon-FFAs) to enter mitochondrial matrix.
○ Why: fatty acid oxidation, Where: rxns start in outer mitochondrial membrane.
○ (1) esterification of CoA to fatty acid-> fatty acyl-CoA, (2) trans-esterification to carnitine, followed by passive transport into matrix, and (3)
esterification back to CoA. Fig. 17-6, pg. 654
○ "Passive transport" is aided by carnitine acyltransferase 1 and inner-membrane integral transporter.
○ Carnitine acyltransferase is inhibited by malonyl-CoA. INC in malonyl-CoA -> fatty acids into the mitochondria, DEC in fatty acid oxidation.
• The B-oxidation of saturated fatty acids has 4 basic steps.
1. Dehydrogenation of fatty acyl-CoA -> trans-delta2-enoyl-CoA, 7 FADH2 -> 10.5 ATP
a. Catalyzed by acyl-CoA dehydrogenase. New double bond is trans, not cis.
b. Flavoproteins steal fatty acyl-CoA electrons, donating them to ETF -> FAD for respiratory chain.
2. Water added to trans-delta2-enoyl-CoA -> L isomer B/3-hydroxyacyl-CoA.
a. Catalyzed by enol-CoA hydratase.
b. H2O adds across the a-B double bond (why its called beta-oxidation).
3. Dehydrogenation of L-B-hydroxyacyl-CoA -> B-ketoacyl-CoA, 7 NADH, 17.5 ATP
a. Catalyzed by B-hydroxyacyl-CoA dehydrogenase.
b. NADH formed donates its e- to NADH dehydrogenase, e- carrier in respiratory chain.
4. Thiolysis: Splits off carboxyl terminal of B-ketoacyl-CoA w/ help of CoA-SH. -> acCoA+Acyl group!
a. Catalyzed by thiolase.
• QUESTION When (16C) palmitate is oxidized, an acetyl-residue is removed in the form of acetyl-CoA (requires 2Cs) from carboxyl end of chain
acetyl-CoA molecules are made after all of palmitate is oxidized?
○ 8 acetyl-CoA
• Purpose of B-oxidation: to destabilize and break stable methylene bonds in fatty acids. Helps begin fatty acid oxidation.
• B-oxidation steps are repeated to yield acetyl-CoA and ATP.
• Oxidation of unsaturated fatty acids requires 2 additional reactions (*).
• Unsaturated fatty acids have one or more double bonds in the cis configuration; cannot be acted upon by enol-CoA hydratase.
• For monounsaturated fatty acids: isomerase
○ Oleate -> Oleoyl-CoA. Carnitine shuttle into mitochondria. Oxidation x3 -> 3 acetyl-CoA and cis-delta3-dodecenoyl-CoA.
○ *Isomerization of cis-delta3-dodecenoyl-CoA -> trans-enoyl-CoA.
• Catalyzed by enoyl-CoA isomerase.
○ ** trans-enoyl-CoA -> trans-delta3-dodecenoyl-CoA (L-3-hydroxyacyl-CoA).
• Can NOW be catalyzed by enoyl-CoA hydratase.
○ Intermediate acted upon by remaining enzymes of B-oxidation.
• For polyunsaturated fatty acids: reductase
• Linoleoyl-CoA. Oxidation x3 -> 3 acetyl-CoA and cis-delta3, cis-delta6
○ Coenzyme A ester is in wrong configuration. Cannot be acted upon by B-oxidation enzymes.
○ 2,4-dienoyl-CoA reductase AND enoyl-CoA isomerase -> 6 acetyl-CoA.
○ Total: 9 acetyl-CoA molecules! Produces 1 more than saturated fatty acids, and more than quadruple during pyruvate oxidation.
• B-oxidation and TCA: first 3 steps are similar to last 3 steps of TCA (starting w/ succinate dehydrogenase).
• Complete oxidation of odd-number of fatty acids requires 3 extra reactions.
• Same pathway, however the substrate for the last pass of B-oxidation sequence is a 5C-fatty acid chain (instead of 4C). Once oxidized/cleaved,
acetyl-CoA + propionyl-CoA.
Acetyl group is transferred from the Cys SH- group of KS enzyme -> acetyl+aceto- ○ Propionyl-CoA -> D-methylmalonyl-CoA -> L-methylmalonyl-CoA -> Succinyl-CoA! Can enter TCA.
group attaches to the -SH of ACP • Fatty acid oxidation is tightly regulated.
• Transferring of fatty acyl groups from cytosol to mitochondrial matrix is important point of regulation!
