lecture 9 - fatty acid metabolism...fatty acid are synthesized and degraded by different pathways....
TRANSCRIPT
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Chem 454: Regulatory Mechanisms in BiochemistryUniversity of Wisconsin-Eau Claire
Lecture 9 - Fatty Acid Metabolism
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TextFatty acids play several important roles:
Building blocks for phopsholipids and glycolipids
Target proteins to membranes
High energy source of fuel
Fatty acid derivatives are used as hormones and intracellular messengers
Introduction
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TextOverview of fatty acid synthesis
Introduction
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TextTriglycerides are a highly concentrated store of energy
9 kcal/g vs 4 kcal/g for glycogenGlycogen is also highly hydrated, 2 g H2O/g glycogen
1. Triglycerides
CO
O CH2
CH
CH2O
OCO
CO
Triacylglycerol
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TextDietary triacylglycerols must be broken down before being absorbed by the intestines.Bile salts, which act as detergents, are used to solublize the triacylglycerols
1.1 Pancreatic Lipases
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TextDietary triacylglycerols must be broken down before being absorbed by the intestines.Bile salts, which act as detergents, are used to solublize the triacylglycerols
1.1 Pancreatic Lipases
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TextPancreatic lipases hydrolyze the ester bonds of the triacylglycerols while in the micelles.
1.1 Pancreatic Lipases
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TextIn the intestinal mucosal cells, the fatty acids and monoacylglycerides are resynthesized into triacylglycerides and packaged into chylomicrons.
1.1 Chylomicrons
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TextThree stages of processing
Triglycerols are degraded to fatty acids and glycerol in the adipose tissue and transported to other tissues.
Fatty acids are activated and transported into the mitochondria.
Fatty acids are broken down into two-carbon acetyl–CoA units and fed into the citric acid cycle.
2. Utilization of Fatty Acids as Fuel
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TextIn the adipose tissue, lipases are activated by hormone signaled phosphorylation
2.1 Breakdown of Triacylglycerols
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TextThe lipases break the triacylglycerols down to fatty acids and glycerol
The fatty acids are transportred in the blood by serum albumin
2.1 Breakdown of Triacylglycerols
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TextThe glycerol is absorbed by the liver and converted to glycolytic intermediates.
2.1 Breakdown of Triacylglycerols
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TextAcyl CoA synthetase reaction occurs in the on the mitochondrial membrane.
2.2 Activation of Fatty Acids
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TextCarnitine carries long-chain activated fatty acids into the mitochondrial matrix
2.3 Transport into Mitochonrial Matrix
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TextCarnitine carries long-chain activated fatty acids into the mitochondrial matrix
2.3 Transport into Mitochonrial Matrix
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TextEach round in fatty acid degradation involves four reactions
1. oxidation totrans-∆2-Enoly-CoA
2.4 Fatty acid oxidation
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TextEach round in fatty acid degradation involves four reactions
2. Hydration to L–3–Hydroxylacyl CoA
2.4 Fatty acid oxidation
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TextEach round in fatty acid degradation involves four reactions
3. Oxidation to3–Ketoacyl CoA
2.4 Fatty acid oxidation
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TextEach round in fatty acid degradation involves four reactions
4. Thiolysis to produce Acetyl–CoA
2.4 Fatty acid oxidation
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TextEach round in fatty acid degradation involves four reactions
The process repeats itself
2.4 Fatty acid oxidation
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TextEach round in fatty acid degradation involves four reactions
2.4 Fatty acid oxidation
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TextThe complete oxidation of the sixteen carbon palmitoyl–CoA produces 106 ATP's
2.5 ATP Yield
Palmitoyl-CoA + 7 FAD + 7 NAD+ 7 CoASH + H2O
8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+
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TextUnsaturated fatty acids (monounsaturated)
3.1 Special Cases
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TextUnsaturated fatty acids (polyunsaturated)
3.1 Special Cases
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3.2 Odd-Chain (skip)
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3.3 Propionyl-CoA (skip)
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3.4 Peroxisomes (skip)
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3.5 Ketone Bodies
Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate.
During starvation or diabetes, OAA is used to make glucose
Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate)
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3.5 Ketone Bodies
Ketone bodies, acetoacetate and 3–hydroxybutarate are formed from Acetyl–CoA
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TextThe liver is the major source of ketone bodies.
It is transported in the blood to other tissues
Acetoacetate in the tissues
Acetoacetate is first activated to acetoacetate by transferring the CoASH from succinyl–CoA.
It is then split into two Acetyl–CoA by a thiolase reaction
3.6 Ketone Bodies as a Fuel Source
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TextEven though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose, Acetyl–CoA cannot be used to synthesize oxaloacetate.
The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO2.
3.7 Fatty Acids Cannot be Used to Synthesize Glucose
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TextFatty acid are synthesized and degraded by different pathways.
Synthesis takes place in the cytosol.Intermediates are attached to the acyl carrier protein (ACP).In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide.The activated donor in the synthesis is malonyl–ACP.Fatty acid reduction uses NADPH + H+.Elongation stops at C16 (palmitic acid)
4. Fatty Acid Synthesis.
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TextFormation of malonyl–CoA is the committed step in fatty acid synthesis.
4.1 Formation of Malonyl Coenzyme A
+ HCO3- + ATPCH3 C
OS CoA CH2 C
OS CoAC
OO + ADP + Pi + H+
Acetyl-CoA Malonyl-CoAAcetyl-CoACarboxylase
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TextThe intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)
4.2 Acyl Carrier Protein
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TextIn bacteria the enzymes that are involved in elongation are separate proteins; in higher organisms the activities all reside on the same polypeptide.
To start an elongation cycle, Acetyl–CoA and Malonyl–CoA are each transferred to an acyl carrier protein
4.3 Elongation
Acetyl-CoA + ACP Acetyl-ACP + CoA
Malonyl-CoA + ACP Malonyl-ACP + CoA
Acetyltransacylase
Malonyltransacylase
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TextAcyl-malonyl ACP condensing enzyme forms Acetoacetyl-ACP.
4.3 Elongation
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TextThe next three reactions are similar to the reverse of fatty acid degradation, except
The NADPH is used instead of NADH and FADH2
The D–enantiomer of Hydroxybutarate is formed instead of the L–enantiomer
4.3 Elongation
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TextThe elongation cycle is repeated six more times, using malonyl–CoA each time, to produce palmityl–ACP.
A thioesterase then cleaves the palmityl–CoA from the ACP.
4.3 Elongation
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TextDomain 1
Substrate entry (AT & MT) and condensation unit (CE)
Domain 2Reduction unit (DH, ER & KR)
Domain 3Palmitate release unit (TE)
4.4 Multifunctional Fatty Acid Synthase
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4.4 Multifunctional Fatty Acid Synthase
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4.5 Fatty Acid Synthase Mechanism
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TextCondensation of Acyl–CoA with Malonyl–CoA:
4.5 Fatty Acid Synthase Mechanism
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TextReduction of the acetoacetate unit:
4.5 Fatty Acid Synthase Mechanism
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TextTranslocation to the condensing enzyme
4.5 Fatty Acid Synthase Mechanism
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TextTransfer of Malonyl group to the other ACP:
4.5 Fatty Acid Synthase Mechanism
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TextThe stoichiometry of palmitate synthesis:
Synythesis of palmitate from Malonyl–CoA
Synthesis of Malonyl–CoA from Acetyl–CoA
Overall synthesis
4.6 Stoichiometry of FA synthesis
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 20 H+
palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O
7 Acetyl-CoA + 7 CO2 + 7 ATP7 Malonyl-CoA + 7 ADP + 7 Pi + 14 H+
Acetyl-CoA + 7 ATP + 14 NADPH + 6 H+
palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi
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TextAcetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol
Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate:
4.7 Citrate Shuttle
Citrate + ATP + CoA + H2O Acetyl-CoA + ADP + Pi + OxaloacetateCitrateLyase
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TextThe malate dehydrogenase and NADP+–linked malate enzyme reactions of the citrate shuttle exchange NADH for NADPH
4.8 Sources of NADPH
Oxaloacetate + NADH + H+Malate
DehydrogenaseMalate + NAD+
Malate + NADP+NADP+-linked
MalateEnzyme
Pyruvate + CO2 NADPH
Pyruvate + CO2 + ATP + H2O PyruvateCarboxylase
Oxaloacetate + ADP + Pi + 2 H+
NADP+ + NADH + ATP + H2O NADPH + NAD+ + ADP + Pi + H+
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4.9 Fatty Acid Synthase Inhibitors (skip)
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4.10 Variations on a Theme (skip)
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TextRegulation of Acetyl carboxylase
Global+ insulin- glucagon- epinephrine
Local+ Citrate- Palmitoyl–CoA- AMP
5. Regulation of Fatty Acid Synthesis
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5.1 Regulation of Fatty Acid Synthesis
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TextEndoplasmic reticulum systmes introduce double bonds into long chain acyl–CoA's
Reaction combines both NADH and the acyl–CoA's to reduce O2 to H2O.
6. Elongation and Unsaturation
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TextElongation and unsaturation convert palmitoyl–CoA to other fatty acids.
Reactions occur on the cytosolic face of the endoplasmic reticulum.Malonyl–CoA is the donor in elongation reactions
6.1 Elongation and Unsaturation
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TextEicosanoid horomones are synthesized from arachadonic acid (20:4).
Prostaglandins20-carbon fatty acid containing 5-carbon ringProstacyclinsThromboxanes
Leukotrienescontain three conjugated double bonds
6.2 Eicosanoid Hormones
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6.2 Eicosanoid Hormones
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6.2 Eicosanoid Hormones
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6.2 Eicosanoid Hormones