Lipids Fatty Acids Metaboilsm Asist prof Dr Alaa

Lipids &Fatty Acids Metaboilsm Asist prof. Dr. Alaa Kamal Jabbar Alhamd M Sc. & Ph. D. In Clinical Biochemistry Ph D. Course-Biology Department of Chemistry College of Sciences University of Almustansirya 2017 -2018 1 . 1. . Lehninger Principle of Biochemistry , David Nelson , 4 th Edition (2008). 2. Biochemistry , Lubbert Steryer, 6 th edition (2006). 3. Harpers Illustrated Biochemistry , Robbert Murray, 26 th edition (2003). 4. The Chemical basis of Life , George Schimd , 2 th edition (1985).

Lipid Metabolism Fatty Acid Metabolism

Introduction ØFatty acids play several important roles: ØBuilding blocks for phospholipids and glycolipids ØTarget proteins to membranes ØHigh energy source of fuel ØFatty acid derivatives are used as hormones and intracellular messengers 3

Introduction Ø Overview of fatty acid synthesis 4

Triglycerides ØTriglycerides are a highly concentrated store of energy Ø 9 kcal/g vs 4 kcal/g for glycogen ØGlycogen is also highly hydrated, 2 g H 2 O/g glycogen 5

Pancreatic Lipases ØDietary triacylglycerols must be broken down before being absorbed by the intestines. ØBile salts, which act as detergents, are used to solublize the triacylglycerols 6

Utilization of Fatty Acids as Fuel ØThree stages of processing ØTriglycerols are degraded to fatty acids and glycerol in the adipose tissue and transported to other tissues. ØFatty acids are activated and transported into the mitochondria. ØFatty acids are broken down into two-carbon acetyl– Co. A units and fed into the citric acid cycle. 7

Degrdation of Triacylglycerols �In the adipose tissue, lipases are activated by hormone signaled phosphorylation 8

ØThe lipases break the triacylglycerols down to fatty acids and glycerol ØThe fatty acids are transportred in the blood by serum albumin 9

ØThe glycerol is absorbed by the liver and converted to glycolytic intermediates. 10

Activation of Fatty Acids Ø Acyl Co. A synthetase reaction occurs in the on the mitochondrial membrane 11

Transport into Mitochondrial Matrix ØCantina carries longchain activated fatty acids into the mitochondrial matrix

Transport into Mitochondrial Matrix ØCarnitine carries long-chain activated fatty acids into the mitochondrial matrix 13

Fatty acid oxidation ØEach round in fatty acid degradation involves four reactions Ø 1. oxidation to trans-∆2 -Enoly-Co. A 14

Fatty acid oxidation Ø Each round in fatty acid degradation involves four reactions Ø 2. Hydration to L– 3– Hydroxylacyl Co. A 15

ØEach round in fatty acid degradation involves four reactions Ø 3. Oxidation to 3–Ketoacyl Co. A 16

ØEach round in fatty acid degradation involves four reactions Ø 4. Thiolysis to produce Acetyl–Co. A 17

ØEach round in fatty acid degradation involves four reactions ØThe process repeats itself 18

ØEach round in fatty acid degradation involves four reactions 19

ATP Yield ØThe complete oxidation of the sixteen carbon palmitoyl– Co. A produces 106 ATP's 20

Special Cases ØUnsaturated fatty acids (monounsaturated) 21

ØUnsaturated fatty acids (polyunsaturated) 22

Odd-Chain 23

Ketone Bodies ØUse of fatty acids in the citric acid cycle requires carbohydrates for the production of oxaloacetate. ØDuring starvation or diabetes, OAA is used to make glucose ØFatty acids are then used to make ketone bodies (acetoacetate and D– 3–hydroxybutarate) 24

ØKetone bodies, acetoacetate and 3–hydroxybutarate are formed from Acetyl–Co. A. 25

Ketone Bodies as a Fuel Source ØThe liver is the major source of ketone bodies. ØIt is transported in the blood to other tissues ØAcetoacetate in the tissues ØAcetoacetate is first activated to acetoacetate by transferring the Co. ASH from succinyl–Co. A. ØIt is then split into two Acetyl–Co. A by a thiolase reaction 26

Fatty Acids Cannot be Used to Synthesize Glucose ØEven though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose, Acetyl– Co. A cannot be used to synthesize oxaloacetate. ØThe two carbons that enter the citric acid cycle as Acetyl–Co. A leave as CO 2. 27

Fatty Acid Synthesis ØFatty acid are synthesized and degraded by different pathways. ØSynthesis takes place in the cytosol. ØIntermediates are attached to the acyl carrier protein (ACP). ØIn higher organisms, the active sites for the synthesis reactions are all on the same polypeptide. ØThe activated donor in the synthesis is malonyl–ACP. ØFatty acid reduction uses NADPH + H+. ØElongation stops at C 16 (palmitic acid) 28

Formation of Malonyl Coenzyme A ØFormation of malonyl–Co. A is the committed step in fatty acid synthesis.

Acryl Carrier Protein The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)

Elongation ØIn bacteria the enzymes that are involved in elongation are separate proteins; in higher organisms the activities all reside on the same polypeptide. ØTo start an elongation cycle, Acetyl–Co. A and Malonyl– Co. A are each transferred to an acyl carrier protein 31

ØAcyl-malonyl ACP condensing enzyme forms Acetoacetyl-ACP. 32

ØThe next three reactions are similar to the reverse of fatty acid degradation, except ØThe NADPH is used instead of NADH and FADH 2 ØThe D–enantiomer of Hydroxybutarate is formed instead of the L–enantiomer 33

ØThe elongation cycle is repeated six more times, using malonyl–Co. A each time, to produce palmityl–ACP. ØA thioesterase then cleaves the palmityl–Co. A from the ACP. 34

Stoichiometry of FA synthesis ØThe stoichiometry of palmitate synthesis: Synythesis of palmitate from Malonyl–Co. A Synthesis of Malonyl–Co. A from Acetyl–Co. A Overall synthesis ØAcetyl–Co. A is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol ØAcetyl–Co. A units are shuttled out of the mitochondrial matrix as citrate:

Citrate Shuttle 36

Sources of NADPH ØThe malate dehydrogenase and NADP+–linked malate enzyme reactions of the citrate shuttle exchange NADH for NADPH

Regulation of Fatty Acid Synthesis ØRegulation of Acetyl carboxylase ØGlobal Ø+ insulin Ø- glucagon Ø- epinephrine ØLocal Ø+ Citrate Ø- Palmitoyl–Co. A Ø- AMP

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Elongation and Unsaturation ØEndoplasmic reticulum systems introduce double bonds into long chain acyl–Co. A's ØReaction combines both NADH and the acyl–Co. A's to reduce O 2 to H 2 O. ØElongation and unsaturation convert palmitoyl–Co. A to other fatty acids. ØReactions occur on the cytosolic face of the endoplasmic reticulum. ØMalonyl–Co. A is the donor in elongation reactions 40