LIPID METABOLISM

Why Fatty Acids? (For energy storage?) Two reasons: The carbon in fatty acids (mostly CH2) is almost completely reduced (so its oxidation yields the most energy possible). Fatty acids are not hydrated (as mono- and polysaccharides are), so they can pack more closely in storage tissues

Naming of fatty acids C18    10 9 CH3-(CH2)7-CH=CH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH Cis 9 18:0, stearic acid : octadecanoic acid 18:1 (9), oleic acid : octadecenoic acid 18:2 (9,12), linoleic acid : octadecadienoic acid 18:3 (9,12,15), -linolenic acid : octadecatrienoic acid

LIPID Metabolism

The body fat is our major source of stored energy. Our adipose tissue is made of fat cells adipocytes. A typical 70 kg (150 lb) person has about 135,000 kcal of energy stored as fat, 24,000 kcal as protein, 720 kcal as glycogen reserves, and 80 kcal as blood glucose. The energy available from stored fats is about 85 % of the total energy available in the body.

Digestion of Triacylglycerols In the digestion of fats (triacylglycerols): Bile salts break fat globules into micelles in the small intestine. Pancreatic lipases hydrolyze ester bonds to form monoacylglycerols and fatty acids, which recombine in the intestinal lining. Lipoproteins form and transport triacylglycerols to the cells of the heart, muscle, and adipose tissues. Brain and red blood cells cannot utilize fatty acids, because fatty acids cannot diffuse across the blood-brain barrier, and red blood cells have no mitochondria, where fatty acids are oxidized. (Glucose and glycogen are the only source of energy for the brain and red blood cells.)

SOURCE OF FAT / fatty acids : Food Biosinthesis de novo Body reserve  adiposit Fatty acids  be emulsified by gall bladder salts – easy to absorb and digest Transport  complex with protein  lipoprotein

Penyerapan oleh sel mukosa usus halus Asam lemak yg diserap  disintesis kembali mjd lemak dalam  badan golgi dan retikulum endoplasma sel mukosa usus halus TAG  masuk ke sistem limfa membentuk kompleks dgn protein  chylomicrons

Digestion of Triacylglycerols

Fat Mobilization Fat mobilization: Breaks down triacylglycerols in adipose tissue to fatty acids and glycerol. Occurs when hormones glucagon and epinephrine are secreted into the bloodstream and bind to the receptors on the membrane of adipose cells activating the enzymes within the fat cells that begin the hydrolysis of triacylglycerols. Fatty acids are hydrolyzed initially from C1 or C3 of the fat. Lipases Triacylglycerols +3H2O→Glycerol + 3Fatty acids

Metabolism of Glycerol. Using two steps, enzymes in the liver convert glycerol to dihydroxyacetone phosphate, which is an intermediate in several metabolic pathways including glycolysis and gluconeogenesis. 1st step: glycerol is phosphorylated using ATP to yield glycerol-3-phosphate. 2nd step: the hydroxyl group is oxidized to yield dihydroxyacetone phosphate. The overall reaction : Glycerol + ATP + NAD+ → Dihydroxyacetone phosphate + ADP + NADH + H+

Glycerol from TAG hydrolysis will be converse to DHAP by : 1 Glycerol Kinase 2 Glycerol Phosphate Dehydrogenase.

Fatty Acid Activation Fatty acid activation: Allows the fatty acids in the cytosol to enter the mitochondria for oxidation. Combines a fatty acid with CoA to yield fatty acyl CoA that combines with carnitine.

Fatty Acid Activation Fatty acyl-carnitine transports the fatty acid into the matrix. The fatty acid acyl group recombines with CoA for oxidation.

Fatty Acid Activation Fatty acid activation is complex, but it regulates the degradation and synthesis of fatty acids.

Beta-Oxidation of Fatty Acids In reaction 1, oxidation: Removes H atoms from the  and  carbons. Forms a trans C=C bond. Reduces FAD to FADH2.  

Beta-Oxidation of Fatty Acids In reaction 2, hydration: Adds water across the trans C=C bond. Forms a hydroxyl group (—OH) on the  carbon.  

Beta ()-Oxidation of Fatty Acids In reaction 3, a second oxidation: Oxidizes the hydroxyl group. Forms a keto group on the  carbon.  

Beta ()-Oxidation of Fatty Acids In Reaction 4, acetyl CoA is cleaved: By splitting the bond between the  and  carbons. To form a shortened fatty acyl CoA that repeats steps 1 - 4 of -oxidation.

Beta ()-Oxidation of Myristic (C14) Acid

Beta ()-Oxidation of Myristic (C14) Acid (continued) 7 Acetyl CoA 6 cycles

Cycles of -Oxidation The length of a fatty acid: Determines the number of oxidations and The total number of acetyl CoA groups. Carbons in Acetyl CoA -Oxidation Cycles Fatty Acid (C/2) (C/2 –1) 12 6 5 14 7 6 16 8 7 18 9 8

-Oxidation and ATP Activation of a fatty acid requires: 2 ATP One cycle of oxidation of a fatty acid produces: 1 NADH 3 ATP 1 FADH2 2 ATP Acetyl CoA entering the citric acid cycle produces: 1 Acetyl CoA 12 ATP

ATP for Lauric Acid C12 ATP production for lauric acid (12 carbons): Activation of lauric acid -2 ATP 6 Acetyl CoA 6 acetyl CoA x 12 ATP/acetyl CoA 72 ATP 5 Oxidation cycles 5 NADH x 3ATP/NADH 15 ATP 5 FADH2 x 2ATP/FADH2 10 ATP Total 95 ATP

Oxidation of Unsaturated Fatty Acids. Oxidation of monounsaturated fatty acyl-CoA requires additional reaction performed with the help of the enzyme isomerase. Double bonds in the unsaturated fatty acids are in the cis configuration and cannot be acted upon by enoyl-CoA hydratase (the enzyme catalyzing the addition of water to the trans double bond generated during β-oxidation. Enoyl-CoA isomerase repositions the double bond, converting the cis isomer to trans isomer, a normal intermediate in β-oxidation.

Oxidation of polyunsaturated fatty acids. Requires two additional reactions and a second enzyme, reductase, in addition to isomerase. NADPH-dependent 2,4-dienoyl-CoA reductase converts trans-2, cis-4-dienoyl-CoA intermediate into the trans-2-enoyl-CoA substrate necessary for β-oxidation.

Oxidation of odd-chain fatty acids. Odd-carbon fatty acids are oxidized by the same pathway as even-carbon acids until three-carbon propionyl-CoA is formed. After that, three additional reactions are required involving three enzymes. Propionyl-CoA is carboxylated by propionyl-CoA carboxylase (with the cofactor biotin) to form the D stereoisomer of methylmalonyl-CoA (The formation of the carboxybiotin intermediate requires energy from ATP). D-methylmalonyl-CoA is changed into L-methylmalonyl-CoA by methylmalonyl-CoA epimerase. L-methylmalonyl-CoA undergoes an intramolecular rearrangment to form succinyl-CoA, which enters the citric acid cycle. This rearrangment is catalyzed by methylmalonyl-CoA mutase, which requires coenzyme B12, derived from vitamin B12 (cobalamin).

Overview of Metabolism In metabolism: Catabolic pathways degrade large molecules. Anabolic pathway synthesize molecules. Branch points determine which compounds are degraded to acetyl CoA to meet energy needs or converted to glycogen for storage.