Fatty Acid Metabolism - Chapter 22 PDF

Chapter 22 Fatty Acid Metabolism “A moment on the lips, a lifetime on the hips” Physiological functions of fatty acids Building blocks of phospholipids and glycolipids – Key is their amphipathic nature Proteins can be modified by having FAs covalently attached to them...

Chapter 22 Fatty Acid Metabolism “A moment on the lips, a lifetime on the hips” Physiological functions of fatty acids Building blocks of phospholipids and glycolipids – Key is their amphipathic nature Proteins can be modified by having FAs covalently attached to them – Targets them to the membrane FAs serve as long term energy storage – Very stable and very reduced FAs are precursors to some hormones – Steroid hormones and certain second messengers Some FAs are essential – we must obtain them through our diet  FA Nomenclature Coventional names used instead of common names – Name is based on the hydrocarbon it is derived from – For saturated FAs, replace “e” with “oic” ie 18C hydrocarbon is octadecane Saturated FA form is octadecanoic acid (18:0) – Ionized form is octadecanoate Mono-unsaturated form is octadecenoic acid (18:1) Di-unsaturated form is octadecadienoic acid (18:2) Tri-unsaturated form is octadecatrienoic acid (18:3)  FA Nomenclature Carbons are numbered in two ways – Usually numbered starting at the carboxyl group Carboxyl C is #1 Next C is #2, etc – Carbon #2 is termed  – Carbon #3 is termed  The last C in the hydrocarbon chain is called  Unsaturations can be noted relative to either end – In relation to carboxyl, they are denoted with  Indicate conformation of bond and position – ie cis-9 means a cis double bond between C9 and C10 – In relation to  denoted with  ie -3 means an unsaturation between C3 and C4 from  Carbon numbering in FAs - Often numbered relative to carboxyl end. - Carboxyl C is #1, next C is #2 or , next C is #3 or  - In  numbering, the position of an unsaturation near the  end is specified. Table 12.1 Fatty acid nomenclature  Triacylglycerols as energy stores Triacylglycerols are efficient energy storage forms – Highly reduced All Cs except carboxyl are fully or nearly fully reduced Yield about 9 kcal/gram – Compared with about 4 kcal/gram for AA or carbohydrates – Very anhydrous being hydrophobic they do not bind water – Thus weigh less than carbs or proteins – Given this fats store about 6X more energy per unit weight than carbohydrates  Adipocytes - Adipose cells synthesize and store triacylglycerols as fat droplets in their cytoplasm. When stimulated by hormones they degrade these into more soluble forms and release them into the blood.  Lipases are regulated by cAMP - First step in triacylglycerol degradation is their cleavage to glycerol and 3 FAs by lipases. - These lipases are stimulated by cAMP. - Adenylate cyclase in adipose tissue is regulated by epinephrine, norepinephrine, glucagon and ADH.  Fate of glycerol from lipases - The liver can carry out these reactions to put glycerol into either glycolysis or gluconeogenesis. -The dehydrogenase step can be reversed and glycerol 3-P can be phosphatased to produce glycerol from glycolytic intermediates.  Preparation for -oxidation of fatty acids -Acyl CoA synthetase catalyzes these two reactions to produce acyl CoA. - The first step is the activation of the FA by forming a mixed acid anhydride by condensing the carboxyl with the  phosphate of an ATP - The FA is then transferred onto CoA to form Acyl CoA - This form can enter -oxidation  Transport of FA into mitochondrial matrix -  oxidation occurs in the mitochondrial matrix but FAs are activated in the cytoplasm -FAs must be transported across the mitochondrial inner membrane - Are attached to carnitine to form acyl carnitine by carnitine acyl transferase I 22.7 The acyl carnitine translocase - The translocase is an integral membrane protein that allows facilitated diffusion of acyl carnitine - Once in the matrix, the FA is transferred back onto CoA by carnitine acyl transferase II - It can now be oxidized  22.8 -oxidation of FAs - Acyl CoA dehydrogenase oxidizes the  and  carbons and reduces an enzyme bound FAD. The electrons are transferred to Q. - The C=C is then hydrated by Enoyl CoA Hydratase - The second oxidation is then catalyzed by L-3-hydroxy acyl CoA dehydrogenase. Note that this oxidation takes place on the  carbon (hence the name). -The #1 and  C are then split off as acetyl CoA by - ketothiolase. This is a thiolytic cleavage in that the bond between the  and  C is broken by the S of CoA. This leaves the FA 2 Cs shorter but still attached to CoA. 22.9, 3 rounds of  oxidation Table 22.1, -Oxidation  Calculation of energy yields Remember that we will use 1 NADH = 2.5 ATP and 1 FADH2 = 1.5 ATP in ETS Start with saturated palmitate (16 C) – Last round of thiolysis gives 2 Acetyl CoA – Thus, only go through 7 round of -oxidation Get 7 FADH2, 7 NADH + H+, 8 Acetyl CoA – Acetyl CoA gives 3 NADH + H+, 1 FADH2 and 1 GTP in TCA – Thus, each equals 10 ATP 7 FADH2 = 10.5 ATP, 7 NADH + H+ = 17.5 ATP, 80 ATP from TCA equals a total of 108 ATP Minus 2 ATP equivalents for the 2 high energy bonds used to activate the FA at the start = 106 ATP Unsaturations - FAs with an unsaturation at an odd numbered C (from #1 end) are dealt with by an isomerase when the double bond is between C3 and C4. The isomerase shifts this double bond to C2 and C3 like in enoyl CoA. - If the unsaturation is at an even #C then it is more complex. - When the double bond gets to C4, the cycle starts out as usual with Acyl CoA dehydrogenase. - NADPH is then used to reduce one unsaturation (2,4 Dienoyl CoA red.) leaving the unsaturation at C3. - This is then shifted to C2 by the same isomerase as was used with odd numbered unsaturated FAs.  22.19 Ketone bodies hydroxymethylglutaryl 3-ketothiolase CoA cleavage enzyme hydroxy-methyl D-3-hydroxy glutaryl CoA synthetase butartate dehydro - If insufficient OAA is available for the acetyl CoA to enter TCA it will be shunted into ketone body formation - Typically seen in diabetes or in prolonged fasting as the OAA is drawn off into gluconeogenesis. - Allows -oxidation to occur and dump the acetyl CoA out to other tissues that may be able to use them (ie heart, renal cortex and brain in starvation).  Degradation versus synthesis In euks, synthesis is in the cytosol, degradation is in the matrix Synthesis intermediates are attached to acyl carrier protein (ACP) through a thioester while FAs in degradation are attached to CoA Enzymes for biosynthesis are all in one polypeptide in higher organisms but degradative enzymes are separate Synthesis uses a 3 C donor (malonyl CoA) but degradation produces a 2C product (acetyl CoA) Synthesis uses NADPH while degradation uses NAD+ and FAD Elongation can only go up to palmitate but degradation can work with any size FA  Malonyl CoA formation is the committed step - Formation of 3C malonyl CoA is performed by acetyl CoA carboxylase - Uses biotin as a prosthetic group - Malonyl CoA is only used in FA biosynthesis, that’s why this is the committed step - Commits acetyl CoA to FA biosynthesis  ACP and CoA - Both use phosphopantetheine group as the business end  Table 22.2 Reactions of FA synthesis - Two reduction steps, both of which use NADPH as a source of electrons  22.22 FA biosynthesis - Acyl-malonyl-ACP condensing enzyme starts the elongation phase by joining acetate from acetyl ACP onto  C of malonyl ACP with release of CO2 - -ketoacyl-ACP reductase then reduces the  carbon from a carbonyl to an alcohol using NADPH - 3-hydroxyacyl-ACP dehydratase then removes water from the  and  Cs to produce a trans double bond - The C=C is then reduced by Enoyl-ACP reductase, again using NADPH  Stoichiometry of Fatty Acid Biosynthesis To make palmitate (16 C FA) – Need 1 acetyl CoA (to start) No cost to transfer it onto ACP to make Acetyl ACP – Need 7 malonyl ACPs Made from 7 Acetyl CoAs at a cost of one ATP each No cost for transfer onto ACP – Seven rounds of condensation required to make palmitate Each round requires 2 NADPH + H+ total reaction is thus 8 Acetyl CoA + 7 ATP + 14 NADPH+ 6 H+ -> palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi  Essential Fatty Acids Mammals cannot make unstaturations past carbon 10 – Fatty acids with unsaturations past that point must come from diet Two types in humans – alpha-linoleic acid (an omega-3) all-cis-octadecatrienoic acid – linoleic acid (an omega-6) cis,cis-octadecadienoic acid Involved in signaling and other functions