Fatty acid metabolism Flashcards
Why are Fatty acids physiologically important
They are building blocks of biological membranes, contribute to post translational modification, sources of energy and stored in TGs, serve as hormones and intracellular messengers
Structure of FA
consist of an alkyl chain (4-36 C long) with a terminal carboxyl group (biological FAs are usually even number of carbons) C16 C18 and C20 (even longer in the brain)
Saturated FAs have no double bonds (CH3)(CH2)n-COOH
Unsaturated FAs can have UP TO SIX double bonds per chain (usually in cis formation), when there is more than one db they are always separated by a methyl group,
specific FAs
Palmitic acid (16:0), Palmitoleic acid (16:1), Steric acid (18:0), Oleic Acid (18:1), arachidonic acid (20:4)
Essential fatty acid 2!
alpha-linolenic acid (18:3)om3, linoleic acid (18:2)om6
Essential FAs
alpha-linolenic acid (18:3)w6, linoleic acid (18:2)w3
Polyunsaturated fatty acids (PUFAs) that humans lack the desaturase enzymes required for production
longer fatty acids can be made from shorter ones (essentials)
Non essential PUFAs but important ones (eicosanoids (precursor-arachidonic acid), endocannabinoids, imbalance of 3/6 CV disease):
omega 3: EPA and DHA
Omega 6: arachidonic acid
Non-essential FAs: some are healthier than others:
Monounsaturated( lowers LDL) , PUFAs, Saturated FAs (raise cholesterol levels), Trans FA (Raise LDL, and lower HDL)
Trans fatty acids
formed by partial dehydrogenation of unsaturated fatty acids (increases shelf life, high temp of oils used in cooking oils)
A trans double bond extends the FA
Trans fats pack more regularly and have higher melting points
CV disease
Properties of Fatty acids
determined by length and saturation level
Solubility: the longer and more saturated, the lower solubility in water
melting point: longer the chain the hight the melting point, unsaturation leads to membrane fluidity
Fatty acid synthesis in the body
Fatty acids are supplied by diet or biosynthesis of palmitate (the precursor FA for all FAs in the body, 16:0)
Fatty acids/palmitic acid is synthesiszed in the liver cytosol
The process incorporates carbons from acetyl coA into the growing FA chain, using ATP and reduced NADPH
Biosynthesis of Fatty Acids/ Palmitic Acids
Step 1: Acetyl CoA provides all the carbons for FAs, which are sequentially added 2 Cs at a time. Pyruvate from glycolysis is converted to Acetyl CoA (and NAD-> NADH, and the making of CO2) via PDH in the mitochondrial matrix. Since FA synthesis is done in cyto, a process involving CITRATE (from TCA) gets the 2 Cs from acetyl coA to the cyto from the mito.
Step 2: Citrate is transported from mito matrix to cyto by the Tricarboxylate/CITRATE transporter, then is converted back to acetyl coA and oxaloacetate via ATP-citrate lyase
Step 3: Commited step to force Acetyl CoA into Malonyl CoA (via Acetyl CoA carboxylase and Co2 and biotin)
Acetyl CoA carboxylase is regulated step in FA synthesis. 3 Functional regions of Acetyl Co Carboxylase (Formation of Co2 from HCO3- on biotin, a cofactor lysine swing, ATP hydrolysis. To form malonyl Coa (via carboxylation of Acetyl CoA)
Fatty Acid synthesis
FAS converts malanyl CoA to Palmitate/ FAs the saturated 16:0 . it also uses reduced NADPH in a 4 step sequence
Saturated acyl group (unit of the chain) is produced by each 4 step series. and becomes the substrate for subsequent condensation with an new activated malonyl CoA.
FA is extended by 2 C each pass through. FAS contains enzymes that catalyze Condensation, Reduction, Dehydration, then another reduction
FAS complex
FAS is composed of one polypeptide chain that has 7 active subunits. The domains function as distinct but linked enzymes, which allows for direct transfer between sites (no floating away), and a coordinated transcriptional regulation. When the Chain length reaches 16 C the product palmitate leaves the cycle, the C15 and C16 of palmitate are derived from carboxyl and methyl of acetyl Coa used to prime the system on onset. The rest of the chain Cs are from acetyl CoA from Malonyl CoA
Acyl Carrier Protein (ACP) (part of the FAS)
Serves as a shuttle in FA synthesis:
During FA synthesis, the intermediates remain covalently attached as thioesters to one of two thiol groups.
the SH group of B-ketoacyl-ACP synthase (KS), and the SH group of acyl carrier protein. The thioesters hydrolysis is highly exergonic allowing condensation in FA synthesis to be favorable.
Intermediates are linked to ACP through the phosphopantetheine group thats attached to ACP
The ACP is a flexible arm that tethers the growing chain and swings it to the next active site
Steps of Fatty acid synthesis: activating the first acetyl and malonyl groups
Two thiol groups on FAS must first be charged with the correct Acyl group:
Malonyl/ Acetyl CoA-ACP transferase (MAT): transfers the acetyl group from acetyl-CoA to ACP, then Actyl group goes to SH of the KS. It also transfers the malonyl group from Malonyl CoA to the SH of ACP
The MAT essentially activates the acetyl and malonyl groups so that chain lengtheining can continue on the FAS
Steps of Fatty acid synthesis: Condensation Step one
Ketoacyl ACP synthase and produces a four carbon unit (acetoacetyl-ACP) from the two carbon unit (acetyl ACP) and a three C unit (malonyl ACP)
Decarboxylation (production of CO2) of malonyl CoA releases energy to push the reaction forward
The next 3 steps reduce the keto group at C3 to a methylene group
Steps of Fatty acid synthesis: step 2
Reduction of the carbonyl group
Beta-ketoacyl-ACP reductase (KR)
Uses NADPH, and makes D-B-hydroxybutyryl-ACP
Steps of Fatty acid synthesis: step 3
Dehydration
beta-hydroxyacyl-ACP dehyratase (DH)
yields a double bond (with the release of H20)
makes Trans-delta2-butenoyl-ACP
Steps of Fatty acid synthesis: step 4
Reduction of the double bond
Enoyl-ACP reductase (ER) forms butyryl ACP using NADPH
Enzymes involved in FAS
Condenation with an acetate: B-ketoacyl-ACP synthase (KS)
Reduction of carbonyl to hydroxyl: B-ketoacyl- ACP reductase (KR)
Dehydration of alcohol to alkene: B-hydroxyacyl-ACP dehydratase (DH)
Reduction of Alkene to alkane: enoyl-ACP reductase (ER)
Lengthening of the fatty acyl chain
production of the 4 C saturated FA (butyryl-ACP) marks the completion of one pass through the FAS complex
Each subsequent elongation cylce adds another 2 C unit to the carboxyl end of the growing chain from a malonoyl CoA
The process continues until C16-Acyl ACP is formed seven rounds in total, and chain elongation stops and free palmitate is released from the ACP by the hydrolytic activity of thioesterase of FAS complex
you use 8 Acetyl CoA, 7 ATP, and 14 NADPH
Synthesis of Long-chain and unsaturated FAs
longer FAs are formed by elongation reactions catalyzed by enzymes inside the mito and on the cytosolic face of smooth ER membrane
The ractions add 2 C units to the carboxyl end of Fatty Acyl CoA substrates rather than ACP derivatives
Donation of malonyl CoA, reduction, dehydration, reduction (like palmitate) with NADPH providing the reducing power
the ER system prefers palmitoyl CoA as a substrate and produces stearate (18:0)
Desaturation of Fatty acids
PUFAS are synthesized in the ER with palmitate and stearate serving as precursors with the comitted step catalyzed by stearoyl-CoA desaturase (high levels is related to T2 DM)
Short term regulation of FA synthesis
when mito ATP and acetyl CoA are high, citrate is transported out of the mitochondria (to stop TCA)
Citrate is an allosteric signal for activation of acetyl-CoA carboxylase
End products of FA synthesis of palmitoyl CoA and steroyl CoA are allosteric inhibitors of acetyl CoA carboxylase
Acetyl CoA carboxylase is the focal regulator point and rate limiting step of B oxidation and fatty acid synthesis
Acetyl CoA carboxylase (ACC)
Rate determining and key regulator of Fatty acid synthesis
ACC is feedback inhibited by palmitoyl CoA, and Activated by citrate
Acetyl CoA carboxylase converts acetyl coA to malonyl CoA
Citrate allosterically stimulates phosphorylated ACC but has little effect on dephosphorylated ACC
ACC is phosphorylated by glucagon and epinephrine
intermediate term regulation of FA synthesis
Phosphorylated ACC is not very active but, de phosphorylated is active
Phosphorylation done through AMPK and dephosphorylation is done through protein phosphatase 2A
Biosynthesis of TGs
Glycerol 3 phosphate (from glycolysis) is the initial acceptor of FA during TG synthesis
Fatty Acyl-CoA (formed by acyl CoA synthetases)
Sequential addition of 2 FAs from fatty acyl CoA to form phosphatidic Acid, removal of phosphate, addition of third Fatty acyl CoA to form TG
Regulation of TG synthesis
hormones (insulin) promote the conversion of carbs to TG
diabetics cant do FA synthesis (increases FA oxidation and ketone body formation)
Glucagon and epinephrine stimulate FA release from adipose tissue, and decrease the rate of glycolysis and increase the rate of gluconeogenesis
Free fatty acids go bag to Tgs in adipose 75% of the time
