Fatty Acid Biosynthesis

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What are the 4 major physiological roles of fatty acids?: 1. Building blocks of phospholipids and glycolipids
2. Post-translational modifcn
3. Energy source - triglyc.
4. Hormones/intracel msngrs
Why are phospholipids/glycolipids important?: They are fundamental components of biological membranes.
How does post-translational modification of proteins w/ lipids help?: Gives them signals for protein targeting.
How are fatty acids stored as energy?: As TRIGLYCERIDES in adipose.
What are the 2 major sources of fatty acids in humans?: 1. Diet
2. Biosynthesis from small molecules
Where does fatty acid synthesis take place in cells?: In the cytosol
What is the basic formula of a completely saturated fatty acid?: CH3-(CH2)n-COOH
What makes a fatty acid UNsaturated?: Presence of a double bond within the molecule
What are the distinct characteristics of unsaturated fatty acids?: -Double bond is cis = kink
-If >1 double bond, always seperated by 2 CH2 groups
Are most fatty acids in biological systems even or odd in carbon atoms?: Even
How long are most common fatty acids in humans?: 16, 18, or 20 carbons long
In fatty acid nomenclature, what do the symbols mean?: # carbons : # double bonds (where they occur)
From which end of a fatty acid are double bonds numbered?: The carboxyl end (if it's from the omega end, it will say)
What fatty acids are essential? What does this mean?: Linolenic acid and Linoleic acid
-Cannot be made so must be obtained in the diet.
What property of fatty acids is directly correlated to their chain length?: Melting point
How do double bonds alter the melting point of fatty acids?: They dramatically reduce it - so melting occurs at colder temperatures.
What fatty acid is 16:0?: Palmitic acid (Palmitate)
Why is palmitic acid important?: It is the first fatty acid made by the biosynthetic pathway; all others are made by its modification.
What molecule provides all of the carbons for fatty acids?: Acetyl CoA
In general how are fatty acids made?: By addition of 2-carbon units to Acetyl Co-A.
What is the major source of Acetyl CoA? What cell compartment does it come from?: Pyruvate dehydrogenase reaction in the mitochondrial matrix.
In what cell compartment does FA biosynthesis occur?: Cytosol
Is the inner mitochondrial membrane permeable to AcCoA?: No
So how does AcCoA get into the cytosol?: By first being converted to citrate by citrate synthase (from oxaloacetate + AcCoA)
How does citrate get from the mitochondrial matrix -> cytosol?: By a tricarboxylate transporter
What happens to citrate after transport from mito matrix to cytosol?: It's converted back to Oxaloacetate + AcCoA by ATP-citrate LYASE
What other ingredients aside from AcCoA are needed for palmitate biosynthesis?: -ATP
-NADPH
-CO2
What is the CO2 source?: HCO3-
Why is Co2 needed?: Because the main reaction that commits AcCoA to FA biosynthesis is addition of CO2
What is the commitment reaction for FA biosynthesis, and what enzyme catalyzed it?: -Carboxylation of AcCoA -> malonyl CoA
-Enzyme is acetyl-CoA carboxylase
What enzymes is AcCoA carboxylase similar to? Why?: Pyruvate carboxylase - they both require a BIOTIN moiety - CO2 gets put on that, then transfers to recipient molecule.
What is a biotin moiety?: A reaction group consisting of a Carboxyl covalently attached to a Lysine residue.
What drives formation of the carboxybiotin intermediate for AcCoA carboxylation?: ATP
Does the CO2 that gets added during the commitment step show up later if radiolabeled?: No; this implies a decarboxylation step somewhere in the biosynthetic pathway.
What, in general terms, is FAS complex?: Fatty Acid Synthase Complex:
A multienzyme system that catalyzes synthesis of saturated long-chain fatty acids
What building blocks are used by FAS?: -Acetyl CoA
-Malonyl CoA
-NADPH
Where does the NADPH for FAS reactions come from?: The Pentose phosphate pathway.
What are the 5 reactions performed by FAS in a cyclical fashion?: 1. Transacetylation
2. Condensation
3. First Reduction
4. Dehydration
5. 2nd Reduction
What is the final product of the FAS complex reactions?: A saturated acyl group!
What happens in Transacetylation?: Acetyl CoA and Malonyl CoA are linked to an acyl carrier protein (ACP) via a Phosphopantetheine group.
What happens in Condensation?: Substantial REDUCTION in energy b/c a 4C unit is produced from AcCoA (2C) + Malonyl CoA (3C)
(decarboxyl MalCoA gives E!!)
Which reaction intermediate loses the carbon during condensation?: Malonyl CoA
Why go to the trouble of carboxylating AcCoA to form Malonyl CoA, if it's just going to lose it anyway?: The decarboxylation step drives condensation of 2 AcCoA's and makes the synthesis more favorable.
What occurs in the 1st reduction reaction?: Ketone reduced to Alcohol via NADPH reducing agent.
What occurs in the dehydration step?: Water loss to form double bond; alcohol -> alkene
What occurs in the 2nd reduction step?: Reduction of double bond to single bond via NADPH reducing agent.
What antibiotic inhibits the enzyme that catalyzes the 2nd reduction step?: Triclosan
What is triclosan commonly found in?: Toothpaste, soaps, and skin creams.
What does the first round of FAS reactions result in?: 4C-ACP molecule; subsequent rounds start from Condensation (don't need the loading step)
How many rounds total are necessary to form C16-ACP?: 7
What enzyme hydrolyzes C16-acyl-ACP to form palmitate?: Thioesterase
In the final palmitate product: -Which end is initial AcCoA on? -Which end is last malonylCoA?: -First AcCoA is on omega end
-Last malonyl CoA on COOH end
What determines chain length in fatty acids?: The thioesterase
What is the FAS structure like?: A dimer
What does each subunit of the Dimeric FAS consist of?: Multiple domains that contain all the necessary catalytic activities for FA synthesis - oriented in a linear array.
What is at the center of each FAS monomer?: ACP - attaches to the substrates and swivels from one catalytic site to the next.
What are the 2 advantages of having a multi-enzyme complex for FA synthesis?: 1. Direct transfer between sites means no diffusion of intermediates to cytosol; increased efficiency
2. Transcriptional regulation is coordinated - one mRNA can encode for ALL enzyme activities
What is the net reaction for palmitate biosynthesis?: 8 AcCoA + 7ATP + 14 NADPH + 14 H+ --> Palmitate + 8 COASH + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O
Why are there 6 not 7 H2O produced?: Thioesterase consumes one
Where are the enzymes that elongate Palmitate to make long chain fatty acids?: -Mitochondrial matrix
-Cytosolic face of ER membrane
How do the enzymes that elongate FA's differ from FAS?: -Elongate saturated OR unsaturated FA's
-Add to Fatty acyl CoA - because ACP only exists on FAS complex.
How does the mitocondrial elongation system work?: -Uses AcCoA to elongate shorter FAs taken in from the diet
-Uses both NADPH and NADH as reducing agents
How does the cytosolic-face ER elongation system work?: -Uses MalonylCoA as donor
-Only NADPH as reducing agent
-Prefers Palmityl CoA substrate
What is the almost exclusive product of the ER elongation?: Stearate
What is the structure of stearate?: 18:0
What tissue contains other elongation systems for making really long chain FAs?: Brain
Where is the enzyme for desaturating fatty aa's located?: Endoplasmic reticulum
What is the Commitment step in this process? Enzyme?: Putting a double bond in
-Palmitate - Carbon 9
OR
-Stearate - Carbon 9
Stearoyl-CoA desaturase
What are the products of Stearoyl-CoA desaturase?: Palmitoleic acid C16:1[9]

Oleic acid C18:1[9]
Enzyme specificity of Stearoyl-CoA desaturase:: There must be at least 6 carbons on the omega end of the alkyl chain.
Why is there always 3 carbons between double bonds in poly-unsaturated fats?: B/c the additional desaturases involve a 2-carbon elongation.
Essential fatty acids:: -Linoleic acid
-Linolenic acid
Why are linoleic and linolenic acid essential?: B/c they contain double bonds within 6 carbons of the omega end - can't do that w/ mammalian enzymes.
Why is Linoleic acid very important?: It is the precursor of Arachidonic acid - the major precursor to Eicosanoid hormones
What is the storage form of Fatty Acids?: Triglyceride
Triglycerides consist of:: 3 FA esterified to glycerol
Why are fatty acids stored this way?: Because esterification neutralizes them.
What is the essential first step of esterifying FA's to Tryglyc?: Activation - to acyl-CoA
Where does the glycerol backbone for triglyceride synthesis come from?: Reduced DHAP from glycolysis
What does reduction of DHAP make?: Glycerol phosphate
How are FA's added to glycerol phosphate, and what yields?: -Activated FA add to C1 and C2
-Yields Phosphatidic acid
What is the enzyme used for triglyceride synthesis?: Glycerol phosphate acyltransferae
What type of FA is usually added -to C1 -to C2: C1 = saturated

C2 = unsaturated
What is the final step in Triglyceride synthesis?: Remove PO4 from phosphatidic acid and replacement w/ 3rd activated FA
When is FA biosynthesis MAX?: When carb/energy are plentiful and FA's are scarce
Focal regulatory point in FA biosynthesis:: ACETYL COA CARBOXYLASE
In what other process is this also the focal reg point?: FA oxidation
What accomplishes short term regulation of AcCoA carboxylase?: Allosteric regulation
What are the allosteric activators of AcCoA carboxylase?: Citrate - stimulates inactive AcCoA carboxylase (when phosphorylated) but not active.
What are the allosteric inhibitors of AcCoA carboxylase?: -FA biosynthesis EndProducts - Palmitoyl CoA and Stearyl CoA.
What accomplishes Intermediate term regulation of AcCoA carboxylase?: Phosphorylation
Which form AcCoA carboxylase is -Active -Inactive: Active = Unphosphorylated

Inactive = Phosphorylated
What causes the phosphorylation and dephosphorylation reactions?: -AMP-dependent protein kinase
(AMPK)

-protein phosphatase 2A
What is important to remember about AMPK?: It is not cAMP-dependent protein kinase - PKA!!!
What does AMPK do?: Converts AcCoA carboxylase to its inactive form by phosphorylating it.
What undoes the work of AMPK?: Protein phosphatase 2A (PP2A)
So what will cause AMPK to be active and thus FA synthesis to be decreased?: High levels of AMP - signaling low energy. Don't want to be making FA during starving.
What inhibits AMPK?: ATP
What activates PP2K to make FA synthesis turn on?: Hormones - insulin
What inactivates PP2K?: Hormones - phosphorylation via PKA (ie Glucagon)
And what accomplishes allosteric control of the inactive form of AcCoA Carboxylase?: Citrate
Why does Citrate ACTIVATE the inactive form of AcCoA carboxylase?: So that if Citrate levels are high but energy is low, FA synthesis can still occur - ie in starving to conserve glucose for brain.
How is Long Term control of FA synthesis achieved?: By up/downregulating ENZYME LEVELS
Under what nutritional condition will AcCoA carboxylase be upregulated?: Fasting
What allows for the coordinated regulation of these enzymes?: SRE - serum response element; a common regulatory element in the gene promotors.
How do enzyme levels change in fasting?: -Initially decrease
-Long term increase
Why do enzymes increase in long term fasting?: Forward thinking - anticipate substrate from diet.

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