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107 Cards in this Set

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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.