FA and TG synthesis week 2 Flashcards
What a fatty acids? What is the basic formula?
What are the different features FA can have? (double bonds, length, etc.)
Fatty acids consist of an alkyl chain with a terminal carboxyl group. The basic formula is CH3-(CH2)n-COOH.
Fatty acids: R-COOH
saturated or unsaturated
short, medium, long or very-long chain
branched or unbranched
essential or non-essential
Unsaturated FA can have up to how many double bonds per chain? What configuration is the double bond usually in?
The most common FA in biological systmes have an (even/odd) number of carbons.
How do animals synthesisze simple branched chain FA?
How many carbons do most FA have?
- Fatty acids with double bonds (Unsaturated FAs) are common with up to 6 double bonds per chain, almost always in the cis configuration. However, not all can be made by human cells (hence called essential fatty acids).
- If there is more than one double bond, they are always separated by a methylene (–CH2–) group.
- The most common fatty acids in biological systems have an even number of carbons. Odd-number carbon fatty acids are mostly used for energy in the human and cannot easily incorporate into complex lipids.
- Some animals, including humans, also make simple branched-chain acids using methyl groups.
- Most fatty acids have C16, C18 or C20 atoms (i.e. ≥ 16).
How many carbons are in each of the following lengths of FA?
short chain
medium chain
long chain
very long chain
C2-4 Short chain FA
C6-10 medium chain FA
C12-18 long chain FA
C20-24 very long chain FA
very long chain FA are important for the membranes of neuronal cells.
Most FA in humans occur as _____.
triacylglycerols
FA occur primarily as esters of glycerols when they are stored (as TGs). In what amounts do monoacylglycerols and diacylglycerols exist? What are they used for?
T or F: Typically 1 out of 3 FA in TGs are unsaturated.
- Compounds with one (monoacylglycerols) or two (diacylglycerols) acids esterified are present only in relatively minor amounts and occur largely as metabolic intermediates in biosynthesis and degradation of glycerol containing lipids.
- Most fatty acids in humans are triacylglycerols with all three OH groups on glycerol esterified with a fatty acid.
- These are called neutral fats or triglycerides.
- The distribution of different fatty acids in the three positions in the body at any given time is influenced by diet and anatomical location.
- There are usually complex mixtures.
- True: Typically 1/3 FA in TGs are unsaturated.
What about FA makes them more efficient for storing energy? (multiple things)
In humans, what is the nature of saturation for de novo synthesized FA?
- This hydrophobic nature of triacylglycerols and their highly reduced state (more protons and less oxygen in the structure) make them more efficient for storing energy than glycogen.
- On a weight basis, pure triacylglycerols yield nearly 2.5 times the amount of ATP on a weight basis than pure glycogen.
- Triacylglycerols can be stored without associated water, whereas glycogen is very hydrophilic and binds twice its weight of water when stored in tissues.
- Thus, on a weight basis, fats actually store 4-times as much energy as glycogen.
- The average person can store enough fat energy for weeks while the glycogen is sufficient only for 24 hours of fasting.
- In humans, most of the de novo synthesized fatty acids are either saturated or contain only one double bond.
- Although they are readily catabolized by appropriate enzymes and cofactors, they are fairly inert chemically.
What are the essential FA? What are 2 uses for essential FA?
- Various animal and vegetable lipids are ingested, hydrolyzed at least partly by digestive enzymes and absorbed through the intestinal mucosa to be distributed through the body, first in the lymphatic system and then in the bloodstream.
- Metabolic processes in various tissues modify both dietary and de novo synthesized fatty acids to produce nearly all the required structures.
- Many higher mammals, including humans, are unable to synthesize fatty acids with double bonds near the methyl end of the molecule (ω-3 or ω-6 fatty acids). These are linoleic and linolenic acid and they are essential fatty acids. They are members of membrane phosphoglycerides and also give rise to eicosanoids.
What FA must be synthesized first before other FA? How many carbons is it? What is the saturation state of this FA?
The saturated straight chain C16 fatty acid, palmitic acid, is first to be synthesized, and all other fatty acids are made by modification of palmitic acid.
Explain/give an overview of the steps of FA synthesis (molecules, enzymes).
What cellular location does FA synthesis occur? Where in the body does most FA synthesis occur?
- Acetyl-CoA (C2) is the source for all the carbons and produced form glucose and some amino acids. Ac CoA is transported from the mitochondrion to the cytosol for FA synthesis.
- Two-carbon units are added to the activated carboxyl end of a growing chain, by fatty acid synthase. In mammals, this is a single multifunctional protein.
- Usually acetyl-CoA is the priming unit for fatty acid synthesis and the methyl end of the primer becomes the methyl end of palmitate.
- The rest of the two-carbon units is added in the form of malonyl-CoA molecules, which are produced from additional acetyl-CoA molecules by acetyl-CoA carboxylase. However, the CO2 added in this process, is lost when condensation of malonyl CoA to the growing FA chain occurs, so carbon atoms in palmitate originate only from acetyl CoA.
- The vast majority of FA are synthesized in the liver. Adipose tissue also synthesizes some FA.
Explain the steps of transportation of Acetyl-CoA to the cytosol for FA formation. List substrates and enzymes involved.
What is the major source of acetyl-CoA used for FA synthesis?
Why must acetyl-CoA be transported to the cytosol?
What does this process cost the cell? What are the products of this step?
- Fatty acid synthase and acetyl-CoA carboxylase are found primarily in the cytosol where biosynthesis of palmitate occurs.
- The major source of acetyl-CoA is the PDH reaction in the matrix of mitochondria that uses pyruvate from glycolysis.
- Since mitochondria are not permeable to acetyl-CoA, a process involving citrate moves the C2 unit to the cytosol.
- Citrate can pass through the membrane readily and be cleaved in the cytosol to liberate Ac-CoA and oxaloacetate. This step requires 1 ATP.
- NADH, produced by glycolysis, then reduces OOA to malate by malate DH and malate is decarboxylated by NADP-linked malic enzyme to produce NADPH, pyruvate and CO2.
- Pyruvate then returns to the mitochondrion.
- One NADH is used and one NADPH is generated for each acetyl-CoA transferred to cytosol, additionally, each transfer requires 1 ATP.
How many AcetylCoA must be transported to the cytosol for the synthesis of one molecule of palmitate?
How many NADPHs does the transport of AcetylCoA to the cytosol produce that can be used for palmitate synthesis?
How many are needed for palmitate synthesis? Where does the additional NADPH come from?
- The transfer of 8 acetyl-CoA molecules for each palmitate supplies 8 NADPH.
- Since palmitate synthesis requires 14 NADPH (see later), the other 6 must be supplied by the cytosolic hexose monophosphate shunt.
What is the commited and rate limiting step of FA synthesis?
What enzyme is involved in this step?
What is needed for this step? What is produced?
Acetyl-CoA carboxylase converts acetyl-CoA + HCO3-+ ATP to Malonyl-CoA + H2O + ADP+ Pi.
This enzyme requires a molecule of biotin coenzyme (and 1 ATP). Note that all carboxylases require biotin as a coenzyme.
Explain the allosteric regulation of acetyl CoA carboxylase.
- The isolated enzyme is inactive in the monomeric state, but when aggregated upon addition of citrate, is active.
- On the other hand, palmitoyl-CoA inhibits the enzyme (feed-back from FA synthesis).
- Thus, when fatty acid synthesis is desirable, citrate will be elevated and pushes FA synthesis forward. When palmitoyl-CoA, the product of FA synthesis, concentration is high, it will inhibit FA synthesis.
Explain the hormonal regulation of acetyl CoA carboxylase.
What type of diet stimulates FA synthesis? Inhibits it?
- Acetyl-CoA carboxylase is also controlled by a cAMP mediated phosphorylationdephosphorylation in which the phosphorylated enzyme is less active.
- Phosphorylation is promoted by glucagon. It is counteracted by insulin.
- Enzyme is synthesized at higher levels when on a high CHO (insulin) or low fat diet.
- Glucagon, fasting or high fat diet decreases enzyme expression.
Explain the synthesis of FA. Include enzymes involved, substrates, and cofactors.
How many Acetyl CoA and how many malonylCoA are required for this process?
- Mammalian fatty acid synthase is a multifunctional enzyme, composed of two identical subunits, each of which contains all the necessary enzyme activities for fatty acid synthesis.
- A single Acetyl-CoA is bound to the enzyme complex first then malonyl-CoA units are added one-by-one. The growing fatty acid chain is constantly bound to fatty acid synthase and is sequentially transferred between the acyl carrier protein (ACP), a domain on the protein, and the β-ketoacyl-ACP synthase domain, the first enzyme of the complex.
- After the addition of every malonyl-CoA units, a reduction, a dehydration and another reduction steps follow. The reductase enzymes use NADPH for their action (synthesized in the hexose monophosphate shunt and transfer of ACoA to the cytosol).
- Eventually, 7 two-carbon units (in the form of malonyl CoA) are added sequentially to the complex until the palmitate is complete.
- Finally, palmitoyl-ACP is acted on by thioesterase with production of free palmitic acid.
What are the allosteric and hormonal regulators of fatty acid synthase?
Allosteric activator: phophorylated sugars (G6P)
Hormonal regulation:
- glucagon –decreases enzyme synthesis
- insulin – increases enzyme synthesis
TGs are synthesized in most tissues from what 2 molecules?
What is needed for this rxn?
- TGs are synthesized in most tissues from activated fatty acids(FA-CoA) and a phosphorylated 3-carbon product of glucose catabolism, which can be either glycerol 3-P or dihydroxyacetone phosphate.
- Fatty acids are activated by conversion to their CoA esters.
- The reaction is driven by hydrolysis of ATP and PPi (pyrophosphate).
- FA-CoA then reacts with Glycerol Phosphate
Where in the body can TGs be synthesized without the formation of phosphatidic acid? Describe how this works.
- There is at least one tissue, intestinal mucosa, in which synthesis of triacylglycerols does not require formation of phosphatidic acid. A major product of intestinal digestion of lipids is 2-monoacylglycerols, which are absorbed as such into mucosal cells.
- An enzyme in these cells catalyzes acylation of these monoacylglycerols with fatty acyl-CoA to form 1,2 diacylgycerol, which then can be further acylated.
