Chapter 27 Flashcards
Fatty Acids
Stored in adipose tissue as triacylglycerol’s (TAG)
- TAG = fatty acids linked to glycerol w/ ester linkages
Adipose tissue is located throughout the body, most prominent places are…
- Subcutaneous (below the skin)
- Visceral (around the internal organs)
TAG is stored in adipocytes as a lipid droplet
Fatty Acids are Processed in 3 Stages
Fatty acids into triacylglycerols in adipose tissues are made accessible in 3 stages:
- Degradation of TAG to release fatty acids and glycerol into blood for transport to energy-repairing tissue
- Activation of the fatty acids and transport into mitochondria for oxidation
- Degradation of the fatty acids to acetyl-CoA for processing by CAC
Seven-transmembrane-helix (7TM) receptors
- transmit info initiated by signals as photons, hormones, neurotransmitters, odorants, etc.
- change conformation in response to ligand binding and activate G-proteins
- These receptors contain 7 helices that span the membrane bilayer
- An example of a 7TM receptor that responds to chemical signals is called B-adrenergic receptor. This protein binds epinephrine (also called adrenaline), a hormone responsible for fight or flight response
Mutations in these receptors and their associated components cause a host of diseases. Examples of these mutations include…
- Color blindness
- Familial hypogonadism
- Short stature due to mutated growth hormone receptor
- Extreme obesity
- Congenital hypothyroidism
- Incomplete bowel innervation (Hirschsprung disease)
- Precocious puberty
- Night blindness
Ligand-receptor binding activates GTP-binding proteins (G-proteins) + Fatty Acid Release Steps
- Begins with fight or flight response or low blood glucose levels occurring, such as in the morning
- The ligand epinephrine is bound to its receptor, B2-adrenergic (a 7TM receptor)
- On the cytoplasmic portion, the Heterotrimeric G-protein consist of alpha, beta, and gamma subunits
- GDP-bound G-alpha is inactive
- GTP-bound G-alpha is active
- Upon ligand-receptor binding, a conformational change takes place within the receptor, which is relayed to the G-protein
- The G-protein releases the bound GDP in exchange for GTP. At the same time, the G-alpha-GTP now dissociates from the beta and gamma subunits
- Activated G-alpha-GTP then transitions towards membrane bound adenylate cyclase to activate this enzyme
- Activated adenylate cyclase then generates cAMP from ATP. cAMP now acts as a second messenger inside the cells to activate protein kinase A
- Activated PKA phosphorylates 2 key proteins: Perilipin and lipase
- Activation of Perilipin allows for the reorganization of the fat droplets, so that the TAG’s are accessible. Phosphorylation also releases coactivator ATGL
- ATGL initiates the mobilization of TAG by releasing a fatty acid from TAG to form DAG
- ATGL removes first fatty acid from TAG to generate diacylglycerol (DAG)
- Phosphorylated lipase removes second fatty acid from DAG to generate monoacylglycerol (MAG) + a free fatty acid
- MAG-lipase completes fatty acid mobilization w/ production of a free fatty acid and a glycerol
STEP 1: Free Fatty Acids & Glycerol: Released into the Blood
Fatty acids (insoluble)
- Since fatty acids are not soluble in solution, the fatty acids will be bound to blood protein albumin
–> Albumin will transport fatty acids through blood to tissue cells that need fuel sources
Glycerol (soluble in plasma)
- The glycerol that’s released during lipolysis and absorbed by liver will be used in glycolysis or gluconeogenesis
STEP 2: Describe how the Fatty Acids get linked to CoA
–> Fatty acids separate from albumin in bloodstream and diffuse across cell membrane w/ assistance of transport proteins
- In cells, fatty acids are shuttled about in association w/ fatty-acid binding proteins
- Activation and attachment to CoA is required before oxidation
–> Fatty acids must be activated by reaction w/ CoA to form acyl-CoA
- Activation takes place on outer mitochondrial membrane, where it’s catalyzed by acyl-CoA synthetase
- Activation takes place in two steps: (partial reactions are freely reversible)
- Fatty acid reacts w/ ATP to form acyl adenylate, and the other 2 phosphoryl groups of the ATP substrate are released as pyrophosphate
- Sulfhydryl group of CoA attacks acyl adenylate to form acyl-CoA and AMP
–> Reaction is driven forward by hydrolysis of pyrophosphate by pyrophosphatase, rendering reaction irreversible (b/c of pyrophosphatases)
STEP 2: Describe how fatty acid entry into the mitochondrial matrix works
- After being activated by linkage to CoA, fatty acid is transferred to carnitine; rection catalyzed by carnitine acyltransferase I (CAT I), generating acyl carnitine
- required for transport of acyl carnitine across inner mitochondrial membrane into mitochondrial matrix
- Translocase transports acyl carnitine into matrix of mitochondria
- In mitochondria, carnitine acyltransferase II (CAT II) transfers fatty acid to CoA
- Fatty acyl CoA is now ready to be degraded
- Carnitine returns to cytoplasmic side in exchange for acyl carnitine (repeats)
acyl-CoA + carnitine <=> acyl carnitine + CoA
STEP 3: explain the 4-steps to fatty acid oxidation in the mitochondria
- Fatty acid oxidation = degrading the fatty acids two carbon atoms one at a time
–> also called B-oxidation b/c oxidation it takes place at beta carbon atom - B-oxidation takes place in 4-reactions that are repeated:Oxidation of B-carbon atom
Hydration of trans-∆2-enoyl CoA
Oxidation of L-3hydroxyacyl CoA
Cleavage of the 3-ketoacyl CoA
- Oxidation of B-carbon atom occurs, catalyzed by acyl-CoA dehydrogenase ~ this generates enol-CoA w/ trans double bond between C2 and C3
- Electrons are transferred to FAD to generate FADH2, which then enter ETC
- Hydration of the double bond between C2 and C3 occurs by enzyme enoyl-CoA hydratase ~ this results in L-isomer of 3-hydroacyl CoA
- Oxidation of L-isomer of 3-hydroacyl CoA occurs by L-isomer of 3-hydroacyl CoA dehydrogenase ~ this generates 3-ketoacyl CoA and NADH
- Cleavage of 3-ketoacyl CoA by B-ketothiolase occurs ~ this forms acetyl-CoA and a fatty acid chain that is 2-carbons shorter than when the reaction started
Fatty acid oxidation takes place with 4-repeating steps: oxidation, hydration, oxidation and cleavage. In each round ______________________________ is formed
a) an acetyl-CoA (shortened by 2-C), 1-FADH2, 1-NADH
b) an acetyl-CoA (shortened by 2-C), 2-FADH2, 2-NADH
c) an acetyl-CoA (shortened by 1-C), 1-FADH2, 3-NADH
a) an acetyl-CoA (shortened by 2-C), 1-FADH2, 1-NADH
In the degradation of palmitate, a 16-carbon fatty acid, complete oxidation of palmitoyl-CoA will yield…
a) 7-acetyl-CoA, 7-FADH2, 7-NADH, and 7-protons
b) 8-acetyl-CoA, 7-FADH2, 7-NADH, and 7-protons
c) 6-acetyl-CoA, 3-FADH2, 3-NADH, and 3-protons
b) 8-acetyl-CoA, 7-FADH2, 7-NADH, and 7-protons
The complete oxidation of palmitate yields ____ molecules of ATP
a) 104
b) 106
c) 128
d) 132
b) 106
Describe fatty acid degradation concerning unsaturated & odd-chain fatty acids
Beta oxidation is straight-forward for complete degradation of saturated fatty acids that have even # of carbon atoms, but degradation of unsaturated fatty acids and/or those w/ odd chain carbons require additional steps
Degradation of unsaturated and odd-chain fatty acids:
- Requires additional steps
- Requires additional enzymes: isomerases and/or reductases
–> isomerase enzyme facilitates the conversion of a cis-double bond into a trans double bond, required to complete beta oxidation of the fatty acid
–> reductase enzymes are required for polyunsaturated fatty acids
- Unsaturated fatty acids are not fully reduced due to at-least 1-double bond, thus slightly less energy will be captured
Polyunsaturated fatty acid (PFAs) require:
- cis-Δ3-enoyl CoA isomerase
- 2,4-dienoyl-CoA reductase
- Ex. Linoeoyl-CoA
Unsaturated fatty acids w/ odd numbers of double bonds require _____
a) isomerase
b) reductase
c) isomerase and reductase
a) isomerase
Unsaturated fatty acids w/ even numbers of double bonds require _____
a) isomerase
b) reductase
c) isomerase and reductase
c) isomerase and reductase
Example: Degradation of Palmitoleoyl-CoA (Monosaturated Fatty Acid)
Beta oxidation of degradation of plamitoleoyl-CoA results in formation of cis-Δ3-enoyl CoA
cis-Δ3-enoyl CoA cannot be processed by acyl-CoA dehydrogenase
An isomerase enzyme (cis-Δ3-enoyl CoA isomerase) will shift the cis-Δ3-enoyl CoA into trans-Δ2-enoyl CoA
trans-Δ2-enoyl CoA is a normal substrate for β oxidation
Polyunsaturated fatty acid (PFAs) require…
a) cis-Δ3-enoyl CoA isomerase AND 2,4-dienoyl-CoA reductase
b) cis-Δ2-enoyl CoA isomerase AND 1,3-dienoyl-CoA reductase
c) cis-Δ3-enoyl CoA isomerase AND 1,4-dienoyl-CoA reductase
a) cis-Δ3-enoyl CoA isomerase AND 2,4-dienoyl-CoA reductase
Explain how the fatty acid chain length is considered for fatty acid degradation
- Chain length also needs to be considered for fatty acid degradation
- For B-oxidation of an odd #ed fatty acid chain, routine B-oxidation will occur until a 3-C propionyl-CoA is generated at the last thiolysis reaction (propionyl-CoA + acetyl-CoA instead of 2 acetyl-CoA entities)
- Biotin enzyme propionyl-CoA carboxylase adds a carbon to propionyl-CoA to form methylmalonyl-CoA (4-C)
- Succinyl-CoA, a CAC component, is formed from methylmalonyl-CoA by methylmalonyl-CoA mutase (a vitamin b12-requiring enzyme)
Ketone bodies…
a) are a fuel source derived from fats
b) are synthesized in the liver
c) all of the above
c) all of the above
Ketone bodies: Acetoacetate, D-3-hydroxybutyrate, Acetone
- Are synthesized from acetyl-CoA in liver mitochondria
- Are secreted into blood for use as fuel source by some tissues (ex. heart muscle)
D-3-hydroxybutyrate
- Formed upon reduction of acetoacetate
Acetone
- Generated by spontaneous decarboxylation of acetoacetate
In tissues using ketone bodies, D-3-hydroxybutyrate is oxidized to acetoacetate, which is metabolized to 2 molecules of acetyl-CoA
In tissues using ketone bodies, D-3-hydroxybutyrate is oxidized to ________, which is metabolized to ___ molecules of acetyl-CoA
a) acetoacetate; 3
b) acetate; 2
c) acetoacetate; 2
c) acetoacetate; 2
Enzymes catalyzing the formation of ketone bodies from acetyl-CoA (Acetoacetate, D-3-hydroxybutyrate, Acetone)
- 3-ketothiolase
- hydroxymethylglutaryl CoA synthase
- hydroxymethylglutaryl CoA cleavage enzyme
- D-3-hydroxybutyrate dehydrogenase
True or False: Animals can convert fatty acids into glucose
False
- Fats are converted into acetyl-CoA, which is then process by CAC
- Oxaloacetate (CAC intermediate) is a precursor to glucose
- Acetyl-CoA derived from fats can’t lead to net synthesis of oxaloacetate or glucose b/c, although 2 carbons enter cycle when acetyl-CoA condenses w/ oxaloacetate, 2 carbons are lost as CO2 before oxaloacetate is regenerated
Metabolism in Context
- Fatty acids metabolism can be altered by physiological conditions
- In diabetes, excess amount of ketone bodies can lead to life threatening conditions
- Ketone bodies = moderately strong acids ~ access production = acidosis ~ in diabetic patients is called diabetic ketosis
Diabetic ketosis
- results when insulin is absent
- In absence of insulin, or when insulin is not functioning, glucose cannot enter cells ~ energy must be derived from fats leading to production of acetyl-CoA
- Access amounts of acetyl-CoA cannot be processed b/c of lack of glucose derived oxaloacetate
- Access ketones bodies generated in liver are released into blood ~ this will contribute to diabetic acidosis
- Fatty acids release from adipose tissue is enhanced in absence of insulin function
