Fatty Acid Catabolism Flashcards
cells can obtain fatty acid fuels from four sources:
- fats consumed in the diet fats
- stored in cells as lipid droplets
- fats synthesized in one organ for export to another
- fats obtained by autophagy
Dietary Fats Are Absorbed in the Small Intestine
apolipoproteins
targets:
proteins in their lipid-free form that bind lipids to form lipoproteins
target triacylglycerols, phospholipids, cholesterol, and cholesteryl esters for transport between organs
chylomicrons
particles consisting of triacylglycerols, cholesterol, and apolipoproteins
Storage of Excess Fatty Acids
- fatty acids are converted to triacylglycerols in the liver
- triacylglycerols are packaged with specific apolipoproteins into VLDLs
- VLDLs are secreted and transported in the blood to adipose tissue
- triacylglycerols are removed and stored in lipid droplets within adipocytes in the adipose tissue
Hormones trigger mobilization of
stored triacylglycerols
lipid droplets
organelles stored in adipocytes and steroid-synthesizing cells that contain neutral lipids
contain a core of triacylglycerols and sterol esters surrounded by a monolayer of phospholipids
perilipins
family of proteins that coats the surface of lipid droplets to restrict access to the content of lipid droplets
prevent untimely lipid mobilization
Mobilization of Triacylglycerols Stored in Adipose Tissue occurs when -
What triggers changes that open the lipd droplet to the action of three cytosolic lipases?
- mobilization occurs when hormones (glucagon and epinepherine) signal the need for metabolic energy
- PKA triggers changes that open the lipid droplet to the action of three cytosolic lipases
free fatty acids, FFAs
fatty acids released by lipases
serum albumin
blood protein that noncovalently binds and transports FFAs to target tissues
makes up ~½ of the total serum protein
most of the biologically available energy of triacylglycerols resides in
their three long-chain fatty acids
phosphorylates glycerol to form glycerol 3-phosphate in the entry of glycerol into the glycolytic pathway
glycerol kinase
glyceraldehyde 3-phospbate can enter
glycolysis
Fatty acids are activated and transported into
mitochondria
small (< _____ carbons) fatty acids diffuse freely across mitochondrial membranes
<12 carbons
Transports long-chain fatty acids (containing 14+ carbons) through the mitochondrial membrane
carnitine shuttle
- requires activation to a fatty acyl-CoA and
- attachment to carnitine
fatty acyl-CoA synthetase
isozymes present in the outer mitochondrial membrane that activate the fatty acid by conversion to fatty acyl-CoA thioesters
fatty acid + CoA + ATP ⇄
fatty acyl-CoA + AMP + PPi
compound that transports fatty acyl-CoAs destined for mitochondrial oxidation across the inner mitochondrial membrane
carnitine
acyl-carnitine/carnitine cotransporter
- allows the passive transport of the fatty acyl-carnitine ester
- moves one carnitine into the intermembrane space as one fatty acyl-carnitine moves into the matrix
_____ pools of coenzyme A located ______
2; cytosol and mitochondria
coenzyme A in the mitochondrial matrix is largely used in:
oxidative degradation of pyruvate, fatty acids, and some amino acids
coenzyme A in the cytosol is used in the biosynthesis of
fatty acids
electron carrier that accepts electrons from FADH2
electron transfer flavoprotein (ETF)
flavoprotein that accepts electrons from ETF
ETF:ubiquinone oxidoreductase
passes electrons through ubiquinone into the mitochondrial respiratory chain
a multienzyme complex associated with the inner mitochondrial membrane that catalyzes steps 2-4 of the β-oxidation pathway for fatty acyl chains of 12+ carbons
allows efficient substrate channeling
trifunctional protein (TFP)
TFP is a ________ of alph4beta4 subunits
heterooctamer
α subunits contain enoyl-CoA hydratase and β-hydroxyacyl-CoA dehydrogenase activity
severe acidification of the blood and urine resulting from accumulated propionyl-CoA in the mitochondria being released to the blood as propionate
uses the carnitine shuttle
propionic acidemia
occurs in ~ 1 in 100,000 babies
the first intermediate of cytosolic fatty acid synthesis
blocks entry of fatty acids into mitochondria to prevent fultile cycling
malonyl-CoA
Oxidation of a Polyunsaturated Fatty Acid requires:
enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase
β oxidation in peroxisomes has four steps:
peroxisomes = organelles found in plants and animals
- dehydrogenation
- addition of water to the resulting double bond
- oxidation of the β-hydroxyacyl-CoA to a ketone
- thiolytic cleavage by coenzyme A
characterized by an inability to make peroxisomes
individuals lack all metabolism related to peroxisomes
Zellwger syndrome
characterized by the inability of peroxisomes to oxidize very-long-chain fatty acids
due to the lack of a functional transporter in the peroxisomal membrane
X-linked adrenoleukodystrophy (XALD)
a long-chain fatty acid with methyl branches that is derived from the phytol side chain of chlorophyll
the methyl group on the β carbon makes β oxidation impossible
phytanic acid
refsum disease
results from a genetic defect in phytanoyl-CoA hydroxylase
catalyzes the oxidation of D-β-hydroxybutyrate to acetoacetate in extrahepatic tissue
D-β-hydroxybutyrate dehydrogenase
Ketone bodies are used as fuel in all tissues except
liver
the liver lacks β-ketoacyl-CoA transferase
the liver is a producer of ketone bodies, not a consumer
α oxidation
removes a single carbon from the carboxyl end of the fatty acid
converts branched fatty acids to products that can undergo β oxidation to yield acetyl-CoA and propionyl-CoA
Two pools of fatty acyl-CoA
One pool is in the _______ and the other is in __________
cytosol; mitochondria
fatty acyl-CoA in the mitochondrial matrix can be used for
oxidation and ATP production
conversion to the carnitine ester commits it to oxidation
fatty acyl-CoA in the cytosolic pool can be used for
membrane lipid synthesis
the rate-limiting step for oxidation of fatty acids in mitochondria
carnitine-mediated entry (carnitine shuttle)
inhibits carnitine acyltransferase 1 and prevents the simultaneous synthesis and degradation of fatty acids
malonyl-CoA, the first intermediate in fatty acid synthesis
Step 1 of Fatty Acid Oxidation
β oxidation
fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-CoA
Stage 2 of Fatty Acid Oxidation
- oxidation of acetyl-CoA groups to CO2 in the citric acid cycle
- occurs in the mitochondrial matrix
- generates NADH, FADH2, and one GTP
Stage 3 of Fatty Acid Oxidation
electron transfer chain and oxidative phosphorylation
generates ATP from NADH and FADH2
flavoprotein with tightly bound FAD that catalyzes the dehydrogenation of fatty acyl-CoA to yield a trans-∆2-enoyl-CoA
acyl-CoA dehydrogenase
Acyl-CoA Dehydrogenase Isozymes
- isozymes are specific for fatty-acyl chain lengths:
- VLCAD (inner mitochondrial matrix): 12-18 carbons
- MCAD (matrix): 4-14 carbons
- SCAD (matrix): 4-8 carbons
Hydration of the Trans-∆2-Enoyl-CoA
_________catalyzes the addition of water to the double bond of the trans-∆2-enoyl-CoA to form….
enoyl-CoA hydratase
…L-β-hydroxyacyl-CoA (3-hydroxyacyl-CoA)
catalyzes the dehydrogenation of L-β-hydroxyacyl-CoA
….to form
β-hydroxyacyl-CoA dehydrogenase
…
β-ketoacyl-CoA
enzyme is specific for the L stereoisomer
NADH dehydrogenase (Complex I)
electron carrier of the respiratory chain
accepts electrons from the NADH formed in the β-hydroxyacyl-CoA dehydrogenase reaction
catalyzes the reaction of β-ketoacyl-CoA with free coenzyme A to yield….
acyl-CoA acetyl-transferase (thiolase)
…acetyl CoA and a fatty acyl-CoA shortened by two carbons
β subunits contain ______ activity
thiolase activity
The Four β-Oxidation Steps Are Repeated to yield
Acetyl-CoA and ATP
The Overall Reaction for Stage 1 of
β Oxidation
palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ + 7H2O ⟶
8 acetyl-CoA + 7FADH2 + 7NADH + 7H+
each FADH2 donates a pair of electrons to ETF
generates -
each NADH donates a pair of electrons to the mitochondrial NADH dehydrogenase
generates -
in total, _______ are formed for each pass through Beta oxidation
FADH2 - 1.5 molecules of ATP
NADH - 2.5 molecules of ATP
4 ATP are formed
The Overall Reaction for Stage 1 of
β Oxidation, Including Electron Transfers and Oxidative Phosphorylations
palmitoyl-CoA + 7CoA + 7O2 + 28Pi + 28ADP ⟶
8 acetyl-CoA + 28ATP + 7H2O
The Overall Reaction for the Complete Oxidation of Palmitoyl-CoA to CO2 and H2O
palmitoyl-CoA + 23O2 + 108Pi + 108ADP ⟶
CoA + 108ATP + 16CO2 + 23H2O
enoyl-CoA hydratase cannot catalyze the addition of H2O to a cis double bond
oxidation of unsaturated fatty acids requires two additional enzymes:
- enoyl-CoA isomerase (converts cis double bonds to trans)
- 2,4-dienoyl-CoA reductase (reduces cis double bonds)
acetone, acetoacetate, and D-β-hydroxybutyrate
formed from acetyl-CoA in the liver
ketone bodies
acetoacetate and D-β-hydroxybutyrate are transported to extrahepatic tissues and converted to acetyl-CoA to be oxidized in the citric acid cycle
oxidation of a monounsaturated fatty acid requires
an enoyl-CoA isomerase
isomerizes the cis-∆3-enoyl-CoA to the trans-∆2-enoyl-CoA
∆3,∆2- enoyl-CoA isomerase
beta oxidation requires double bond between
C2 and C3
Complete oxidation of odd-number fatty acids require _______extra reactions
three
three-carbon compounds formed by cattle and other ruminant animals during carbohydrate fermentation
propionate (CH3–CH2–COO−)
odd-number fatty acids are oxidized by the β-oxidation pathway to yield acetyl-CoA and a molecule of
propionyl-CoA
_____catalyzes the carboxylation of propionyl-CoA to form D-methylmalonyl-CoA
cofactor:
propionyl-CoA carboxylase
requires the cofactor biotin
Oxidation of Propionyl-CoA Step 2
__________catalyzes the epimerization of D-methylmalonyl-CoA to its L stereoisomer
methylmalonyl-CoA epimerase
Oxidation of Propionyl-CoA – Step 3
_________catalyzes the intramolecular rearrangement of L-methylmalonyl-CoA to form succinyl-CoA (which can enter the citric acid cycle)
requires:
methylmalonyl-CoA mutase
requires: 5′-deoxyadenosylcobalamin, or coenzyme B12, as its coenzyme
catalyzes the enzymatic condensation of two acetyl-CoA molecules to form acetoacetyl-CoA
reversal of the last step of β oxidation
thiolase
Transcription factors turn on the synthesis of proteins for __________
lipid catabolism
transcription factors that affect many metabolic processes in response to a variety of fatty acid–like ligands
PPAR family of nuclear receptors
stimulates the synthesis of enzymes required in β oxidation when there is an increased demand for energy from fat catabolism
PPARα
acyl-CoA dehydrogenase isozyme that acts on fatty acids of 4-14 carbons
medium-chain acyl-CoA dehydrogenase (MCAD)
individuals with two mutant MCAD alleles cannot oxidize fatty acids of_______
symptoms includes:
6-12 carbons
symptoms include fatty liver, high blood levels of octanoic acid (8:0), coma, and death
Other Genetic Defects in Fatty Acid Transport or Oxidation
- loss of the long-chain β-hydroxyacyl-CoA dehydrogenase activity of the trifunctional protein, TFP
- defects in the α or β subunits that affect all three activities of TFP
catalyzes the condensation of acetoacetyl-CoA with acetyl-CoA to form β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
HMG-CoA synthase
Differences Between the Peroxisomal and Mitochondrial Pathways
in peroxisomes, the flavoprotein acyl-CoA oxidase that introduces the double bond passes electrons directly to O2, producing H2O2
the enzyme catalase cleaves H2O2 to H2O and O2
the peroxisomal system is much more active on very-long-chain fatty acids and branched-chain fatty acids
catalyzes the cleavage of HMG-CoA to free acetoacetate and acetyl-CoA
HMG-CoA lyase
catalyzes the decarboxylation of acetoacetate to aceton
acetoacetate decarboxylase
catalyzes the reversible reduction of acetoacetate to D-β-hydroxybutyrate
D-β-hydroxybutyrate dehydrogenase
catalyzes the activation of acetoacetate
β-ketoacyl-CoA transferase
acetyl-CoA enters the citric acid cycle
Ketone Bodies are Overproduced in _______ and during ________
Diabetes; starvation
the accumulation of acetyl-CoA accelerates formation of ketone bodies
extrahepatic tissues do not have the capacity to oxidize them all
lowered blood pH
can be caused by increase levels of acetoactate, and D-β-hydroxybutyrate
acidosis
high levels of ketone bodies in the blood and urine
ketosis
condition when ketosis and acidosis are combined
ketoacidosis
Individuals with untreated diabetes have high _______ levels
acetone
individuals with untreated diabetes produce large quantities of acetoacetate
acetone formed from the decarboxylation of acetoacetate is volatile
imparts a characteristic odor to the breath
catalyzes the decarboxylation of acetoacetate to acetone
acetoacetate decarboxylase
