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Fatty Acid Metabolism (Ch 22)
CHEM 4352, University of Minnesota Duluth, Johnson
145
Biochemistry
Undergraduate 3
03/24/2015

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Term
Physiological roles of fatty acids
Definition
-Fuel molecules
-Building blocks
-Covalent modification of proteins
-Hormones and intracellular messengers
Term
How are fatty acids stored for fuel?
Definition
as triacylglycerols
Term
Fatty acids serve as the building blocks for...
Definition
Phospholipids and glycolipids
Term
Fatty acids covalently modify proteins for...
Definition
targeting lipid bilayer
Term
Fatty acid ______ serve as hormones and intracellular messengers.
Definition
derivatives
Term
Order of reaction TYPES in fatty acid degradation
Definition
Oxidation->Hydration->Oxidation->Cleavage
Term
Order of reaction TYPES in fatty acid synthesis
Definition
Condensation->Reduction->Dehydration->Reduction
Term
Triacylglycerols are highly concentrated...
Definition
sources of energy
Term
Why do triacylglycerols have so much energy?
Definition
They are a REDUCED carbon source (good electron donor)
Term
Compare the energy output of fatty acids vs. proteins and carbohydrates
Definition
38 kJ g-1 fatty acids
17 kJ g-1 proteins/carbs
Term
_____ character of triacylglycerols results in nearly _____ storage.
Definition
Nonpolar
anhydrous
Term
Triacylglycerol increases the energy per dry weight to ____ times over carbohydrates.
Definition
6.75
Term
Glycogen stores sustain function for ~24 hours vs. triacylglycerol stores that sustain function for...
Definition
several weeks
Term
Triacylglycerols are degraded to ____ for absorption
Definition
fatty acids
Term
How do lipases gain access to insoluble substrates?
Definition
Triacylglycerols are presented to lipases on the surface of micelles, i.e., ester head groups on surface with tails buried on micelle interior
Term
Micelles are formed by...
Definition
bile salts
Term
Bile salts...
Definition
-are amphipathic
-are secreted from the gall bladder
-are synthesized from cholesterol
-aid in the formation of micelles, orienting ester head groups
Term
Deficient production of bile salts due to liver disease leads to...
Definition
large amounts of fats in the feces
Term
Three ways fatty acids are used as fuel...
Definition
-Mobilization of triacylglycerols within adipocytes and conversion to free fatty acids and glycerol followed by transport to energy-requiring tissues
-Activation of fatty acids and transport into mitochondria
-Stepwise fatty acid degradation forming acetyl CoA, which feeds into the citric acid cycle
Term
In hormonal signaling leading to lypolysis, what are the activators?
Definition
epinephrine and glucagon
Term
In hormonal signaling leading to lypolysis, what is the inhibitor?
Definition
insulin
Term
What is perilipin and what does it do?
Definition
It is a fat droplet associated protein which makes triacylglycerols more accessible and triggers release of ATGL coactivator
Term
Glycerol is taken up by the ____, phosphorylated, and brought into the glycolytic or gluconeogenic pathway (to form glucose or pyruvate)
Definition
liver
Term
Is it possible to form glycerol from DHAP?
Definition
Yes
Term
When making acyl CoA, what is the first step and where does it occur?
Definition
Reaction of fatty acid with ATP to give acyl adenylate intermediate
Occurs in outer mitochondrial membrane
Term
Essentially reversible reactions are made irreversible by ____
Definition
the hydrolysis of pyrophosphate
Term
When making acyl CoA, what is the second step?
Definition
attack on the tightly bound acyl adenylate intermediate by the sulfhydryl of CoA--yields activated acyl CoA
Term
What is acyl carnitine ester formed from?
Definition
acyl CoA thioester
Term
Acyl carnitine translocase exchanges incoming ____ for outgoing ____
Definition
acyl carnitine
carnitine
Term
_____ character of carnitine gives rise to its high group-transfer potential
Definition
Zwitterionic
Term
Impairment of acyl carnitine translocase action can give rise to...
Definition
pathological condition
-cramping, muscle weakness, death
-primarily in muscle, kidney, and heart
-medium chain can be processed normally
Term
What are the recurring four reactions in B-oxidation pathway?
Definition
Oxidation by FAD
Hydration
Oxidation by NAD+
Thiolysis by CoA
Term
What are the products of B-oxidation?
Definition
NADH
FADH2
Acetyl CoA
Fatty acid shorter by two carbon atoms
Term
The oxidation of acyl CoA is catalyzed by _____ to give ______ with a ____ bond between C-2 and C-3
Definition
acyl CoA dehydrogenase
enoyl CoA
trans
Term
In first step of B oxidation, FADH2 electrons are transferred to _____
Definition
ETF (electron-transferring flavoprotein)
Term
ETF donates electrons to ______ and then ___ is reduced to ____
Definition
ETF ubiquinone reductase
ubiquinone
upiquinol
Term
How many ATP are generated per FADH2 in B oxidation?
Definition
1.5
Term
The hydration of the trans double bond in B-oxidation is catalyzed by ______
Definition
enoyl CoA hydratase
Term
Hydration in B-oxidation is _____
Definition
stereospecific
Term
Hydration of the trans double bond in B oxidation results in _____
Definition
L isomer of 3-hydroxyacyl CoA
Term
Hydration of the cis double bond in B oxidation results in _____
Definition
D isomer of 3-hydroxyacyl CoA (rare)
Term
The oxidation of the alcohol to a ketone in B-oxidation is catalyzed by ____
Definition
L-3-hydroxyacyl CoA dehydrogenase
Term
How many ATP result from each NADH (via electron transport chain)?
Definition
2.5
Term
The cleavage of 3-ketoacyl CoA by thiol group is catalyzed by ____
Definition
B-ketothiolase
Term
Acetyl CoA gives how many ATP?
Definition
10
Term
Define long-chain, medium-chain, and short-chain
Definition
Long: 12-18 C
Medium: 4-14 C
Short: 4-6 C
Term
Acyl CoA dehydrogenase is unique because it is sensitive to ____
Definition
length
Term
Which two enzymes are also required for the oxidation of unsaturated fatty acids?
Definition
cis (delta)3-Enoyl CoA isomerase
2,4-Dienoyl CoA reductase
Term
Propionyl CoA carboxylase is a ___ requiring enzyme homologous to ____
Definition
biotin
pyruvate carboxylase
Term
Which enzyme uses vitamin B12 to catalyze an intramolecular rearrangement via group migration?
Definition
Methylmalonyl CoA mutase
Term
Another name for Vitamin B12?
Definition
Cobalamin
Term
Unique groups on vitamin B12?
Definition
Corrin ring
Benzimidazole
Term
What is the purpose of vitamin B12?
Definition
A biological source of free radicals
Coenzyme
Term
Which three reactions is B12 a coenzyme for?
Definition
Intramolecular rearrangements
Methylations
Reduction of ribonucleotides to deoxyribonucleotides
Term
Methylmalonyl CoA catalyzes______
Definition
an intramolecular rearrangement reaction
Term
In the intramolecular rearrangement reaction catalyzed by methylmalonyl CoA, what exchange happens?
Definition
Exchange of two groups on adjacent carbons, in this case a hydrogen for a thioester
Term
In the methylmalonyl CoA reaction, what happens first?
Definition
Homolytic cleavage of the carbon-cobalt bond to give Co2+ (cobalamin) and 5'-deoxyadenosyl radical
Term
Coenzyme B12 in intramolecular migration serves as a _____ to drive the ______
Definition
source of free radicals
abstraction of hydrogen atoms
Term
What does the CH2 radical do in the methylmalonyl CoA reaction?
Definition
Pulls hydrogen from the substrate yielding a substrate radical
Term
The yielding of a substrate radical in the methylmalonyl CoA reaction induces ___
Definition
an intramolecular rearrangement (carbonyl CoA)
Term
The new substrate radical in the methylmalonyl CoA reaction does what?
Definition
abstracts hydrogen from 5'-deoxyadenosine methyl group
Term
______ is an essential feature of coenzyme B12
Definition
Weakness of Co-C bond
Term
Enzyme ___ residue displaces benzimidazole
Definition
His
Term
The displacement of benzimidazole facilitates....
Definition
cobalt-carbon bond cleavage and hydrogen abstraction
Term
_____ contributes to bond weakness in cobalt-carbon bond
Definition
Steric crowding
Term
Fatty acids can also be oxidized in ____
Definition
peroxisomes
Term
FA oxidation stops at _____
Definition
octanoyl CoA
Term
The initial dehydrogenation reaction in peroxisomes is catalyzed by ____ to give ____
Definition
acyl CoA
H2O2
Term
High _____ concentration within peroxisomes
Definition
catalase
Term
____ is caused by dysfunctional peroxisomes due to enzyme importing defect
Definition
Zellweger syndrome
Term
Acetyl CoA can only enter TCA cycle if ____ is available
Definition
oxaloacetate
Term
In fasting or diabetes, ______ consumes oxaloacetate
Definition
gluconeogenesis
Term
______ can be diverted to form ketone bodies
Definition
Acetyl CoA
Term
Three examples of ketone bodies
Definition
-Acetoacetate
-D-3-hydroxybutyrate
-Acetone
Term
______ combines two acetyl CoA to form _______
Definition
3-ketothiolase
acetoacetyl CoA
Term
_______________ formed from acetyl CoA and acetoacetyl CoA to give _________ and _
Definition
Hydroxymethylglutaryl CoA synthase
3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
CoA
Term
Which enzyme in ketone body formation is similar to citrate synthase?
Definition
hydroxymethylglutaryl CoA synthase
Term
Which reaction in ketone body formation is the reverse of thiolysis in FA oxidation?
Definition
3-ketothiolase combining two acetyl CoA to form acetoacetyl CoA
Term
What is the net reaction for ketone body formation?
Definition
2 acetyl CoA + H2O -> acetoacetate + 2 CoA + H+
Term
D-3-hydroxybutyrate is formed from...
Definition
reduction of acetoacetate in mitochondrial matrix by D-3-hydroxybutyrate dehydrogenase (subject to NADH availability)
Term
_____ is the major site of ketone body production (3-hydroxybutyrate and acetoacetate)
Definition
Liver mitochondria
Term
What is the preferred energy source for heart muscle and renal cortex?
Definition
ketone bodies
Term
Brain prefers ____ as a fuel source, but can use ____ when starved
Definition
glucose
acetoacetate
Term
What is the first step in utilization of ketone bodies?
Definition
Activation by CoA transfer from succinyl CoA
Term
Succinyl CoA is ____ in the liver
Definition
lacking
Term
Acetoacetyl CoA is cleaved by a ____ to yield 2 acetyl CoA
Definition
thiolase
Term
_______ is oxidized to acetoacetate
Definition
D-3-hydroxybutyrate
Term
High acetoacetate ____ lipolysis by adipose tissue
Definition
decreases
Term
What happens to the blood if there are excess ketone bodies present?
Definition
pH drops, coma and death can result
Term
Insulin-dependent diabetes mellitus can lead to...
Definition
diabetic ketosis
Term
Insulin signals _____
Definition
glucose uptake
Term
Steps leading to acidosis in diabetic ketosis:
Definition
-Insulin signals glucose uptake (deficit means liver cannot uptake glucose to provide oxaloacetate to process fatty-acid derived acetyl CoA)
-Decreases fatty acid mobilization by adipose tissue (FA continue to be released, taken up by liver, and converted to ketone bodies)
-Leads to acidosis, affecting tissue function
Term
Ketogenic diets are rich in ____ and low in ___ with some protein, forcing ketone bodies as main fuel source
Definition
fats
carbs
protein
Term
Fatty acid synthesis takes place in the ____
Definition
cytoplasm
Term
Fatty acid intermediates are covalently linked to...
Definition
sulfhydryl group of an acyl carrier protein (ACP)
Term
The association of synthetic enzymes in FA synthesis is catalyzed by...
Definition
fatty acid synthase
Term
FA chain is elongated by _ carbons at a time in synthesis, driven by _____
Definition
2
malonyl CoA decarboxylation
Term
_____ serves as the reductant in FA synthesis
Definition
NADPH
Term
The defaul production of FA synthesis is of ______
Definition
palmitate, C16
Term
What is the committed step in FA synthesis?
Definition
formation of malonyl CoA
Term
The carboxylation of acetyl CoA in the formation of malonyl CoA is catalyzed by...
Definition
acetyl CoA carboxylase
Term
Biotin prosthetic group attached to ____
Definition
Lys residue
Term
Carboxybiotin intermediate formed through ____
Definition
ATP hydrolysis
Term
In the ACP, ______ group attached to a serine residue contains a terminal ___
Definition
phosphopantetheine
thiol
Term
Fatty acid synthase in bacteria can be ___
Definition
dissociated into individual components
Term
Malonyl transacylase is _____
Definition
specific
Term
Acetyl transacylase can transfer ____
Definition
acyl groups other than acetyl
Term
What two compartments make up mammalian fatty acid synthase?
Definition
Modification, selecting and condensing
Term
Carnitine only carries ____
Definition
long chain fatty acids
Term
____ acts as a carrier of acetyl groups across the inner mitochondrial membrane
Definition
Citrate
Term
What drives transport from mitochondria to cytoplasm?
Definition
High citrate concentration
Term
What is the default fatty acid?
Definition
palmitate
Term
Where does elongation occur?
Definition
Cytoplasmic face of the ER membrane
Term
What does elongation do?
Definition
Adds two carbon units to carboxyl end of saturated and unsaturated FAs
Term
What drives elongation of FAs?
Definition
decarboxylation of malonyl CoA
Term
What catalyzes unsaturation of FAs?
Definition
oxidase
Term
What substrates are needed for FA unsaturation?
Definition
molecular oxygen
NADH or NADPH
Term
Unsaturation is catalyzed by three membrane-bound proteins. What are they?
Definition
NADH-cytochrome b5 reductase
Cytochrome b5
Desaturase
Term
What does NADH-cytochrome b5 reductase do?
Definition
NADH reduces bound FAD coenzyme
Term
____ of cytochrome b5 is reduced to ____ to form desaturase
Definition
heme, Fe2+
Term
In desaturase, the ____ is reduced to Fe2+. It interacts with ___ and ____, and a double bond is formed with the production of____
Definition
non-heme iron
O2
fatty acyl CoA
two H2O molecules
Term
Unsaturated FAs are derived from... (4 answers)
Definition
palmitoleate (16:1)
oleate (18:1)
linoleate (18:2)
linolenate (18:3)
Term
Other unsaturated FAs formed by...
Definition
various combinations of elongation and desaturation reactions
Term
Mammals cannot incorporate double bonds at carbons beyond...
Definition
C-9 (linoleate and linolenate)
Term
Essential FAs must be obtained from...
Definition
diet
Term
Arachidonate (20:4) is derived from...
Definition
linoleate
Term
_____ are derived from arachidonate
Definition
Eicosanoid hormones
Term
What are eicosanoid hormones?
Definition
Short range or local hormones
Act on producing cell or neighboring cells
Effects vary from one cell to another
Term
Examples of eicosanoid hormones?
Definition
Prostaglandins, Thromboxanes, Prostacyclin
Term
Aspirin blocks _____, blocking downstream eicosanoid production and their effects (ie: inflammation, fever, pain, blood clotting)
Definition
prostaglandin H2 synthase
Term
Prostaglandin
Definition
20-carbon FA containing 5-membered ring
Modified by reductases and isomerases
9 classes (A-I), subscript denotes # of double bonds
Term
Prostacyclin
Definition
derived from prostaglandins by prostacyclin synthases
Term
Thromboxanes
Definition
derived from prostaglandins by thromboxane synthases
Term
Leukotrienes
Definition
catalyzed by lipoxygenase
Term
____ is the key enzyme in the regulation of FA metabolism
Definition
Acetyl CoA
Term
Acetyl CoA carboxylase is inactivated by
Definition
phosphorylation
Term
AMP-dependent protein kinase (AMPK) modifies...
Definition
3 Ser residues
Term
AMPK is activated by ___ and inhibited by ___
Definition
AMP
ATP
Term
Acetyl CoA carboxylase is activated by _____
Definition
dephosphorylation
Term
Acetyl CoA carboxylase is allosterically stimulated by...
Definition
citrate
Term
Citrate induces _____, overcoming inhibition by phosphorylation
Definition
polymerization into filaments
Term
Palmitoyl CoA inhibits...
Definition
by inducing filament dissociation
Citrate translocase
Glucose 6-phosphate dehydrogenase
Term
Malonyl CoA inhbits...
Definition
carnitine acyltransferase I, especially in heart and muscle
Term
Glucagon and epinephrine...
Definition
-Stimulate release of FAs from triacylglycerols in adipocytes
-Inhibit FA synthesis by inhibiting acetyl CoA carboxylase (augment inhibition by AMPK)
Term
Insulin...
Definition
-Inhibits FA mobilization
-Stimulates deposition as triacylglycerols in muscle and adipocytes
-Activates acetyl CoA carboxylase by stimulating phosphatase
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