Chapter 17 Flashcards
Atherosclerosis
Lipid accumulation in vessel walls = inflammation/recruit WBC (macrophages)
Macrophage- consume lipids, recruit more macrophages
Plaque forms- cholesterol/dead macrophages, SMCs, this could lead to calcification
Function of lipoproteins
transport dietary triacylglycerols to adipose tissue
and cholesterol to the liver
Chylomicrons
Intestine –> Other tissues
TAGs –> Adipose
Cholesterol –> Liver
How does liver repackage cholesterol/lipids?
As VLDL
VDLD
Release TAGs and become LDL
50-65% TAG
LDL
Circulating Lipoprotein, “bad”
Taken up by adipose tissue/liver
45-50% cholesterol
HDL
Transport extra cholesterol from tissue back to the liver
40-55% protein
How LDL gives cell cholesterol
Receptor mediated endocytosis
LDL receptor recycled, but LDL protein degraded
How HDL removes excess cholesterol from adipose tissue
Flippase (ABC)
Tangier disease- defect in transporter gene = accumulation in tissues
Familial hypercholesterolemia
Genetic defect in LDL receptor
Causes rise in serum levels, atherosclerosis, early death
Nonfamilial hypercholesterolemia
Treated with PCSK9 inhibitor leads to increased recycling of LDL receptor to cell surface (PCSK9 causes degradation of LDL receptor)
More LDL receptor = increased uptake of circulating LDL
What is the primary source of fatty acids used as metabolic fuel?
Dietary triacylglycerols
Triacylglycerol —-> glycerol and 3x fatty acyl groups by
lipoprotein lipase (extracellular peripheral)
add 3H2O
Hydrolysis of triacylglycerols occurs
extracellularly
Why is the concentration of free fatty acids in body very low?
These molecules are detergents and could disrupt cell membranes
How are TAGs mobilized?
How do released TAGS travel?
Mobilized: via intracellular hormone-sensitive lipase
Travel: albumin carrier
Where are free fatty acids taken to?
Liver/muscles (especially heart muscle)
To be degraded, first, fatty acid must be…
activated
How are fatty acids activated?
2 steps by acyl-CoA synthetase
Fatty acid 2 step activation
1) F.a. displaces diphosphate group of ATP. This creates an acyladenylate
2) HSCoA displaces AMP from acyladenylate froming acyl-CoA
Why is fatty acid synthesis spontaneous and irreversible?
the hydrolysis of PPi is highly exergonic
Synthases are specific depending on
length of fatty acids
Fatty acid activation occurs
in the cytosol
then use carnitine system to get out
Carnitine shuttle
carnitine acyltransferase: transfers acyl group to carnitine
In mitochondria: carnitine acyltransferase acyl group to HSCoA
Carnitine returns to cytosol via transporter; acyl group remains in matrix for oxidation
Beta oxidation
4 steps
acyl-CoA –> Acetyl-CoA
Beta oxidation mnemonic
Fatty acyl-CoA, Enoyl-CoA, 3-hydroxyacyl-CoA, ketoacyl-CoA, 2C shorter fatty acyl-CoA and acetyl-CoA
(F.A. E HOA K)
dehydrogenase, hydratase, dehydrogenase, thiolase
DHDT
Why is beta oxidation called spiral pathway?
2 less C per round
Where does beta oxidation occur?
Matrix, but also…
C3 (two carbons from carbonyl carbon)
Where are acetyl units lost from in beta oxidation?
activated CoA end (not methyl end)
Why does beta oxidation happen?
Source of free energy when CH2O unavailable (especially during fast, when no carbs)
Total ATP from beta oxidation
14 ATP (10 per acetyl –> 3 NADH, 1 QH2, 1 GTP)
- 5 = QH2
- 5 = NADH
Regulation of Beta oxidation depends on availability of free CoA as well as
NAD+/NADH
Q/QH2
Cis Fatty acids: Beta oxidation
Where is problem?
Problem is in second step of round 4: 3,4 DB
Solution: enoyl-CoA isomerase
cis 3,4 –> Trans 2,3
But for linoleate, 2x DB?
Round 5: reductase uses NADPH to convert trans 2,3 & cis 4,5 —> Trans 3,4
Then, isomerase trans 3,4 –> trans 2,3
Why do unsaturated fatty acids yield less energy than saturated fatty acids?
need isomerases for beta oxidation
QH2 bypass =1.5
NAPH reduction =2.5
Total 4 ATP lost
Propinyl-CoA to Acetyl-CoA
Please, may Mary sell seashells for money, please
Propinyl-CoA CARBOXYLASE Methylmalonyl-CoA RACEMASE Methylmalonyl-CoA MUTASE Succinyl-CoA SYNTHETASE Succinate DEHYDROGENASE Fumarase Malic Enzyme Pyruvate DEHYDROGENASE
Why must propionyl-CoA be fully converted to pyruvate to enter CAC as acetyl-CoA?
to utilize energy in thioester bond
What’s weird about Methylmalonyl-CoA Mutase?
Prosthetic group derived from cobalamin
Obtained from B12
Peroxisome fatty acid oxidation: what’s so special about that?
Where it happens in all plants
Step 1 is special: acyl-CoA OXIDASE
FAD FAH2
O2 –> H2O2
Peroxisomes are a chain shortening system: why?
Peroxisomal enzymes specific for very long chain fatty acids.
Branched chains not recognized by mitochondrial enzymes; peroxisomes compensate for lack of recognition due to branched methyl groups
Beta oxidation summary:
1) Location
2) Acyl-group attached to what?
3) Where does it funnel e-?
4) ATP involved?
1) M. Matrix
2) Coenzyme A
3) Q and NAD+
4) 2x ATP to activate
Fatty acid synthesis:
1) Location
2) Fatty acid chain attached to what?
3) Reducing agent
4) ATP involved?
1) Cytosol
2) acyl-carrier protein (ACP)
3) NADPH
4) Consumes 1 ATP for every 2C incorporated
How do we get acetyl-CoA to cytosol for fatty acid synthesis
CITRATE transporter
How does citrate transporter regenerate pyruvate?
Malic enzyme
What is the main regulatory step of fatty acid synthesis?
Acetyl-CoA Carboxylase
Acetyl-CoA Carboxylase
Similar to propionyl-CoA/pyruvate carboxylase
Co2 activated by biotin (consumes ATP)
carboxylate transferred to acetyl-coA
Malonyl-CoA donates 2-carbon acetyl unit to build FA
Fatty acid synthesis: enzyme
multifunctional, 7 catalytic reactions
Pantothenate arm in ACP swings
6 active sites
MAT, KS, KR, DH, ER, TE
(Married Kangaroos Kick Dirty Elves Tirelessly)
First two reactions of fatty acid synthesis
Transacylations
prime/load the enzyme with reactants for condensation reaction
MAT
Condensation (KS) reaction of Fatty acid synthesis (step 3)
decarboxylates malonyl-ACP, which allows C2 to attack acetyl thioester to form acetoacetyl-ACP
Product similar to product of step 2 beta-oxidation, but for this it’s in the D configuration
Growth of acyl chain occurs at thioester end
Fatty acid synthesis step 4
KR
Reduction (NADPH –> NADP+)
Fatty acid synthesis step 5
DH
H2O released
Dehydration
Fatty acid synthesis step 6
ER
NADPH –> NADP+
Reduction
Fatty acid synthesis step 7
acyl group transferred from ACP to enzyme Cys group
Another malonyl loaded onto free ACP for another condensation reaction
1 malonyl-CoA per round of fa synthesis costs 1 ATP per molecule
How much for 7 rounds for palmitate?
42 ATP
7 ATP + 35 ATP from the 14 NADH
Why is using multienzyme protein advantage?
Allows enzymes to be synthesized and controlled in a coordinated fashion
Product of one reaction can quickly diffuse to the next active site
In mammals, fatty acid synthase produces mostly 16C saturated f.a. Palmitate.
Where does elongation occur?
Either ER OR mitochondria
ER: use malonyl-CoA as the acetyl-group donor
Mitochondria: fatty acids elongated by reactions that more closely resemble the reversal of beta oxidation but use NADPH
