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102511 Fatty Acid Metabolism
UC MED 2015
83
Medical
Graduate
10/27/2011

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Term
What is the primary energy source for the body and why?
Definition
Fatty acids
-more compact storage than glycogen
-stored in specialized cells
-unlimited capacity for storage
Term
Where does fatty acid synthesis and degradation occur?
Definition
synthesis- cytoplasm
degradation- mitochondria
Term
What is derived from fatty acid degradation to use as an alternative energy source for glucose? Why is this used?
Definition
ketone bodies- used when glucose supplies are limiting
Term
Why is fatty acid storage more compact than glycogen storage?
Definition
hydrophobic effect in fatty acids
Term
Fatty acids have both a polar head and a hydrophobic tail, what is this called?
Definition
the molecules are amphipathic
Term
How little and how long can the fatty acid tail be?
Definition
As little as 3 carbons up to 24 carbons
Term
What is the common name for C16:0?
Definition
palmitate
Term
What is the common name for cis-∆9-C16:1?
Definition
palmitoleate
Term
What is the common name for C18:0?
Definition
stearate
Term
What is the common name for cis∆9-C18:1?
Definition
oleate
Term
What is the common name for cis∆9,12-C18:2?
Definition
linoleate
Term
What is the common name for cis∆9,12,15-C18:3?
Definition
linolenate
Term
What is the common name for cis∆5,8,11,14-C20:4?
Definition
arachidonate
Term
What are three of the main biological functions of fatty acids?
Definition
1) energy storage in the form of triacylglycerol
2) membrane structure (as a component of phospholipids)
3) second messengers (prostaglandins, thromboxanes are derived from fatty acids)
Term
What consists of a glycerol molecule to which is esterified three fatty acids?
Definition
Triacylglycerol
Term
Are the fatty acids at the three positions in triacylglycerols the same?
Definition
No, they don't have to be.
Term
What is the first step in the activation of adipocytes? It leads to the production of glycerol and free fatty acids(FFA)?
Definition
Activation of Hormone-sensitive lipase(HSL)
Term
What activates HSL?
Definition
PKA- phosphorylates it, thus another function of the cAMP
Term
Does HSL remove all 3 FFA?
Definition
No, it removes the first one and the other two are removed by non-regulated lipases
Term
FFA released from the adipocyte travel to tissues bound to?
Definition
serum albumin in the blood
Term
What is glycerol's fate?
Definition
conversion to DHAP in the liver
Term
ß-oxidation oxidizes how many carbons at a time?
Definition
2 carbons
Term
Can the brain do ß-oxidation?
Definition
No
Term
What other pathway utilizes ß oxidation?
Definition
TCA cycle- generation of succinyl-CoA
Term
Where is fatty acid activated and what makes it active?
Definition
activated to acyl-CoA derivative in the cytoplasm (side not, its bound to a fatty acid binding protein to increase solubility)
Term
What helps fatty get into the mitochondria?
Definition
carnitine
Term
How many high energy bonds are required for fatty acid activation?
Definition
2 high energy bonds
Term
What enzyme gets Acyl-CoA into the mitochondria?
Definition
Carnitine Acyl-Transferase I (CAT-I)
Term
What inhibits CAT-I?
Definition
Malonyl-CoA
Term
If a person has CPT-II deficiency, what would happen?
Definition
hypoglycemia
Term
What are the four main enzyms in fatty acid oxidation?
Definition
1) Acyl-CoA dehydrogenase- makes FADH2
2) Enyl-CoA hydrate
3) L-3-hydroxyacyl CoA dehydrogenase- makes NADH
4) ß-ketothilolase- makes Acetyl-CoA
Term
There are many isoforms of which enzyme from ß-oxidation?
Definition
Acyl-CoA dehydrogenase
Term
What are the different isoforms of Acyl-CoA Dehydrogenase and what do they work on?
Definition
SCAD- 4-8
MCAD- 8-12
LCAD- 14-20
VLCAD- >20
Term
Where do you find VLCAD?
Definition
peroxisome only
Term
What happens to the electrons from FADH2 in the peroxisome created by VLCAD?
Definition
reduce O2 to H2O2 (catalase converts H2O2 to H2O and O2)
Term
Why are very long chain fatty acids such a poor source of energy?
Definition
They are digested in the peroxisome and some of the electrons bypass the ETC, instead used to create H2O2, and the fatty acid won't go to the mitochondria until it is about 8 carbons in length, so a lot of potential energy is lost.
Term
What uses NADPH and reduces are fatty acid molecule?
Definition
2,4 Dienoyl-CoA Reductase(used for unsaturated fatty acid degradation)
Term
What moves a double bond in unsaturated fatty acids?
Definition
Isomerase
Term
Unsaturated fatty acid, what is the effect of an odd numbered double bond?
Definition
-Only use the isomerase rxn
-lose step at which FADH2 is produced
- loss of 1.5 ATP compared to a saturated fatty acid of the same length
Term
Unsaturated fatty acid, what is the effect of an even numbered double bond?
Definition
-Use up and NADPH; all other steps are the same
- loss of 2.5 ATP as compared to a saturated fatty acid of the same length
Term
What is produced instead of acetyl-CoA at the end of an odd-chain fatty acid oxidation?
Definition
Propinoyl-CoA
Term
What is produced instead of acetyl-CoA at the end of an odd-chain fatty acid oxidation?
Definition
Propinoyl-CoA
Term
What will propinoyl-CoA enter the TCA cycle after undergoing processing? What cofactors are required in this processing?
Definition
It will enter as succinyl-CoA

Requires biotin and B12
Term
What three enzymes are required to process Propinoyl-CoA into succinyl-CoA?
Definition
1) Propinoyl-CoA Carboxylase (uses ATP; requires biotin)
2) Racemase
3) Methyl-malonyl-CoA Mutase (requires B12)
Term
How much ATP is produced from propinoyl-CoA?
Definition
16.5
Term
What will accumulate in the blood in an individual with MCAD deficiency?
Definition
6-10 carbon dicarboxylic acids
Term
Tell me more about alpha-oxidation?
Definition
1) oxidize alpha carbon of branched cain fatty acids
2) create a-keto acid, which then undergoes oxidative decarboxylation
Term
Tell me more about mega-oxidation?
Definition
-omega-carbon oxidized to alcohol, then to aldehyde, then to carboxylic acid
-used to get energy from fatty acids, when ß-oxidation not occuring, primarily due to disease
Term
How does fatty acid derived FADH2 deliver e- to the ETC?
Definition
-Uses ETF(electron transfer flavoprotein)-contains a bound FAD
-ETF will then directly transfer the e- to CoQ via ETC-CoQ oxidoreductase enzyme
Term
What is produced in the liver when Acetyl-CoA levels are elevated?
Definition
ketone bodies- when glucose supplies are limiting
Term
What are some of the ketone bodies?
Definition
1) acetoacetic acid
2) ß-hydroxy butyric acid
3) acetone (we can't deal with it directly so its exhaled)
Term
What is an intermediate in cholesterol synthesis that is made in ketone biosynthesis?
Definition
HMG-CoA
Term
When is ß-hydroxy butyrate made?
Definition
Only when the NADH/NAD+ ratio is high within the mitochondria; it is reconverted to acetoacetate for metabolism
Term
Acetoacetate is metabolized everywhere except the______, and it is metabolized by which enzyme?
Definition
liver

CoA-transferase
Term
What happens to glucose levels when ketone body levels rise?
Definition
glucose levels drop to about 70% of normal
Term
Defects in Fatty Acid Oxidation: What happend when lacking ETF(Electron Transfer Flavoprotein) or ETF:CoQ Oxidoreductase?
Definition
Both are usually fatal- not enough energy generation fro fatty acid oxidation
Term
Defects in Fatty Acid Oxidation: What happens with a Carnitine deficiency?
Definition
-Inability to transport activated fatty acids into the mitochondria: weakness, cramping
-Treat by adding carnitine to the diet
Term
Defects in Fatty Acid Oxidation: What happens with a MCAD deficiency?
Definition
-Affects 1/15,000 live births (similar to PKU)
-Glu to Lys mutation due to a single base change; charge difference, unstable prtoein
-Hypoglycemia results when glycogen stores are low
--Cannot obtain full energy from fatty acid oxidation (hexanoylglycine also accumulates: hexanoyl-CoA + glycine, a catalyzed reaction)
--Insufficient energy to allow gluconeogenesis to continue
--ketone bodies not formed due to a lack of acetyl-CoA
Term
What are the two substrates for fatty acid biosynthesis?
Definition
acetyl-CoA and Malonyl-CoA
Term
What enzyme forms Malonyl-CoA from acetyl-CoA in one step?
Definition
Acetyl-CoA Carboxylase (uses ATP and requires Biotin)- this is a regulated step-
Term
When does a build-up of acetyl-CoA occur?
Definition
when malate is leaving for gluconeogenesis
Term
What does unripe Ackee(jamaican fruit) do to you?
Definition
It blocks ß-oxidation and makes you sick and can lead to death of children
Term
All carboxylase reactions require what cofactor?
Definition
Biotin; except for in blood clotting which requires Vit K
Term
What does Fatty acid biosynthesis require for the reduction reactions?
Definition
NADPH
Term
Where does fatty acid elongation occur?
Definition
ER
Term
Desaturation of fatty acids...
1) where are the enzymes located
2) requires what?
3)what is oxidized in this rxn?
4) what is reduced in this rxn?
Definition
1) located in the ER
2) requires cytochrome b5
3) NADH and fatty acid are oxidized
4) O2 is reduced to water
Term
Where can insert double bonds?
Definition
At positions 5,6,9
Term
What are the essential fatty acids?
Definition
Linoleic acid- cis∆9,12 C18:2
Linolenic acid- cis ∆9,12,15 C18:3
Term
What enzyme does this rxn and where does it occur?

Acetyl-CoA + OAA--> citrate
Definition
Citrate synthase in the mitochondria
Term
What enzyme does this rxn and where does it occur?

Citrate + ATP-->OAA + acetyl-CoA +ADP +Pi
Definition
Citrate lyase in cytosol
Term
What enzyme does this rxn and where does it occur?

OAA +NADH--> malate + NAD+
Definition
Malate dehydrogenase- in cytosol for transport of acetyl-CoA, but this rxn in mitochondria for TCA cycle
Term
What enzyme does this rxn and where does it occur?

Malate + NADP+ --> Pyruvate + CO2 + NADPH
Definition
Malic enzyme- in the cystosol
Term
What enzyme does this rxn and where does it occur?

Pyruvate +ATP +CO2 --> OAA + ADP +Pi
Definition
Pyruvate Carboxylase- in the mitochondria
Term
What enzymes of fatty acid metabolism are subject to long-term adaptation?
Definition
1) Fatty acid synthase
2) Acetyl-CoA carboxylase
3) Citrate Lyase
4) Malic enzyme
5) Glucose-6-phosphate dehydrogenase
Term
How long does it take for long-term adaptation to occur in fatty acid metabolism? What causes this adaptation?
Definition
It takes 2-3 weeks, in result to a higher/lower calorie diet
Term
HSL (hormone sensitive lipase) is hormonally regulated by?
Definition
PKA-phosphorylated and activated-leads to fat oxidation;ie we need energy
Term
Acetyl-CoA Carboxylase is hormonally regulated by?
Definition
AMP activated protein kinase- it is inactivated; ie energy is low, we don't need fat synthesis (muscle does the same thing)
Term
Insulin promotes the dephosphorylation of?
Definition
1) HSL
2) acetyl-CoA carboxylase

ie-too much glucose, make some fat
Term
HSL has allosteric regulation from?
Definition
ketone bodies-inhibits slightly
Term
Acetyl-CoA has allosteric regulation from?
Definition
citrate-activator (don't forget citrate inhibits PFK-I)
Term
CAT-I is inhibited by?
Definition
malonyl-CoA (to prevent futile cycles)
Term
malonyl-CoA decraboxylase is activated in the muscle by?
Definition
AMP-activated PK
Term
From what we have learned so far...what happens when glucagon is released?
Definition
1) Adenylate cyclase activated, cAMP levels rise
2) PKA activated
3) HSL phosphorylated and activated, fatty acids are released for travel to the tissues(bound to serum albumin)-sidenote epinephrine more effective at working on adipocytes
4) Glycogen phosphorylase is activated (glycogen synthase inactivated) to generate glucose from glycogen
5) PFK-2, PK phosphorylated-inactivated in liver so glycolysis inhibited( gluconeogenesis favored)
6) Acetyl-CoA carboxylase inactivated by phosphorylation by AMP dependent kinase; fatty acid oxidation favored, also provides energy for gluconeogenesis
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