Hardman - Oxidation of Fatty Acids Flashcards
Cystic Fibrosis
Pancreatic dysfunction
Growth failure, ADEK deficiency, bone disease
Not digesting fats
Need for Lipids
- Building blocsk for phospholipids and glycolipids
- Modification of proteins
- Fuel
- Hormones and intracellular messaging
3 Sources of Fatty Acids
- Diet
- Storage lipid droplets
- Fats synthesized in liver
Dietary Fats
90% TAGs
Multiple enzymes needed to digest each type
Stomach Fat Digestion Enzymes
Acid resistance lingual lipases
Gastric lipases
Enzyme which removes first two FA’s from TAGs?
Which does it remove?
Pancreatic Lipase removes FA at carbons 1 and 3
Colipase
How is it activated?
Anchors lipase at the lipase-aqueous interface
Cleavage by trypsin
Enzyme for digestion of cholesterol esters
Cholesterol esterase from pancreas
Enzymes for phospholipid (ex. phosphatidylcholine) digestion
Which carbons do these remove?
- Phospholipase A2 (#2 Carbon)
- Lysophospholipase (#1 Carbon)
How is lipid digestion hormonally controlled?
Cholecystokinin (CCK) - from jejunum and duodenum
(+) Gall Bladder - bile release
(+) Pancrease - enzyme release from exocrine cells
Secretin - produced in response to low pH of chyme (rich in bicarb)
What happens to fatty acids following intestinal lipase processing?
The TAGs which have been degraded to FAs / Glycerol are taken up by intestinal mucosa, and converted back into TAGs, and packaged on chylomicrons
What apolipoproteins label chylomicrons?
B-48
C-III
C-II
Chylomicron components
How do these components reach tissues?
TAGs incorporated with cholesterol, apolipoproteins (ApoC-II)
Move through lymphatic system and bloodstream to tissues
What enzyme converts chylomicrons to their components?
How is it activated?
Lipoprotein Lipase
Activated by apoC-II in capillary
What are fatty acids associated with when transported to other cells?
Albumin
Glycerol use during fat synthesis
Used by liver to produce glycerol-3-phosphate for:
glycolysis
gluconeogenesis
How are fatty acids transported into the cellular cytoplasm?
- Travel blood as TAGs (chylomicrons)
- Membrane bound lipases break down for transit
- Reform as TAGs in cytoplasm
MCAD
Medium Chain Acyl-CoA Dehydrogenase Deficiency
Symptoms: Lethargy, vomiting, appetite supression
Tests: Hypoketotic, hypoglycemia
3 Stages for Mobilization of fatty acids as fuel
- Mobilization
- Activation and Transport to mitochondria
- Breaking down FA to acetyl-CoA
What regulates mobilization of storage fatty acids?
Think: Under what conditions would you start to tap into your stored fatty acids?
Hormonally controlled lipase–activated by glucagon / epinephrine
Your glucose stores are low, and you need to produce energy if you’re burning your fat stores
What is the fate of glycerol when all the FAs are cleaved off?
Enters glucose pathway, need to add phosphate first
Converted to Glycerol 3-Phosphate
What is required for transport of FAs into mitochondria?
Activation w/ Acetyl-CoA (ATP dependent)
What two major organ systems do not use Fatty Acids for fuel?
RBCs (no mitochondria)
Brain (blood brain barrier)
What carriers activated fatty acids into mitochondria?
Hint: Hardman reaaaally emphasized this
Carnitine
Do all fatty acids require carnitine?
No, short/medium (< 12 Carbons) can cross without carnitine
What are sources for carnitine?
- Meat
- Synthesized from lysine and methionine by liver or kidney–not skeletal or heart muscle
What is the membrane enzyme that is responsible for transfering acyl group from long chain fatty acid to carnitine?
What inhibits this?
Why?
Carnitine Acyltransferase I
aka Carnitine Palmitoyltransferase
aka CPT - I
(all same thing)
INHIBITED BY MALONYL CoA
Malonyl CoA is the first commited step of Fatty Acid Synthesis–can’t have breakdown/synthesis going on at the same time!
Carnitine Deficiency (or CPT-1)
Source?
Results?
Source:
Liver Disease
Vegetarian Diet
Burns, Pregnancy
Hemodialysis (kidney disease)
Gentics
Results:
- Inability to synthesize glucose during a fast–low blood sugar, coma, death
2. Sustain exercise
Steps for Fatty Acid B-Oxidation
Oxidation
Hydration
Oxidation
Thiolysis
- Shortened by 2-carbons each cycle
What are the electron acceptors in B-Oxidation?
FADH2, NADH
What type of enzyme drive an oxidation rxn?
Dehydrogenase
What are net products each OHOT round of B-Oxidation?
1 FADH2
1 NADH
1 Acetyl CoA
How many cycles would a n-(even)-carbon require for complete oxidation?
(n/2) - 1
-1 because the last step cuts four carbons into two Acetyl CoA, so in reality the true “net” would be 2 Acetyl CoA for the last step
Total ATP from complete B-Oxidation of Palmitate?
106 ATP
If B-Oxidation handles even carbon fatty acids, what about Odd?
Final step (5-carbon) yields:
3-carbon Propionyl CoA and
2-carbon Acetyl CoA
- Propionyl CoA converted to Succinyl CoA (5-carbon) to enter Citric Acid Cycle
What coenzymes or vitamins are required for conversion of propionyl coa to succinyl coa?
Biotin (B7, Vitamin H)
B12
What additional steps are required for unsaturated fatty acid processing in B-Oxidation?
Odd # Double Bonds: Isomerase
Even # Double Bonds: Reductase
iso** - **odd
r_e_d - _e_ven
Refsum Disease
Genetic defect in peroxisomal enzyme responsible for initial step in oxidation of phytanic acid
Symptoms: Retinitis pigmetosa, progressive peripheral neuropathy, skeletal malformations, severe motor weakness
a-Oxidation
(alpha-ox)
Takes place in peroxisomes
branched chain fatty acids
very long chain fatty acids
hydrogen peroxide byproduct
Ketosis
3 major ketone bodies
Ketone bodies formed from acetyl CoA when fat degradation predominates
Ketone Bodies:
- Acetoacetate
- 3-hydroxybutyrate
- Acetone
Conversion of 3-Hydroxybutyrate or Acetone from Acetoacetate depends on what?
NADH/NAD+ ratio,
High NADH = 3-hydroxy butyrate
High NAD+ = Acetone
What will excess acetyl CoA eventually lead to?
High ketone production
Diabetic Ketosis
Absence of insulin:
- Liver cannot provide ocaloacetate
- Insulin normally decreases fatty acid metabolism
– Liver will produce large amount of ketone bodies, lowering pH
