FA Metabolism Flashcards
Nomenclature for double bonds
Number corresponds to number of carbons away from carbonyl carbon, inclusive
Most common saturated FA
Palmitic acid
Most common unsaturated FA
Oleic acid
Overview
Glycerol-3P is created from DHAP, then combined with free FA’s to create triglycerides
Where is Triglyceride stored?
In adipose tissue, for use of other tissues
In muscle, for its own use
What is the result of an overflow of excess lipids
Lipids begin to be stored in other tissues, such as the liver and muscle leading to insulin resistance
What breaks down TG to DAG?
Adipose Triglyceride Lipase
What breaks down DAG to MAG?
Hormone Sensitive Lipase
What breaks down MAG to glycerol and free FA?
MAG Lipase
Which hormones stimulate lipolysis?
Epinephrine, Glucagon
3 macro steps of FA breakdown
1) Acylation of FA’s via acyl-CoA
2) Transport into mitochondria via Carnitine shuttle
3) ß-oxidation
What is special about acyl-CoA synthase in terms of energy?
It uses ATP which gets converted into AMP and PPi because the bond is so high-energy, which allows the reaction to be pulled to the right
Describe the Carnitine shuttle
CPT-1 combines Acyl-CoA with Carnitine to produce fatty acyl-carnitine, which is then transported across the IMM by Translocase
CPT-II splits fatty acyl-carnitne into Acyl-CoA and Carnitine which is cycled back out
CPT = Carnitine Palmitoyl Transferase
First step of beta-oxidation
Acyl-CoA to trans-∆2-enoyl-CoA via Acyl CoA DH
FAD -> FADH2
Feeds into ETC
Second step of beta-oxidation
trans-∆2-enoyl-CoA to L-3-hydroxyacyl-CoA
via Enoyl-CoA hydratase
Input of H2O
Third step of beta-oxidation
L-3-hydroxyacyl-CoA to 3-Ketoacyl-CoA
via L-3-hydroxyacyl-CoA DH
NAD to NADH
Feeds into ETC
Fourth step of beta-oxdation
3-Ketoacyl-CoA to Acyl-CoA + Acetyl-CoA
via ß-ketothiolase
Input of CoA
Inhibition of Carnitine shuttle via Malonyl-CoA
ACC (acetyl-CoA carboxylase) creates Malonyl-CoA (inhibitory)
Inhibition of ACC via AMPK/PKA signals a low-energy state and stopping of FA synthesis
Prevention of Malonyl-CoA synthesis, resulting in de-inhibiton of Carnitine shuttle
AMPK
AMP-activated protein kinase
Describe MCAD
Medium-chain Acyl-CoA DH deficiency (first step in ß-oxidation)
Hypoglycemia
- no FA oxidation, so glucose used up
- no FA, so no gluconeogenesis
Ketone body pathway synthesis first step
2 Acetyl-CoA via Thiolase to Acetoacetyl-CoA
Ketone body pathway synthesis second step
Addition of another Acetyl-CoA to produce HMG-CoA via HMG-CoA synthase
Ketone body pathway synthesis third step
Loss of acetyl-CoA produces acetoacetate
Ketone body pathway synthesis fourth step
Acetoacetate can produce acetone and D-3-Hydrozybutyrate (all ketone bodies) via DH
Ketone body breakdown first step
D-3-Hydroxybutyrate via DH to Acetoacetate
Ketone body breakdown second step
Acetoacetate to Acetoacetyl-CoA via Succinyl-CoA to Succinate
enzyme is transferase
Ketone body breakdown third step
Acetoacetyl-CoA to 2x Acetyl-CoA via Thiolase
Diabetic Ketoacidosis
T1D - decreased insulin, increased epinephrine and glucagon trigger mass lipolysis
This puts many FA’s into circulation, which are broken down into ACetyl-CoA
Leads to mass production of ketone bodies (H+ is a byproduct, creating acidosis)
FA synthesis differences to oxidation
1) All in cytoplasm
2) Reactants attached to ACP
3) FAS complex
4) Uses NADPH
FA synthesis step one
Acetyl-CoA to Malonyl-CoA by Acetyl-CoA carboxylase
FA synthesis step two
Attachment of ACP
Transacylase
FA synthesis step three
Condensation step of acetyl and malonyl ACP to create acetoacetyl-ACP via Condensing enzyme
Loss of ACP and CO2
FA synthesis step four
Reduction via reductase to D-3-Hydroxybutyryl-ACP
NADPH to NADP
FA synthesis step five
Dehydration of D-3-Hydroxybutyryl-ACP to Crotonyl-ACP
FA synthesis step six
Reduction of Crotonyl-ACP to Butyryl-ACP
NADPH to NADP
FA synthesis after 16C
Hydration of Palmitoyl-ACP to Palmitic Acid via Thioesterase
Overall reaction for Palmitate synthesis
8 Acetyl CoA + 14 NADPH + 7 ATP
Where do the NADPH for FA synthesis come from?
8 from Citrate Pyruvate shuttle
6 from PPP
Which enzymes are part of Fatty Acid Synthase?
All of them except for Acetyl-CoA Carboxylase
Acetyl-CoA Carboxylase inhibitors and activators
Inhibitor: long chain acyl-CoA and PKA/AMPK
Activator: Citrate
Goal of the Citrate-Pyruvate shuttle
Bring Acetyl-CoA into the cytoplasm for FA synthesis, and produce NADPH
Citrate-Pyruvate shuttle mechanism
OAA + Acetyl-CoA -> Citrate -> OAA -> Malate -> Pyruvate -> OAA
Which enzyme releases Acetyl-CoA in the cytosol for FA synthesis?
Citrate to OAA via ATP-Citrate Lyase
Which enzyme reoxidizes NADP in the cytosol for FA synthesis?
Malic enzyme converts Malate to Pyruvate and produces NADPH
FA elongation
Process of extending Palmitic acid up to 24 C using Malonyl CoA and NADPH
FA desaturation
Uses desaturases to remove carbon atoms
What are essential fatty acids
Linoleic and Linolenic acid must be supplied in the diet because double bonds cannot be synthesized beyond C9
Source of glycerol for TAGs
DHAP and phosphorylation of glycerol by glycerol kinase (liver)
