Lipid Degradation Prep

Three stages of FA processing from lipids

1. Mobilization via hormones

2. Activation of FAs

3. Beta oxidation of FAs

Epinephrine and glucagon = THE hormones

Step 1: Bind hormone to 7TM receptor to induce conformational change

Step 2: GTP activates adenylate cyclase

Step 3: Adenylate cyclase catalyzes conversion of ATP into cAMP

Step 4: cAMP activates PKA

Step 5: PKA phosphorylates peripellin

Step 5: PKA phosphorylates HS-lipase

Step 6: Activated Peripellin induces fat droplet rearrangement

Step 7: Release of cofactor for ATGL (lipase)

Step 8: Degrade TAG into DAG

Step 9: DAG degraded into MAG via phosphorylated HS-lipase

Step 6: Degrade DAG into MAG

Step 7: Degrade MAG into glycerol and FA using MAG lipase

Step 8: Transport FA to other fuel deprived tissues using blood-derived albumin protein

Step 10: Degrade MAG into glycerol and FA using MAG lipase

Step 11: Transport FA to other fuel deprived tissues using blood-derived albumin protein

Step 8: Glycerol absorbed by liver and phosphorylated

Glycerol --> L-glycerol-3P

Step 9: L-glycerol-3P ---> DHAP

Step 10: DHAP ---> D-GAP via TPI (Triose Phosphate Isomerase)

Produces one NADH and one H+ as a result of G-3P dehydrogenase activity

D-GAP = GAP = equivalent of intermed. in glycolysis and gluconeogenesis

Can be used to make glucoses or pyruvates

Step 1. ATP hydrolyzes to AMP and PPi via Nu: attk by -COOH end of FA

Requires Acyl CoA synthase (the enzyme resp. for catalyzing FA activation), FA, ATP, and CoA (with -SH group)

Step 2: AMP binds its PO4-3 group to COO- of FA

Step 3: FA-AMP undergoes Nu: attk by deprotonated -SH of CoA-SH at carbonyl

Recall from an earlier chapter that PPi does not exist normally in cells, and is irreversibly hydrolyzed by pyrophosphatase

Step 4: Likely tetrahedral intermediate formed

Step 5: AMP kicked off as good LG to create FA-S-CoA, an activated FA w/ a thioester

ATP-->AMP +PPi is the equivalent of hydrolyzing two ATP mlcs.

FA-AMP is an acyl adenylate, found in pathways that need activated carboxyl groups (ex. amino acid synthesis)

Occurs on outer mitochondrial membrane

Occurs in mitochondrion matrix

Requires specialized transport of activated acyl CoA (if longer than 10C) from inner membrane to matrix

Step 1: Transfer acyl from CoA to zwitterion alcohol carnithine via carnitine acyltransferase 1 (CA1)

Step 2: Use translocase to shuttle acyl carnitine across mitochondrial membrane into mitochondrial matrix

If the acyl-CoA is less than 10C long, then no carnitine transferase, translocase enzymes needed b/c it can pass thru. membr into matrix directly

Step 3: Use CA2 to transfer acyl from carnitine to CoA

Step 4: One carnitine transferred out of matrix for every acyl carnitine transferred into matrix

FADH2, NADH, and ATP prod. during FA Beta oxidation

Step 1: Oxidation of acyl-CoA into trans-Δ²-enoyl CoA via...

Isozymes exist for acyl CoA dehydrogenase depending on FA length

Contains Flavin (as FAD) in AS

Acyl-CoA dehydrogenase

Isozymes = enzymes with diff a.a structure but same specificity for catalyzing certain reactions

E2 mechanism to remove Beta H+ using a general base

Steps of aβ unsaturation

1. General base takes away α H+ to form enolate (enolate formation)

2. Carbonyl of thioester reforms again and α Carbon is a carboanion

3. Radical rxn. initiation has FAD take an e- from the 2x bond of acyl-CoA and abstract a H+ from an acid (HA).

4. Used to form an FA radical and semiquinone

5. Abstraction of β H+ from acyl CoA by FAD derived semiquinone (Termination)

5. FADH2 transferred to high-E flavoprotein

6. That flavoprotein transfers the e- to the new ETF: ubiquinone reductase

7. Ubiquinone reductase reduces ubiquinone to ubiquinol

8. Ubiquinol transfers e- to second H+ pumping ETC protein site

Ubiquinone reductase = an Fe-S protein

Step 2: Hydration of trans-Δ²-enoyl CoA into L-3-hydroxyacyl CoA via...

Its FAD in its active site is reduced by E2 elimination @ β, and which then reduces the FAD of an ETF, which reduces an ETF with an Fe-S component, which reduces ubiquinone to ubiquinol

enoyl CoA hydratase

Only hydrolyzes into the L isomer of 3-hydroxyacyl CoA with the trans-Δ²-enoyl CoA

Only hydrolyzes into the D isomer of 3-hydroxyacyl CoA with the cis-Δ²-enoyl CoA