• Catabolic → Degradation
  
• Anabolic →  Synthesis
• Catabolic and Anabolic pairs of major fuel molecules
  

What are the comparisons between the degradation and synthesis pathways of fatty acids, in terms of:

1. Regulation
2. Electron carriers
3. Acyl carriers
4. Intermediates
5. Enzymes

1. Regulation →  sequestration of rxns in cellular compartments

    *Synthesis →  Cytoplasm

       *Degradation → Mitochondria

2. Different electron carriers involved

       * NADH → catabolic rxns (degradation)

       *NADPH →  anabolic/synthetic rxns

3. Different acyl carriers involved

      *Both involve movie 2 carbon units around

          - Acetyl CoA → 2C-molecule in degradation

         - Malonyl CoA →3C-molecule in synthesis

4. Intermediates linked to "scaffold"

      *CoA → degradation

      *Acyl Carrier proteins → synthesis

5. Enzymes

     *Synthesis → catalyzed by a single enzyme w/ multiple functionalities

     *Degradation → 4 separate enzymes.

Fatty Acid Synthesis:

How is it initiated?

Where does it take place?

• Begins with acetyl CoA → made in mitochondria by pyruvate dehydrogenase
• Occurs in Cytoplasm
  

Acetyl CoA Transport:

How is it transported out of the mitochondria?

what are the steps involved?

• Transported out of mitochondria by tricarboxylic acid transport system 
• Step 1: same as first step in CAC→ make citrate (citrate synthase)
• Step 2: citrate transported into cytosol by TCA transport system
  
• Step 3: citrate in cytosol cleaved by citrate-ATP lyase

                *restores acetyl CoA

                *requires energy input

• Step 4: oxaloacetate is reduced by NADH to malatate
  

Oxidatevily decarboxylated to pyruvate by NADP⁺-linked malate enzyme → Generates NADPH, which is necessary to make fatty acid synthesis

NADPH for FA Synthesis:

How many molecules needed to add one molecule of acetyl CoA to FA chain?

How many molecules formed for each molecule of acetyl CoA transferred?

• 1 NADPH formed for each acetyl CoA transferred (via citrate) to cytoplasm
  
• Need 2 NADPH to add a molecult of acetyl CoA growing FA chain. (pentose phosphate pathway)
  

Fatty Acid Synthesis: Activation

What is the committed step?

• Malonyl CoA → carrier of 2C units
• Acetyl CoA Carboxylase 

            * 2 step reaction → occurs on same enzyme

            *Regulatory step in synthetic pathway → committed step

• Mirror, but different from, those in fatty acid oxidation
  
• Intermediates → linked to Acyl Carrier Protein (not CoA)
• Two C units added to growing fatty acid chain by malonyl ACP
• Co-substrate in the reduction reaction is NADPH (not NAD⁺, FAD)
• Reaction stops at a 16-C chain (Palmitate)
  

• Large polypeptide chain w/ phophopantetheine group
• Reacts w/ acetyl CoA & malonyl CoA
• Acetyl CoA & Malonyl CoA → react in condensation rxn as first step of FA synthesis
  

• Multifunctional enzyme → homodimer
• 7 enzyme activities → multiple active sites, 3 domains
• Also contain an acyl carrier protein
  

• Activate acyl groups from CoA transferred to ACP (acyl carrier protein)
• Condensing enzyme decarboxylates malonyl ACP & catalyzes condensation to acetyl group (bound to enzyme)  → breaks thioester bond and releases ACP
• Acetoacetyl ACP reduced to D-hydroxybutyrate → NADPH (e^- donor)
  
• Remove water to make double bond
  
• Treduce trans-enoyl product → NADPH (e- donor)
• Load 4C acyl group on FA synthesis associated  ACP and repeat steps
  
• After 7 cycles → Have C16 acyl group
  
• Last rxn catalyzed by thioesterase
  

Making Longer Chain FA:

what precursors are involved?

• Palmitate → precursor to all longer FA
• Fatty Acid Elongation system (smooth ER & mitochondria) → rxns are similar but new C's added by malonyl CoA (no ACP as carrier)
  

Desaturation

What enzymes are involved?

• Fatty acyl-CoA desaturase enzymes → add double bonds
• Mammals can only make Δ9 fatty acids→ must get linoleate and α-linoleate from diet 
  

• Acetyl CoA carboxylase → key regulatory step; low ATP → less activity
  
• Acetyl CoA carboxylase inhibited by AMP-dependent protein kinase (AMPK)
  

          *High levels of AMP activate kinase

          *Converts carboxylase into inactive form (covalent

            modification)

         *AMPK inhibited as ATP levels increase → disinhibition of

           Acetyl CoA carboxylase

• High levels of citrate can partially overcome the inhibition produced by phosphorylation → partly activating carboxylase

• FAS is inhibited by palmitate

Fatty Acid metabolism:

What are the substrates and products of fatty acid degradation?

What are the substrates and products of fatty acid synthesis?

• Fatty Acid Degradation

            *Substrates: LC fatty acids, FAD, NAD⁺, CoA

            *Products: Acetyl CoA, NADH, FADH₂

• Fatty Acid Synthesis

          *Substrates: Acetyl CoA, Malonyl CoA, NADPH

          *Products: LC fatty acids