Lipogénesis PT. 2 - Bioquímica

Main ideas and concepts (lipogenesis—“part 2”)

• Lipogenesis is built around enzyme complexes: the key reactions occur largely inside a multi-enzyme complex, rather than as a relay where one enzyme works elsewhere and the product is transported.
• The central catalytic machinery is a “dimer” (multi-enzyme complex): multiple identical enzymes arranged as a complex (described as 6 or 7, depending on how it’s counted/seen).
• Each enzyme within the complex has a specific role, including enzymes for:
  • adding/handling acetyl and malonyl groups,
  • reduction steps (using NADPH),
  • dehydration/unsaturation formation,
  • final saturation and chain extension.

Multi-enzyme complex: what it does and why two attachment enzymes matter

Two particularly important binding/transfer partners inside the complex:

• Ketoacyl-CoA
  • Holds/positions the acetyl-derived portion.
• Acyl Carrier Protein (ACP)
  • Holds the growing chain via a phosphopantetheine group on a residue.

Core lesson: these components bind substrates tightly so the growing fatty-acid intermediate can be processed repeatedly within the complex.

Step-by-step methodology for the first cycle of fatty-acid synthesis (lipogenesis)

The pathway is organized similarly to β-oxidation’s reverse, with “step zero” as preparation, then repeating cycles to build the chain.

Pre-cycle / “Step 0”: Preparation (loading acetyl + malonyl and decarboxylation)

Goal: set up the complex with the right chain-attachment state.

Step 0 has two parts (described as a two-step preparation):

1. Transfer/loading of groups onto the complex

   • Acetyl and malonyl are attached to the enzyme complex via the relevant active-binding components.
   • The process “adds” to the cysteine residue equivalent behavior and involves ACP handling (as described in the subtitles).

2. Decarboxylation and transfer

   • The incoming malonyl loses CO₂ (expelled as part of the preparation/activation logic).
   • The remaining acetyl-derived portion is transferred so the complex proceeds into reduction.

Step 1: Reduction (reverse of β-oxidation’s oxidation)

• Enzyme: ketoacyl reductase
• Cofactor: NADPH
• Action:
  • Reduces the intermediate by adding hydrogen (explicitly described as opposite oxidation).
  • The reduction forms an intermediate with a new hydroxyl group at carbon 3.

Next step: Dehydration (removal of water → forms an unsaturated intermediate)

• Conceptual action: remove H₂O (dehydration step).
• Result:
  • formation of a 2,3-unsaturated acyl intermediate (naming attributed to Harper).
• Note: the instructor flags a minor possible drawing error in where the double bond is placed, but keeps the intended naming.

Next step: Second reduction (saturating the double bond → forms the saturated acyl product)

• Enzyme: “enoyl reductase” (described as using NADPH)
• Cofactor: NADPH
• Action:
  • adds hydrogen across the double bond, saturating it.
• Result:
  • the intermediate becomes a more saturated acyl product with an increased chain length state.

Chain elongation strategy: repeating cycles to reach 16 carbons

Key goal: synthesize fatty acids up to 16 carbons (then termination/hydrolysis occurs).

How repetition works:

• The pathway repeats with new malonyl units rather than restarting the entire system.
• After the first “round,” the intermediate is a 4-carbon acyl intermediate (X).
• The ACP phosphate-linked portion transfers X to the next active site in the second enzyme complex (described as moving from enzyme complex 2 back into complex 1 for continued processing).

Cycle logic (incremental growth):

• Starting from 4 carbons, each added malonyl unit increases the chain by 2 carbons per cycle (typical for malonyl-based elongation).
• The instructor summarizes that this happens about 6 times after the first turn to reach 16 carbons.

Termination (final step when reaching 16):

• An enzyme “comes into action” that hydrolyzes to release the product (breaking the bond to yield the final 16-carbon fatty acid).

Cellular location (major difference vs β-oxidation)

• Lipogenesis: occurs in the cytosol.
• β-oxidation: occurs in the mitochondria.

Two key transport/availability questions answered

1. Where does NADPH come from?

   • Mainly from pentose sugars via their oxidative phase.

2. How does acetyl-CoA reach the cytosol?

   • Citrate shuttle:
     • Acetyl-CoA + oxaloacetate → citrate in mitochondria
     • Export citrate via a tricarboxylate transporter
     • In the cytosol, citrate lyase (ATP-dependent, as described) regenerates acetyl-CoA

Additional extension and unsaturation concepts

Chain length beyond 16 carbons

• The described system synthesizes fatty acids up to 16 carbons.
• For longer chains, an elongase system extends them:
  • elongates to 17–24 (etc.) carbons by adding carbons iteratively.
• The instructor notes elongation uses enzymes that act in a less “bound-inside-complex” style than the core lipogenesis complex.

Unsaturation limits in humans

• Humans have only one delta desaturase mentioned: Δ9 desaturase.
• Implication:
  • humans can introduce unsaturation effectively up to carbon 9,
  • but cannot make certain later unsaturations required for essential fatty acids.
• Therefore, the body must obtain essential polyunsaturated fats from the diet, including:
  • linoleic acid (as referenced in the subtitles).
• The process uses:
  • cytochrome b5
  • oxygen
  • NADPH (as described)

Speakers / sources featured

• Diego (addressed by the instructor as questions to “Diego”)
• Harper (textbook/authority for naming and descriptions)
• ATP (ATP-dependent reaction mentioned: citrate lyase step)
• Cytochrome b5 (cofactor in Δ9 desaturation)
• Pyruvate dehydrogenase (mentioned as the acetyl-CoA source in mitochondrial context)
• Tricarboxylate transporter (citrate export transporter)
• Citrate lyase (enzyme that regenerates acetyl-CoA in the cytosol)
• NADPH and Pentose sugars (sources of reducing power in the cytosol per explanation)