Lipid Metabolism › Fatty Acids

Fatty Acid Biosynthesis

Notes

Fatty Acid Biosynthesis

Sections

FATTY ACID BIOSYNTHESIS

  • Occurs in the liver and adipose tissue (cytosol)
  • After a carbohydrate-rich meal (high insulin:glucagon ratio)
  • Not just reverse of beta-oxidation: distinct enzymes and compartments

Reactions

  1. Citrate Shuttle
  • Acetyl CoA in mitochondrial matrix transported to cytosol as citrate
  • Citrate synthase: citrate from oxaloacetate and acetyl CoA (also first CAC rxn)
  • Citrate a marker of high intracellular energy (CAC intermediate)
  1. Malonyl CoA Formation
  • Acetyl CoA carboxylase: adds 1 carbon to acetyl CoA to form malonyl CoA
  • ABC carboxylase reaction
  • Citrate activates rxn
  • Long-chain fatty acyl CoA (intermed. of FA breakdown): inhibits rxn

ABC carboxylase reactions: consume ATP, require biotin, consume CO2

  • Malonyl CoA synthesis in fatty acid biosynthesis
  • Gluconeogenesis: pyruvate carboxylase
  • Odd chain fatty acid oxidation: propionyl carboxylase
  1. Palmitate Synthesis
  • Palmitate: 16-carbon fatty acid
  • Catalyzed by fatty acid synthase
  • ACP is carrier protein component of fatty acid synthase
  • Series of 4 reactions:
    i. Condensation: acetyl-ACP + malonyl-ACP = 4-C intermediate + CO2
    ii. Reduction (NADPH)
    iii. Dehydration: water molecule released
    iv. Reduction (NADPH)
  • First condensation = 4C molecule
  • 6 increments x 2C (malonyl-ACP) = 12 C
  • Total = 16 C palmitate
  1. Palmitate Modification
    i. Elongation: in smooth ER or mitochondria
  • 2-carbon increments using malonyl CoA (NOT malonyl-ACP)
  • Each increment includes four rxn's from palmitate synthesis
    ii. Desaturation: in smooth ER or peroxisomes
  • Fatty acyl-CoA desaturase
  • Short electron transport chain (requires O2 and NADPH)

CLINICAL CORRELATION
Essential fatty acids: linoleic acid and linolenic acid cannot be synthesized endogenously.

  • Mammals cannot induce double bonds beyond C9

Full-Length Text

  • Here we will learn how fatty acids are synthesized in the body.
  • To begin, start a table to learn some key features of fatty acid synthesis.
  • Denote that the primary sites of fatty acid synthesis are the liver and adipose tissue, and at the cellular level, the cytosol.
  • Denote that it occurs after a carbohydrate-rich meal when the insulin to glucagon ratio is high.
    • Fatty acids store carbohydrates and energy.
  • Next, denote that de novo fatty acid synthesis is not just the reverse of beta-oxidation.
    • It requires a distinct set of enzymes in different intracellular compartments.

Now, let's draw the biosynthetic pathway.

  • First, label the four major phases of this pathway:
    • Citrate shuttle
    • Malonyl CoA formation
    • Palmitate synthesis
    • Palmitate modification.

Let's start with the citrate shuttle.

  • To begin, draw the double-membrane of a mitochondrion.
  • Label the mitochondrial matrix and the cytosol.
  • Draw acetyl CoA in the matrix; it is the substrate for fatty acid synthesis.
    • It needs the citrate shuttle to cross the mitochondrial membranes and enter the cytosol where fatty acid synthesis occurs.
  • Show that it combines with oxaloacetate (OAA) in the matrix to produce citrate.
  • Indicate that citrate synthase catalyzes this reaction – highlight it because it is the first enzyme in the biosynthetic pathway.
  • Show that coenzyme A is released.
  • Draw multiple arrows to indicate that this is also the first step in the citric acid cycle.
  • Next, show citrate cross the mitochondrial membranes and enter the cytosol.
  • Now, circle citrate.
    • Write that it is a marker of high intracellular energy – as a citric acid cycle intermediate, its accumulation reflects an accumulation of ATP in the cell.
  • Denote that fatty acid synthesis is energetically expensive, so it only occurs under high-energy conditions.
  • Next, show that citrate reconverts to 2-carbon acetyl CoA and OAA in the cytosol.
  • Show that this reaction consumes one ATP.

Now we're ready for malonyl CoA synthesis.

  • Show that acetyl CoA carboxylase (the second key enzyme) catalyzes the formation of three-carbon malonyl CoA from acetyl CoA.
  • Show that this is an A-B-C carboxylase reaction: it consumes ATP, requires biotin as a cofactor and consumes carbon dioxide.
  • List the other key ABC-carboxylase reactions.
    • Gluconeogenesis – pyruvate carboxylase converts pyruvate to OAA.
    • Odd chain fatty acid oxidation – propionyl-CoA carboxylase produces methylmalonyl CoA from propionyl CoA.
  • Show that citrate activates acetyl CoA carboxylase.
  • Indicate that long-chain fatty acyl CoA, an intermediate in fatty acid breakdown inhibits acetyl CoA carboxylase.
  • Now, the third phase of synthesis: palmitate synthesis.
    • The product, palmitate, is a 16-carbon fatty acid.
  • Show that this phase comprises four reactions:
    • Condensation
    • Reduction
    • Dehydration
    • and another reduction.

Let's illustrate these reactions, now.

  • Show that fatty acid synthase (a dimeric multi-enzyme complex) catalyzes these reactions.

Step 1: Condensation: 2-carbon acetyl-group and 3-carbon malonyl-group combine.

  • Draw an acyl carrier protein (ACP) domain at the end of each of these groups, which is actually a carrier protein of fatty acid synthase that replaces coenzyme A just before the condensation step.
  • Show that one carbon dioxide molecule is released during condensation, leaving us with a 4-carbon molecule.

Next, step 2: Reduction.

  • Indicate that one NADPH powers this reaction. NADPH primarily powers biosynthetic pathways; whereas, NADH is the reducing power in molecular breakdown.

Step 3: Dehydration: a water molecule is released.

Step 4: A final reduction: another NADPH is oxidized.

  • These reactions leave us with a 4-carbon molecule.
  • Indicate that this series of reactions occurs six more times to produce 16-carbon palmitate!
  • How does this add up?
    • Show that in each increment, a malonyl group adds 2-carbons to the chain.

Let's track the number of carbons through palmitate formation.

  • Write that the first condensation reaction gives us a 4-carbon molecule (one carbon is lost as CO2).
  • Write that the following 6 increments add 2 carbons each: 6 x 2 = 12.
    • Again the third carbon in the malonyl-group is lost as CO2 during each condensation reaction.
  • Thus, 4 carbons + 12 carbons gives us 16-carbon palmitate!

But what if we need a fatty acid that's longer than palmitate or one that is unsaturated?

  • Draw a portion of smooth endoplasmic reticulum to illustrate modification.
  • Write that elongation can also occur in mitochondria.
  • Indicate that ER enzymes elongate palmitate in 2-carbon increments using malonyl CoA, much like palmitate synthesis.
  • Write that the intermediates are CoA esters.
    • Thus, coenzyme A is not replaced by ACP as it is in palmitate formation.
  • Show that each 2-carbon increment also include the four key reactions in palmitate formation: condensation, reduction, dehydration and a second reduction.

This brings us to desaturation, which can also occur in peroxisomes.

  • Show that it is catalyzed by fatty acyl-CoA desaturase.
  • Indicate that a short electron transport chain facilitates these oxidation reactions, and that it requires oxygen and the reducing power NADPH.
  • Finally, as a clinical correlation, denote that linoleic acid and linolenic acid are essential fatty acids; they cannot be synthesized endogenously. Why?
    • Mammals cannot induce double bonds beyond carbon 9, which is a feature of both of these fatty acids.
    • They can be obtained from fish (specifically salmon, mackerel, albacore, sardines and halibut).