Fatty acid metabolism I

Fatty Acid Metabolism I

• Dr. David Watson

• Contact: d.watson@keele.ac.uk

• Location: Room 303b

Learning Outcomes

• Describe the structure and physiological roles of fatty acids

• Describe anabolic pathways of fatty acid synthesis and storage

• Describe catabolic pathways of fatty acid mobilization and degradation, including beta oxidation

• Explain the regulation of fatty acid metabolism

Further Reading

• Berg et al., Biochemistry (Chapter 22)

• Garrett and Grisham (Module E-book, Chapters 23 and 24)

Fatty Acid Structures

• Basic Structure: Long carbon chain (C-C) with a carboxylic acid group

  • Carboxyl end (α-carbon)

  • Methyl end (ω-carbon)

• Classification of Fatty Acids:

  • Length: Short, medium, long

  • Saturation: No. of C=C double bonds

  • Shape: Cis and trans (trans fats present in small amounts)

• Examples:

  • Palmitic acid (C16:0)

  • Palmitoleic acid (C16:1 Δ9 ω-7) - catalyzed by Δ9 desaturase

  • Arachidonic acid (C20:4) - synthesized from linoleic acid

Fatty Acids, Glycerol and Triglycerides/TAG

• Formation: Sequential condensation reactions (MAG → DAG → TAG)

• Role of Diacylglycerides (DAG): Important cellular roles, including signaling

• Enzyme: Diglyceride acyltransferase (DGAT) catalyzes the formation of TAG from DAG

Fatty Acid Sources

• Source from Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin

• Digestion and Absorption of Lipids (Figure 25.27)

Fatty Acid Synthesis: Sources

• Sources Include:

  • Glucose

  • Alcohol

  • Proteins

• Key Processes:

  • Glycolysis and Pyruvate: Generate two-carbon acetyl groups

  • Acetyl CoA and Glycerol involved in Fatty Acid Synthesis

Fatty Acid Synthesis

• Requirements:

  • Cytosolic Acetyl-CoA

  • NADPH (co-enzyme)

  • ATP

• Catalysis: By the large enzyme complex, fatty acid synthase

• First Committed Step: Synthesis of Malonyl-CoA from Acetyl-CoA

  • Reaction: 8 acetyl CoA + 7 ATP + 14 NADPH + 6H+ → Palmitate (C16:0)

  • Malonyl-CoA formed in the cytosol; citrate exported from mitochondria

Fatty Acid Synthesis Process

• Monomer to Polymer Conversion:

  • Malonyl unit (3C) condensed with an acyl group

  • Carbonyl is reduced, dehydrated, and reduced again, increasing chain length by 2

  • Process repeats until C16 fatty acid (palmitate) is synthesized

• Activated refers to the formation of a thioester linkage

Additional Steps in Synthesis

• Carboxylation of Acetyl CoA to Malonyl CoA:

  • ATP-driven reaction catalyzed by acetyl CoA carboxylase

  • Regulated process

• Intermediates:

  • Linked to acyl carrier proteins (ACP): acetyl ACP and malonyl ACP

  • Condensation forms acetoacetyl ACP, releasing CO2

Reduction and Dehydration Steps

• Reduction, Dehydration, and Second Reduction:

  • Using NADPH as reductant

  • Carbonyl reduced to an alcohol

  • Introduces a C=C bond

  • Second reduction yields butyryl ACP

  • Enters series of elongation reactions starting with malonyl ACP

  • Total of seven rounds of elongation results in palmitoyl ACP, hydrolyzed to palmitate

Comparison of Synthesis vs. Degradation

• Synthesis:

  • Elongates acyl chain

  • Adds sequential 2C units from activated Malonyl ACP

• Degradation:

  • Shortens acyl chain

  • Releases units as acetyl CoA

• Key differences: Synthesis increases chain length; degradation decreases it.