12 Fatty Acid and TAG Biosynthesis 20141115

Malic enzyme: Malate Pyruvate + CO2

NADP+ NADPH + H+

Glyoxysomes

Subcellular Locations of Lipid Metabolism

Glyoxysomes

Fatty Acid Biosynthesis

Different enzymes from those in fatty acid -oxidation Activation of acetyl-CoA required Spiral metabolic pathway

Formation of Malonyl-CoA by acetyl-CoA carboxylase - An irreversible and committed step for fatty acid biosynthesis in

animals - Biotin as a prosthetic group in the enzyme

Formation of Palmitic Acid (16:0) by Fatty Acid Synthase - A multifunctional enzyme complex (7 enzymatic activities)

Summary of 2 parts

Formation of 7 malonyl-CoA:

7 acetyl-CoA + 7 CO2 + 7ATP → 7 malonyl-CoA + 7ADP + 7Pi

7 cycles of condensation and reduction:

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+

Palmitic acid + 7 CO2 + 8 CoA-SH + 14 NADP+ + 6 H2O

Acyl carrier protein (ACP) - A protein co-enzyme for attachment of substrates and intermediates

during fatty acid biosynthesis - Part of the fatty acid synthase complex

Overall reaction:

8 Acetyl-CoA + 7 ATP + 14 NADPH + 14 H+

Palmitic acid + 7 ADP + 7 Pi + 6 H2O + 8 CoA-SH (Co-enzyme A)

H – SACP (Abbreviated form)

Fatty acid biosynthesis by fatty acid synthase (FAS) complex:

Initiation reactions of fatty acid biosynthesis

HS-Cys (FAS),

Fatty acid catabolism vs anabolism

oxidation

hydration

oxidation

thiolysis

reduction

dehydration

reduction

condensation

Tricarboxylate transport system

Inner membrane - Impermeable to acetyl CoA

What are the sources of acetyl-CoA for fatty acid biosynthesis?

Fatty acid biosynthesis

Glucose

Amino acids

Pyruvate

dehydrogenase

Elongation and desaturation of fatty acids

Formation of Acyl-CoA is required

before elongation or saturation:

*Essential

fatty acids

*

*

(ARA)

[Animals and human do not have enzymes to introduce double bonds beyond C-9]

ARA + CoA-SH thioesterase

Linolenate + CoA-SH

ATP AMP + PPi

[Both the acyl chain and NADH are oxidized by O2]

(condensation)

Biosynthesis of Triacylglycerols (in cytosol) Fatty acids are stored in adipose tissues as triacylglycerols ~15 kg triacyglcerol in a 70-kg man Excess carbohydrate is converted to triacylglycerols

(in liver and kidney)

(DHAP)

Glycerol-3-phosphate dehydrogenase

NADH

Formation of glycerol backbone:

(fatty acid)

Acylation of free hydroxyl groups

acyl transferase

acyl transferase

Phosphatic acid phosphatase

(a diacylglycerol-P)

Phospholipid biosynthesis

acyl transferase

Pi

Triacylglycerol

Sites of regulation of fatty acid metabolism

Triacglycerols - Fuel for energy-requiring

processes - Storage for future use - Synthesis and breakdown

involve different tissues (liver and adipocytes)

Action of hormones - Glucagon increases cAMP levels - Insulin decreases cAMP levels

Malonyl-CoA - Inhibits entry of fatty acyl-CoA

into mitochondria

Long term regulation - Changes in enzyme quantities