Question

Starting with a fatty acid located in the cytosol of the cell, explain “mechanistically” how an iron deficiency may result in reduced acetyl CoA production from beta oxidation of palmitic acid

Answer 1

Liver is the tissue where lipids are metabolized and iron is stored. Palmitic acid is a 16 carbon atom fatty acid, which undergoes 7 rounds of beta oxidation to produce 8 acetyl CoA, 7 FADH2 and 7 NADH2. Palmitate is first converted to palmitoyl CoA and then transported to the mitochondria for beta oxidation. Palmitate will be activated when it reacts with ATP in presence of CoA-SH to form palmitoyl CoA, AMP and pyrophosphate. Enzyme involved is acyl CoA synthetase. Pyrophosphate then hydrolyzes to 2 inorganic phosphates.

Palmitoyl CoA then binds to carnitine (β-hydroxy-γ-trimethylammonium butyrate) to form palmitoyl carnitine via carnitine palmitoyltransferase I. This palmitoyl CoA is then transported across the mitochondrial membrane by a fatty acid translocase. Palmitoyl Carnitine is converted back to palmitoyl CoA and carnitine by carnitine palmitoyltransferase II enzyme. Palmitoyl CoA then undergoes beta oxidation cycles to release acetyl CoA. There are four steps in beta oxidation. In a beta oxidation step, acyl CoA (palmitoyl CoA) is first oxidized to trans-delta 2 enoyl CoA, which undergoes hydration to form L-3 hydroxyacyl CoA. L-3 hydroxyacyl CoA is oxidized to 3-ketoacyl CoA. Thiolysis converts L-3 hydroxyacyl CoA to 2 C shortened acyl CoA and acetyl CoA.

The two hydroxylases, ϵ-N-trimethyllysine hydroxylase and γ-butyrobetaine, hydroxylase contain ferrous ions. These two enzymes are involved in synthesis of carnitine. They convert trimethyllysine released by proteolytic cleavage from histones, myosin etc to carnitine via hydroxylations reactions. In case of iron deficiency, carnitine levels decline. This will converted the transporter Carnitine palmitoyl transferase I into a reduced form. Carnitine Palmitoyl transferases requires iron as a cofactor. Thus, in iron deficiency, there will be inhibition of these transferases, thereby preventing translocation of palmitoyl CoA into the mitochondria. This will decrease beta oxidation in iron deficiency and thereby affect acetyl CoA production.