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Suraj Prakash Sharma | Ekta Chotia

FATTY ACID OXIDATION
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21.1.      Steps of fatty acid oxidation

1.            Activation of Fatty acid

It is activated by the addition of coenzyme A (CoA) to the fatty acid. This reaction is catalyzed by acyl CoA synthetase in which the energy is stored in the thioester bond.

Fatty acid+ CoA +ATP $\fn_phv \rightarrow$ acyl-CoA +AMP + PPi

2.            Transport across the membrane-

The activation of fatty acid occurs in the cytosol whereas oxidation of fatty acid occur inside the mitochondrial matrix. So it is compulsory for the fatty acid to transport across the mitochondrial membrane. So this activity is done by a carrier protein named as carnitine. Carnitine is synthesized from lysine and methionine in liver. The reaction of fatty acyl CoA with carnitine is shown below -

Carnitine acyl transferase I is inhibited by the malonyl CoA and prevents the entry of fatty acids into mitochondria. Insulin also inihibits this transport by activating acetyl CoA carboxylase (fatty acid synthesis) and increase the malonyl CoA concentration in the cytoplasm.

21.2.      $\fn_phv \beta$ oxidation of fatty acid

After entry into the mitochondrial matrix fatty acyl is degraded in the steps of $\fn_phv \beta$ oxidation by flavin adenine dinucleotide (FAD), hydration, oxidation by NAD+, and thiolysis by CoA. This reaction occurs at the $\fn_phv \beta$ position of carbon thats why it is named as $\fn_phv \beta$ oxidation. The brief reaction of the fatty acid oxidation are-

• Dehydrogenation – this reaction catalyzed by acyl CoA dehydrogenase which catalyzes removal of two Hydrogen atoms.
• Hydration – one molecule of water is added and reaction catalyzed by enoyl CoA hydratase.
• Debydrogenation – Again removal of two H atoms by 3–hydroxy acyl dehydrogenase.
• Thiolysis – CoA SH is added to the molecule and reaction catalyzed by thio esterase which breaks the SH bond and release one molecule of acetyl CoA and rest of the molecule get back to oxidation process.

Overall reaction of a fatty acid molecule -

Fate of Products

• FADH2 and NADH are transported to electron transport chain and generate ATP.
• Acetyl CoA is transported-

21.3.      Formation of ketone bodies and degradation of ketone bodies.

Either for the generation of more NADH and FADH2 by entering into Krebs cycle and produce ATP. or transported for the generation of ketone bodies which are used by other tissues as energy source. For the formation of ketone bodies 2 molecules of Acetyl CoA are condensed into acetoacetyl CoA which is further processed and converted to b hydroxybutyrate.

21.4.      Other Fatty acid oxidation :

Alpha oxidation – it is an alternative form of lipid oxidation. It does not require the activation of fatty acid. COOH group of lipid is decarboxylated and then this undergoes the cycle of $\fn_phv \beta$ oxidation.

This oxidation occurs for the synthesis of $\fn_phv \alpha$-OH fatty acid like cerebronic acid which constitutes cerebrosides in brain.

It oxidize phytanic acid which is produced by dietry phytols of chlorophyll by phytate $\fn_phv \alpha$-oxidase  and pristanic acid is oxidized by $\fn_phv \beta$- oxidation.

Defect in a oxidation causes a rare genetic disorder Refsum disease in which deficiency of phytate a oxidase enzyme.

omega ($\fn_phv \omega$) oxidation – It is found in liver and microsomes. It causes the hydroxylation of omega carbon.

Peroxisomal fatty acid oxidation – it is a modified form of $\fn_phv \beta$ oxidation in which acetyl CoA and H2O2 is formed as final products. This pathway does not generate ATP. Zellweger Syndrome is the condition of absence of peroxisome in all the cells of body so the patient is unable to oxidize long fatty acid chains of C26–C38.

21.5.      Lipid synthesis

Synthesis of fatty acids is catalyzed by fatty acid synthase which is a multifunctional enzyme. This enzyme is located in the cytoplasm which acts upon the acetyl CoA as a primer molecule. NADPH is used reducing agent in this reaction.

Fatty acid synthase enzyme catalyzes all the seven reactions of this process. It is a homodimer contains two identical peptide chains. Every reaction catalyzed by a specific enzyme. This enzyme has 3 domains – Domain one catalyze the condensation of acetyl CoA and malonyl CoA, Domain two catalyze the formation of final product of the process  and Domain three catalyze the release of final product.

Steps

• Formation of Malonyl CoA – acetyl CoA is impermeable to mitochondrial membrane so it is converted to malonyl CoA. It is catalyzed by the enzyme actyl CoA carboxylase. It uses Mn+2 and biotin as a coactivator which donates a CO2 molecule and one ATP molecule.

• Now further process is catalyzed by the fatty acid synthase which have Cys-SH and Pan-SH as two arms of it. Both of these arms accepts acetyl CoA and Malonyl CoA respectively. Both arms acts as transacylase which removes CoA from both of the molecules and Acyl Carrier Protein is attached.
• Condensation – As acetate attacks on malonate to form acetoacetyl ACP which is catalyzed by Keto acyl synthase. Single molecule of CO2 is lost in this reaction and the acetoacetyl ACP remain attached to Pan SH.
• Reduction – NADPH is converted to NADP+ and reaction is catalyzed by B-keto acyl reductase.
• Dehydration – single water molecule is removed by b-OH-butyryl dehydratase.
• Reduction – NADPH is used and catalyzed by enoyl reductase.
• Thiolysis – it is the final reaction of a molecule. If synthesizing lipid is to be larger molecule than all of these steps are repeated. SH bond is cleaved by thioesterase enzyme and ACP molecule is release from the molecule and final product is released from the enzyme.

For the synthesis of a 16 carbon molecule i.e. palmitic acid, final reaction will be –

So the overall reaction will be

21.6.      Regulation of fatty acid synthesis

Allosteric Control – This is sudden or short term control in which enzymes can be controlled by covalent modification.

Hormonal Control – hormones affect the enzyme and regulate the process of lipid synthesis.

• Acetyl CoA Carboxylase – this enzyme catalyze the rate limiting step of this process. It is regulated by phosphorylation and dephosphorylation by protein kinases. Citrate acts as activator for this enzyme.
• Glucagon – it inhibits glycolysis by inactivating PFK enzyme so thereby decrease in the synthesis of citrate in Krebs cycle. So decrease in citrate inactivates the acetyl CoA carboxylase and reduces fatty acid synthesis.
• Insulin – it acts in contrast to glucagon. It enhances citrate there by activating AcetylCoA carboxylase and more lipid synthesis.
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