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Fatty acid oxidation – part-2- A quick revision
Steps of beta oxidation
Step-1 Dehydrogenation-The first step is the removal of two hydrogen atoms from the 2(α)- and 3(β)-carbon atoms, catalyzed by acyl-CoA dehydrogenase and requiring FAD. This results in the formation of Δ2-trans-enoyl-CoA and FADH2.
Figure-1- Acyl co A is dehydrogenated to form α-β Unsaturated Acyl Co A (Δ2trans- Enoyl Co A)
- Electrons from the FADH2 prosthetic group of the reduced acyl CoA dehydrogenase are transferred to electron-transferring flavoprotein (ETF).
- ETF donates electrons to ETF: ubiquinone reductase, an iron-sulfur protein of the electron transport chain, Consequently, 2 (1.5) molecules of ATP are generated per molecule of FADH2 formed in this dehydrogenation step.
There are chain specific acyl co A dehydrogenases- Short chain, medium and long chain acyl co A dehydrogenases.
1) Jamaican Sickness- Jamaican vomiting sickness is caused by eating the unripe fruit of akee tree, which contains the toxin hypoglycin, that inactivates medium and short-chain acyl-CoA dehydrogenases, inhibiting β oxidation and thereby causing hypoglycemia.
2) Nonketotic hypoglycemia which is caused by lack of mitochondrial medium chain acyl-CoA dehydrogenases. Impaired fatty acid oxidation results in energy imbalance producing hypoglycemia.
3) Dicarboxylic aciduria is characterized by excretion of C6–C10 -dicarboxylic acids and by nonketotic hypoglycemia, and is caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase.
4) Acute fatty liver of pregnancy
- Manifests in the second half of pregnancy, usually close to term, but may also develop in the postpartum period.
- The patient developed symptoms of hepatic dysfunction at 36 weeks of gestation.
- Short history of illness, hypoglycemia, liver failure, renal failure, and coagulopathy are observed.
- Diagnosis is made based on an incidental finding of abnormal liver enzyme levels.
- Affected patients may become jaundiced or develop encephalopathy from liver failure, usually reflected by an elevated ammonia level.
- Profound hypoglycemia is common.
Water is added to saturate the double bond and form 3-hydroxyacyl-CoA, catalyzed by Δ 2-enoyl-CoA hydratase (figure-2).
Figure-2- Reaction catalyzed by hydratase enzyme
The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by L(+)-3-hydroxyacyl-CoA dehydrogenase to form the corresponding 3-ketoacyl-CoA compound. In this case, NAD+ is the coenzyme involved (Figure-3).
Figure-3- Reaction catalyzed by Beta hydroxy acyl co A dehydrogenase
Biological Significance– NADH and H+ thus produced enter the electron transport chain through Complex-I to yield 3 ATP molecules.
3-ketoacyl-CoA is split at the 2,3- position by thiolase (3-ketoacyl-CoA-thiolase), forming acetyl-CoA and a new acyl-CoA two carbons shorter than the original acyl-CoA molecule (figure-4). The acyl-CoA formed in the cleavage reaction reenters the oxidative pathway at reaction 2.
Since acetyl-CoA can be oxidized to CO2 and water via the citric acid cycle the complete oxidation of fatty acids is achieved
Figure-4- Reaction catalyzed by Thiolase enzyme
Figure-5- Long-chain acyl-CoA is cycled through reactions 2–5, each time acetyl-is split off through each cycle, by thiolase (reaction 5). When the acyl radical is only four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5.
The overall reaction can be represented as follows-
Energy yield by the complete oxidation of one mol of Palmitic acid-
The degradation of palmitoyl CoA (C16-acyl Co A) requires seven reaction cycles. In the seventh cycle, the C4-ketoacyl CoA is thiolyzed to two molecules of acetyl CoA.
106 (129 As per old concept) ATP are produced by the complete oxidation of one mol of Palmitic acid.
Per cycle energy output
1NADH +1FADH2 = 3 + 2 = 5 ATP
In 7 cycles of beta oxidation
7×5 = 35
Energy output from complete oxidation of Acetyl co A
Per Acetyl co A = 12 ATP
8 Acetyl co A = 8X12 = 96
Total output = 35 +96 = 131
Energy consumed during activation of palmitate to Palmitoyl CoA
2 ATP equivalents (ATP ————> AMP + PPi)
(PPi ————-> 2 Pi)
Net Energy output- 131-2 = 129 ATP
131-2 = 129
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