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Rate limiting enzyme of fatty acid biosynthesis
A 30- year-old pregnant woman has a sugar craving and consumes a hot fudge sundae. Her serum glucose level increases, which causes release of Insulin. Insulin is known to increase the activity of acetyl co A carboxylase, the rate limiting enzyme of fatty acid biosynthesis. Which of the following best describes this regulatory enzyme?
A. It is activated by carboxylation
B. It catalyzes a reaction that condenses an acetyl group with malonyl group
C. It catalyzes a reaction that requires biotin and ATP
D. It converts Malonyl co A to Acetyl co A
E. It is activated by malonyl Co A.
The correct answer is- C, It catalyzes a reaction that requires Biotin and ATP.
Acetyl co A carboxylase is the first enzyme of fatty acid biosynthesis that catalyzes the carboxylation of Acetyl co A to Malonyl CoA . The reaction catalyzed can be represented as follows :
Figure- Reaction catalyzed by Acetyl co A carboxylase. It is a carbon-carbon condensation, an energy requiring process. ATP is the source of energy, and biotin is the coenzyme for this carboxylation process.
Acetyl co A carboxylase is the rate controlling enzyme in the pathway of lipogenesis. It is regulated by-
1) Allosteric modification-Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA. Citrate converts the enzyme from an inactive dimer to an active polymeric form, with a molecular mass of several million. Inactivation is promoted by long-chain acyl-CoA molecules.
2) Feedback inhibition -The enzyme is inhibited by malonyl co A and palmitoyl co A, an example of negative feedback inhibition by a product of a reaction. Thus, if acyl-CoA accumulates because it is not esterified quickly enough or because of increased lipolysis or an influx of free fatty acids into the tissue, it will automatically reduce the synthesis of new fatty acid
3) Covalent Modification- Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via changes in its phosphorylation state
4) Induction and Repression-Insulin is an important hormone causing gene expression and induction of enzyme biosynthesis, and glucagon (via cAMP) antagonizes this effect. These mechanisms for longer-term regulation of lipogenesis take several days to become fully manifested. Prolonged consumption of high calorie or high carbohydrate diets causes an increase in acetyl co A carboxylase concentration by increasing the gene expression (induction). Conversely, a low-calorie diet or fasting causes a reduction in fatty acid synthesis by decreasing the synthesis of acetyl co A carboxylase (repression) .
Thus Insulin stimulates the synthesis of fatty acids by covalent modification and induction . It also provides glycerol-3-Phosphate through glycolytic pathway that can be used for esterification. That is the reason for weight gain in individuals on insulin therapy.
Based on the similar concept, obesity related with high carbohydrate diet can also be explained.
Excessive carbohydrate ingestion promotes triglyceride synthesis through following mechanisms-
1) Glycolysis yields pyruvate and hence Acetyl coA which is a precursor for fatty acid biosynthesis.
2) Glycolysis provides glycerol-3-p through dihydroxyacetone phosphate, that is used for esterification
3) HMP pathway provides NADPH which can be used for reductive biosynthesis.
All the pathways of glucose utilization are stimulated by Insulin and by these mechanisms, fatty acids are synthesized and esterified with glycerol to produce triglycerides. The adipose mass increases and the person becomes obese. That is the reason, low carbohydrate diet is recommended to those who want to lose weight.
As regards other options
Acetyl co A Carboxylase, the enzyme for fatty acid biosynthesis-
- It is not activated by carboxylation
- It does not catalyze a reaction that condenses an acetyl group with malonyl group.
- It does not convert Malonyl co A to Acetyl co A, instead Acetyl co A is converted to Malonyl co A .
- It is not activated by malonyl Co A. Malonyl co A, the product of this reaction inhibits this enzyme by feedback inhibition.
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