a) Acetyl co A carboxylase-Fatty acid synthesis starts with the carboxylation of acetyl CoA to malonylCo A catalyzed by Acetyl co A carboxylase . This irreversible reaction is the committed step in fatty acidsynthesis.
Acetyl CoA carboxylase, contains a biotin prosthetic group. The carboxyl group of biotin is covalently attached to the epsilon amino group of a lysine residue, as in pyruvate carboxylase and propionyl CoA carboxylase .The enzyme is a multienzyme protein containing a variable number of identical subunits, each containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and transcarboxylase, as well as a regulatory allosteric site.
The reaction takes place in two steps: (1) carboxylation of biotin involving ATP and (2) transfer of the carboxyl to acetyl-CoA to form malonyl-CoA.
Regulation of Acetyl co A carboxylase- This enzyme is also the essential regulatory enzyme for fatty acid metabolism.
a) Hormonal control- The carboxylase is controlled by three global signals glucagon, epinephrine, and insulin that correspond to the overall energy status of the organism. Insulin stimulates fatty acid synthesis by activating the carboxylase, whereas glucagon and epinephrine have the reverse effect.
b) Allosteric modification-The levels of citrate, palmitoyl Co A, and AMP within a cell also exert control. Citrate, a signal that building blocks and energy are abundant,activates the carboxylase. Palmitoyl CoA and AMP, in contrast, lead to the inhibition of the carboxylase. Citrate facilitates the polymerization of the inactive octamers into active filaments. The level of citrate is high when both acetyl CoA and ATP are abundant.
The stimulatory effect of citrate on the carboxylase is antagonized by palmitoyl CoA, which is abundant when there is an excess of fatty acids. Palmitoyl CoA causes the filaments to disassemble into the inactive octamers.
Palmitoyl CoA also inhibits the translocase that transports citrate from mitochondria to the cytosol, as well as glucose 6-phosphate dehydrogenase, which generates NADPH in the pentose phosphate pathway
c) Covalent Modification- is carried out by means of reversible phosphorylation and dephosphorylation mediated by hormonal action. AcetylCoA carboxylase is switched off by phosphorylation and activated by dephosphorylation. Epinephrine and glucagon activate protein kinase A to bring about phosphorylation. Hence, these catabolic hormones switch off fattyacid synthesis by keeping the carboxylase in the inactive phosphorylated state.
Insulin stimulates the carboxylase by causing its dephosphorylation by stimulating phosphatase enzyme.
d)Response to Diet
Fatty acid synthesis and degradation are reciprocally regulated so that both are not simultaneouslyactive. In starvation, the level of free fatty acids rises because hormones such as epinephrine and glucagon stimulate adipose-cell lipase. In well fed state, Insulin, in contrast, inhibits lipolysis. Acetyl CoA carboxylase also plays a role in the regulation of fatty acid degradation. Malonyl CoA, the product of the carboxylase reaction, is present at a high level when fuel molecules are abundant. Malonyl CoA inhibits carnitine acyl transferaseI, preventing access of fatty acyl CoA s to the mitochondrial matrix in times of plenty.
e) Long-term control is mediated by changes in the rates of synthesis and degradation of the enzymes participating in fatty acid synthesis.Animals that have fasted and are then fed high-carbohydrate, low-fat diets show marked increases in their amounts of acetyl CoA carboxylase and fatty acid synthase (Another multienzyme complex of fatty acid bio synthetic pathway) within a few days. This type of regulation is known as adaptive control.
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