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Fatty acid synthesis- A quick revision- Enzymes of pathway of de novo fatty acid synthesis
1) Acetyl co A carboxylase catalyzes the initial and rate controlling step in Fatty acid synthesis . Fatty acid synthesis starts with the carboxylation of acetyl CoA to malonyl CoA. Acetyl CoA carboxylase contains a biotin prosthetic group. The carboxyl group of biotin is covalently attached to the € amino group of a lysine residue. This multienzyme complex contains
- Biotin carboxylase
- Biotin carboxyl carrier protein
- A regulatory allosteric site
Reaction catalyzed by Acetyl co A carboxylase
The input to fatty acid synthesis is acetyl-CoA, which is carboxylated to malonyl-CoA. The reaction is catalyzed by Acetyl co A carboxylase (Figure-1).
As with these other enzymes, a carboxy biotin intermediate is formed at the expense of the hydrolysis of a molecule of ATP. The activated CO2 group in this intermediate is then transferred to acetyl CoA to form malonyl CoA (Figure-2)
Figure-2-This ATP-dependent carboxylation provides energy input. The CO2 is lost later during condensation with the growing fatty acid.The spontaneous decarboxylation drives the condensation reaction.
2) Fatty acid Synthase complex
- The Fatty Acid Synthase complex is a polypeptide containing seven enzyme activities
- In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP).
- In yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA.
- Each chain is folded into three domains joined by flexible regions (Figure-3).
- Domain-1-Condensation unit- The substrate entry and condensation unit, contains acetyl transferase, malonyl transferase, and β-ketoacyl synthase (condensing enzyme).
- Domain-2-Reduction unit- The reduction unit, contains the acyl carrier protein, β-ketoacyl reductase, dehydratase, and enoyl reductase.
- Domain-3-Releasing unit- the palmitate release unit, contains the thioesterase.
Figure-3- i ) Domain 1- condensation unit (blue); ii ) Reduction unit ( yellow); iii) Releasing unit (pink).
AT- Acetyl transacylase ; MT- Malonyl transacylase ; CE- Condensing enzyme (Keto acyl synthase) ; DH- Dehydratase ; ER- Enoyl reductase ; KR- Keto acyl reductase ; ACP- Acyl carrier protein ; TE- Thioesterase
The —SH of the 4′-phosphopantetheine of one monomer is in close proximity to the —SH of the cysteine residue of the ketoacyl synthase of the other monomer, suggesting a “head-to-tail” arrangement of the two monomers (figure-2 and 3).Though each monomer contains all the partial activities of the reaction sequence, the actual functional unit consists of one-half of one monomer interacting with the complementary half of the other. Thus, two acyl chains are produced simultaneously.
Biological Advantage of having Multienzyme complex-
1) An advantage of this arrangement is that the synthetic activity of different enzymes is coordinated since it is encoded by a single gene.
2) A multienzyme complex consisting of covalently joined enzymes is more stable than one formed by non covalent attractions.
3) Furthermore, intermediates can be efficiently handed from one active site to another without leaving the assembly.
Simple representation of Fatty acid synthase complex (Figure-4)-
Figure-4- Fatty acid synthase complex. There are two polypeptide chains, each containing 7 enzyme activities and ACP. The long flexible arm of phosphopantetheine helps its thiol to move from one active site to another within the complex.
Overview of fatty acid synthesis and role of enzymes
Fatty acid synthesis is a cyclic process. The initial step of carboxylation of acetyl co A is catalyzed by Acetyl co A carboxylase, the remaining steps are catalyzed by fatty acid synthase complex. In each cycle, the general processes involved are-
c) Dehydration and
The process of condensation (addition of 2 carbons to the existing chain in each cycle) is carried out by keto acyl synthase enzyme of condensation unit, while the remaining steps-(reduction, dehydration and reduction) are catalyzed by the enzymes of reduction unit. Once a fatty acid of required chain length is synthesized the releasing enzyme (thioesterase) catalyzes the release of newly synthesized fatty acid from the enzyme complex.
Details of steps in next post….
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