The synthesis of fatty acids starts from acetyl coenzyme A and corresponds roughly to the reverse path of their degradation; in the synthesis of fatty acids a series of bicarbonate fragments are added to the starting acetyl coenzyme A.
The synthesis of fatty acids is completely cytoplasmic (ie the enzymes that catalyze this synthesis are found in the cytoplasm). The acetyl coenzyme A used in the cytoplasm for the synthesis of fatty acids is of mitochondrial origin: a small part is transported through carnitine, by the action of two acyl transferase enzymes (one cytoplasmic and one mitochondrial) and a translocase enzyme. part of acetyl coenzyme A from mitochondrial origin is obtained through a specialized route: the citrate lyase (the name derives from the first enzyme of this path).
Acetyl coenzyme A present in mitochondria derives from glycolysis after the action of pyruvate dehydrogenase; Acetyl coenzyme A undergoes the action of the enzyme citrate synthase: this enzyme catalyzes the formation of citrate by the reaction of acetyl coenzyme A with oxaloacetate. If the krebs cycle is able to meet the energy needs, it starts of citrate (the amount unnecessary in the krebs cycle) can leave the mitochondria and reach the cytoplasm, where the citrate lyase enzyme, expending energy, converts it back into acetyl coenzyme A and oxaloacetate. In this way it is possible to have acetyl coenzyme A available in the cytoplasm; the oxaloacetate that is formed, however, must be returned to the mitochondria in order to be available again for the citrate synthase enzyme.
The oxaloacetate is then transformed into malate by the action of the enzyme malate dehydrogenase cytoplasmic (a cytoplasmic NADH is spent): the malate is a permeable metabolite and can re-enter the mitochondria where, under the action of the mitochondrial malate dehydrogenase enzyme, it is reconverted into oxaloacetate (a NADH is also obtained); the cytoplasmic patient can, alternatively, undergo the action of the malic enzyme, which carries out a decarboxylation and dehydrogenation, to be converted into pyruvate. The malic enzyme works on NADP + (it is similar to nicotinamide adenindinucleotide but, unlike this, it has a phosphoric group on the second hydroxyl group on one of the two ribose units) therefore in the transition from malate to pyruvate, NADPH is produced (which is used in biosynthesis) Pyruvate then enters the mitochondria where it is transformed into oxaloacetate by the action of pyruvate carboxylase or into acetyl coenzyme A through pyruvate dehydrogenase.
Let's see an example: eight molecules of acetyl coenzyme A are needed to synthesize palmitic acid (chain with sixteen carbon atoms) but only one of them is used as such: seven molecules of acetyl coenzyme A are converted into malonyl coenzyme A by the " enzyme acetyl coenzyme A carboxylase (this enzyme uses a CO2 molecule and has biotin as a cofactor).
The acetyl coenzyme A carboxylase enzyme can exist in an almost inactive dispersed form and an active aggregate form (about twenty units); the transition from the dispersed to the aggregate form occurs when in the cytoplasm there is a "high concentration of citrate : citrate is a positive modulator of the acetyl coenzyme A carboxylase enzyme.
The acetyl coenzyme A carboxylase enzyme has other positive (insulin) and negative (glucagon, adrenaline and acyl coenzyme A) modulators.
We will analyze the synthesis of fatty acids in the bacterium escherichia coli in which this synthesis occurs by the action of seven distinct proteins; in eukaryotic cells, the mechanism by which the synthesis of fatty acids takes place is similar to that of bacteria but, in eukaryotes, the seven enzymes responsible for the synthesis are grouped into two multienzyme complexes A and B.
In bacteria, seven distinct genes code for:
- ACP (acyl carrier protein);
- ACP-acetyl transacetylase;
- ACP.malonyl transacetylase;
- β-keto-acyl-ACP synthase (condensing enzyme);
- β-keto-acyl-ACP reductase;
- D-β-hydroxy-acyl dehydratase;
- enoil-ACP redacted.
In eukaryotes, two genes code for:
Subunit A
ACP;
Condensing enzyme
β-keto-acyl-ACP reductase.
Subunit B
ACP-acetyl transacetylase;
ACP-malonyl transacetylase;
D-β-hydroxy-acyl dehydratase;
enoil-ACP redacted.
The seven proteins of Escherichia coli are arranged in such a way that there is a central one (the ACP) and the other six around it.
Two sulfhydryl groups are involved in its enzymatic action: one belonging to a cysteine and one belonging to the long arm of a phosphopantheteine; ACP binds to the substrate which, through the phosphopanthetheine arm, is put in contact with the other enzymes which are thus able to carry out their enzymatic action.
Acetyl coenzyme A (by means of ACP acetyl transacylase) binds to the ACP-enzyme (more precisely to the sulfur of cysteine forming the cysteyl-derivative) and coenzyme A is released; ACP-malonyl transacylase then intervenes which catalyzes the attack of malonyl on phosphopanthetheine (also in this process coenzyme A which was initially bound to malonyl is released).
The next step involves the β-keto-acyl ACP synthase which is a condensing enzyme: it allows the fusion between the two skeletons; malonyl is easily decarboxylated and a carbonyl of the cysteine derivative of acetyl is formed: the cysteine is released and a β-keto (acetyl vinegar) phosphopantethin derivative is formed.
Subsequently, the β-keto-acyl-ACP reductase intervenes which reduces the carbonyl further to the ACP-enzyme (a hydroxide is formed by NADPH which is reduced to NADP +).
Now, 3-hydroxy-acyl ACP dehydratase acts (dehydration occurs) which leads to the formation of an unsaturated system (alkene).
The next process involves the enoyl-ACP-reductase (it carries out a hydrogenation: the alkane is formed and NADPH is reduced to NADP +).
The last phase involves the conversion of the acyl product obtained from the first cycle into a compound capable of starting a second cycle: the transacylase enzyme transfers the acyl onto the cysteine, leaving free the site of the pantethine which will now be willing to bind another malonyl.
In β-oxidation, a FAD molecule is used to obtain the unsaturated α-β metabolite trans enoyl coenzyme A by dehydrogenation; in the synthesis of fatty acids, instead, a molecule of NADPH is used to cause the opposite reaction to take place.
Usually, fatty acids with sixteen carbon atoms are synthesized, but fatty acids with eighteen, twenty or twenty-two carbon atoms can also be produced; the fatty acids are then esterified to form triglycerides with activated glycerol (ie glycerol 3-phosphate). The latter can be obtained from dihydroxy acetone phosphate by the action of the enzyme glycerol phosphate dehydrogenase or from glycerol via the enzyme glycerol kinase.
The synthesized fatty acids must be sent to the adipose tissue; they are transported in the bloodstream in the form of triglycerides or, in part as such, with the use of a transporter protein which is albumin.
