SYNTHESIS OF LIPIDS: TYPES AND THEIR MAIN MECHANISMS - BIOLOGY - 2025

The synthesis of lipids consists of a series of enzymatic reactions by means of which short-chain hydrocarbons condense to form longer-chain molecules that can subsequently undergo different chemical modifications.

Lipids are a class of highly varied biomolecules synthesized by all living cells and which are specialized in multiple functions essential for the maintenance of cellular life.

Some examples of common lipids: glycerophospholipids, sterols, glycerolipids, fatty acids, sphingolipids and prenols (Source: The original uploader was Lmaps at English Wikipedia. / GFDL 1.2 (http://www.gnu.org/licenses/old-licenses/ fdl-1.2.html) via Commons, adapted by Raquel Parada)

Lipids are the main components of biological membranes, a fact that makes them fundamental molecules for the existence of cells as entities isolated from their environment.

Some lipids also have specialized functions such as pigments, cofactors, transporters, detergents, hormones, intra- and extracellular messengers, covalent anchors for membrane proteins, etc. Therefore, the ability to synthesize different types of lipids is critical for the survival of all living organisms.

This large group of compounds is traditionally classified into several categories or subgroups: fatty acids (saturated and unsaturated), glycerides (phosphoglycerides and neutral glycerides), non-glyceride lipids (sphingolipids (sphingomyelins and glycolipids), steroids and waxes), and complex lipids (lipoproteins).

Types of lipids and their main synthesis mechanisms

All the reaction sequences of the lipid biosynthesis pathways are endergonic and reductive. In other words, they all use ATP as an energy source and a reduced electron carrier, such as NADPH, as a reducing power.

Next, the main reactions of the biosynthetic pathways of the main types of lipids will be described, that is, of fatty acids and eicosanoids, of triacylglycerols and phospholipids and of sterols (cholesterol).

- Synthesis of fatty acids

Fatty acids are extremely important molecules from the lipid point of view, as they are part of the most relevant lipids in cells. Its synthesis, contrary to what many scientists thought during the first studies in this regard, does not consist of the reverse route of its β-oxidation.

In fact, this metabolic pathway occurs in different cell compartments and requires the participation of a three-carbon intermediate known as malonyl-CoA, which is not necessary for oxidation.

Malonyl-CoA. NEUROtiker / Public domain

In addition, it is closely related to the sulfhydryl groups of proteins known as acyl carrier proteins (ACP, from English Acyl Carrier Proteins).

In general lines, the synthesis of fatty acids, especially those of long chain, is a sequential process where four steps are repeated in each "turn", and during each turn a saturated acyl group is produced that is the substrate for the next, which involves another condensation with a new malonyl-CoA molecule.

In each turn or cycle of reaction, the fatty acid chain extends two carbons, until it reaches a length of 16 atoms (palmitate), after which it leaves the cycle.

Malonyl-CoA formation

This intermediate of three carbon atoms is irreversibly formed from acetyl-CoA thanks to the action of an enzyme acetyl-CoA carboxylase, which has a prosthetic group of biotin that is covalently bound to the enzyme and that participates in this catalysis in Two steps.

In this reaction, a carboxyl group derived from a bicarbonate molecule (HCO3-) is transferred to biotin in an ATP-dependent manner, where the biotinyl group acts as a "temporary transporter" of the molecule while transferring it to acetyl-Coa., producing malonyl-CoA.

In the fatty acid synthesis sequence, the reducing agent used is NADPH and the activating groups are two thiol groups (-SH) that are part of a multi-enzyme complex called fatty acid synthase, which is the most important in catalysis synthetic.

In vertebrates, the fatty acid synthase complex is part of a single large polypeptide chain, in which the 7 characteristic enzymatic activities of the synthesis route are represented, as well as the hydrolytic activity necessary to release the intermediates at the end of the synthesis.

Structure of the fatty acid synthase enzyme (Source: Boehringer Ingelheim / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0) via Wikimedia Commons)

The 7 enzymatic activities of this complex are: acyl group transporter protein (ACP), acetyl-CoA-ACP transacetylase (AT), β-ketoacyl-ACP synthase (KS), malonyl-CoA-ACP transferase (MT), β- ketoacyl-ACP reductase (KR), β-hydroxyacyl-ACP dehydratase (HD), and enoyl-ACP reductase (ER).

Before the condensation reactions can occur to assemble the fatty acid chain, the two thiol groups in the enzyme complex become "charged" with the acyl groups: first, an acetyl-CoA is transferred to the -SH group of a cysteine ​​in the β-ketoacyl-ACP synthase part of the complex, a reaction catalyzed by the enzyme acetyl-CoA-ACP transacetylase (AT).

Subsequently, a malonyl group is transferred from a malonyl-CoA molecule to the -SH group of the acyl group transporter part (ACP) of the enzyme complex, a reaction catalyzed by a malonyl-CoA-ACP transferase (MT) enzyme, which also It is part of the fatty acid synthase complex.

The sequence of four reactions for each "turn" of the reaction cycle is as follows:

1. Condensation: The "charged" acetyl and malonyl groups on the enzyme condense to form an acetoacetyl-ACP molecule, which is attached to the ACP moiety through a -SH group. In this step, a CO2 molecule is produced and catalyzed by β-ketoacyl-ACP synthase (the acetyl group occupies the "terminal methyl" position of the acetoacetyl-ACP complex).
2. Reduction of the carbonyl group: the carbonyl group in the C3 position of acetoacetyl-ACP is reduced to form D-β-hydroxybutyryl-ACP, a reaction catalyzed by β-ketoacyl-ACP reductase, which uses NADPH as an electron donor.
3. Dehydration: the C2 and C3 carbons of D-β-hydroxybutyryl-ACP are devoid of water molecules, forming a double bond that ends with the production of the new compound trans -∆2-butenoyl-ACP. This process is mediated by a β-hydroxyacyl-ACP dehydratase (HD) enzyme.
4. Double bond reduction: the double bond of the compound formed in the dehydration step is saturated (reduced) to give butyryl-ACP through the reaction catalyzed by the enzyme enoyl-ACP reductase (ER), which also uses NADPH as a reducing agent.

Synthesis reactions occur until a molecule of palmitate (16 carbon atoms) is formed, which is hydrolyzed from the enzyme complex and released as a possible precursor for fatty acids with longer chains, which are produced by elongation systems. of fatty acids located in the smooth portion of the endoplasmic reticulum and in the mitochondria.

The other modifications that these molecules can undergo, such as desaturations, for example, are catalyzed by different enzymes, which generally occur in the smooth endoplasmic reticulum.

- Synthesis of eicosanoids

Eicosanoids are cellular lipids that function as "short-range" messenger molecules, produced by some tissues to communicate with cells in their neighboring tissues. These molecules are synthesized from polyunsaturated fatty acids of 20 carbon atoms.

Prostaglandins

In response to hormonal stimulation, the enzyme phospholipase A attacks membrane phospholipids and releases arachidonate from the 2-carbon glycerol. This compound is converted into prostaglandins thanks to an enzyme of the smooth endoplasmic reticulum with bifunctional activity: cyclooxygenase (COX) or prostaglandin H2 synthase.

Thromboxanes

Prostaglandins can be converted into thromboxanes thanks to thromboxane synthase present in blood platelets (thrombocytes). These molecules participate in the initial steps of blood clotting.

- Synthesis of triacylglycerols

Fatty acids are fundamental molecules for the synthesis of other more complex compounds in cells, such as triacylglycerols or membrane lipids glycerophospholipids (processes that depend on cellular metabolic needs).

Animals produce triacylglycerols and glycerophospholipids from two common precursors: fatty acyl-CoA and L-glycerol 3-phosphate. Fatty acyl-CoA are produced by acyl-CoA synthetases that participate in β-oxidation, while L-glycerol 3-phosphate is obtained from glycolysis and by the action of two alternative enzymes: glycerol 3-phosphate dehydrogenase and glycerol kinase.

Triacylglycerols are formed by the reaction between two molecules of fatty acyl-CoA and one molecule of diacylglycerol 3-phosphate; These transfer reactions are catalyzed by specific acyl transferases.

In this reaction, phosphatidic acid is initially produced, which is dephosphorylated by an enzyme phosphatidic acid phosphatase to produce 1,2-diacylglycerol, which is again capable of accepting a third molecule of fatty acyl-CoA, producing triacylglycerol.

- Phospholipid synthesis

Phospholipids are highly variable molecules, since many different ones can be formed by the combination of fatty acids and different "head" groups with the glycerol (glycerophospholipids) or sphingosine (sphingolipids) skeleton that characterize them.

The general assembly of these molecules requires the synthesis of the glycerol or sphingosine backbone, the union with the corresponding fatty acids, either by esterification or amidation, the addition of a hydrophilic "head" group through a phosphodiester bond and, if necessary, the alteration or exchange of the latter groups.

In eukaryotes this process occurs in the smooth endoplasmic reticulum and also in the inner mitochondrial membrane, where they can remain indefinitely or from where they can be translocated to other places.

Reaction steps

The first steps of the synthesis reaction of glycerophospholipids are equivalent to those of the production of triacylglycerols, since a molecule of glycerol 3-phosphate is esterified to two molecules of fatty acid at carbons 1 and 2, forming phosphatidic acid. It is common to find phospholipids that have fatty acids saturated in the C1 and unsaturated in the C2 of glycerol.

Phosphatidic acid can also be produced by phosphorylation of an already synthesized or "recycled" diacylglycerol molecule.

The polar "head" groups of these molecules are formed through phosphodiester bonds. The first thing that must happen for this process to occur correctly is the "activation" of one of the hydroxyl groups that participates in the process by binding to a nucleotide such as cytidine diphosphate (CDP), which is nucleophilically displaced by the other group. hydroxyl that participates in the reaction.

If this molecule binds to diacylglycerol, then CDP-diacylglycerol (the "activated" form of phosphatidic acid) is formed, but this can also occur on the hydroxyl group of the "head" group.

In the case of phosphatidylserine, for example, diacylglycerol is activated by condensation of the phosphatidic acid molecule with a cytidine triphosphate (CTP) molecule, forming CDP-diacylglycerol and eliminating a pyrophosphate.

If a molecule of CMP (cytidine monophosphate) is displaced by a nucleophilic attack of the hydroxyl of serine or of the hydroxyl at the 1-carbon of glycerol 3-phosphate, phosphatidylserine or phosphatidylglycerol 3-phosphate can be released, from which the phosphate monoester can be released and produce phosphatidylglycerol.

Both molecules produced in this way serve as precursors for other membrane lipids, which often share biosynthetic pathways with each other.

- Synthesis of cholesterol

Cholesterol is an essential molecule for animals that can be synthesized by their cells, so it is not essential in the daily diet. This molecule of 27 carbon atoms is produced from a precursor: acetate.

This complex molecule is formed from acetyl-CoA in four main stages:

1. Condensation of three acetate units to form mevalonate, a 6-carbon intermediate molecule (first a molecule of acetoacetyl-CoA is formed with two acetyl-CoA (thiolase enzyme) and then another of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) (HMG-CoA synthetase enzyme) Mevalonate is formed from HMG-CoA and thanks to the enzyme HMG-CoA reductase.
2. Conversion of mevalonate to isoprene units. First 3 phosphate groups are transferred from 3 ATP molecules to the mevalonate. One of the phosphates is lost along with the adjacent carbonyl group and ∆3-isopentenyl pyrophosphate is formed, which is isomerized to produce dimethylallyl pyrophosphate
3. Polymerization or condensation of 6 C 5 isoprene units to form C 30 squalene (a linear molecule).
4. Cyclization of squalene to form the 4 rings of the steroid nucleus of cholesterol and subsequent chemical changes: oxidations, migration and elimination of methyl groups, etc., which yields cholesterol.

References

1. Garrett, RH, & Grisham, CM (2001). Principles of biochemistry: with a human focus. Brooks / Cole Publishing Company.
2. Murray, RK, Granner, DK, Mayes, PA, & Rodwell, VW (2014). Harper's illustrated biochemistry. Mcgraw-Hill.
3. Nelson, DL, Lehninger, AL, & Cox, MM (2008). Lehninger principles of biochemistry. Macmillan.
4. Jacquemyn, J., Cascalho, A., & Goodchild, RE (2017). The ins and outs of endoplasmic reticulum ‐ controlled lipid biosynthesis. EMBO reports, 18 (11), 1905-1921.
5. Ohlrogge, J., & Browse, J. (1995). Lipid biosynthesis. The Plant Cell, 7 (7), 957.