The synthesis of fatty acids is the process by which the fundamental components of the most important lipids in cells (fatty acids) are produced, which participate in many very important cellular functions.
Fatty acids are aliphatic molecules, that is, they are essentially composed of carbon and hydrogen atoms bound to each other in a more or less linear manner. They have a methyl group at one end and an acidic carboxylic group at the other, for which they are called "fatty acids."
Summary of fatty acid synthesis (Source: Mephisto spa / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)
Lipids are molecules used by different cellular biosynthetic systems for the formation of other more complex molecules such as:
- membrane phospholipids
- triglycerides for energy storage and
- the anchors of some special molecules found on the surface of many types of cells (eukaryotic and prokaryotic)
These compounds can exist as linear molecules (with all carbon atoms saturated with hydrogen molecules), but those with a straight chain and some saturations can also be observed, that is, with double bonds between their carbon atoms.
Saturated fatty acids can also be found with branched chains, whose structure is slightly more complex.
The molecular characteristics of fatty acids are crucial for their function, since many of the physicochemical properties of the molecules that are formed by them depend on them, especially their melting point, their degree of packaging and their capacity to form bilayers.
Thus, the synthesis of fatty acids is a highly regulated matter, as it is a series of sequential events critical for the cell from many points of view.
Where does fatty acid synthesis occur?
In most living organisms, the synthesis of fatty acids occurs in the cytosolic compartment, while their degradation occurs mainly between the cytosol and the mitochondria.
The process depends on the energy contained in the ATP bonds, on the reducing power of NADPH (usually derived from the pentose phosphate pathway), on the biotin cofactor, on bicarbonate ions (HCO3-) and on manganese ions.
In mammalian animals the main organs for the synthesis of fatty acids are the liver, kidneys, brain, lungs, mammary glands and adipose tissue.
The immediate substrate for the de novo synthesis of fatty acids is acetyl-CoA and the end product is a molecule of palmitate.
Acetyl-CoA derives directly from the processing of glycolytic intermediates, which is why a diet high in carbohydrates promotes the synthesis of lipids (lipogenesis) ergo, also of fatty acids.
Enzymes involved
Acetyl-CoA is the two-carbon synthesis block that is used for the formation of fatty acids, since several of these molecules are linked consecutively to a malonyl-CoA molecule, formed by the carboxylation of an acetyl-CoA.
The first enzyme in the route, and one of the most important from the point of view of its regulation, is the one in charge of the carboxylation of acetyl-CoA, known as acetyl-CoA carboxylase (ACC), which is a complex An enzymatic compound made up of 4 proteins and using biotin as a cofactor.
However, and despite the structural differences between the different species, the fatty acid synthase enzyme is responsible for the main biosynthetic reactions.
This enzyme is, in reality, an enzyme complex composed of monomers that have the 7 different enzymatic activities, which are necessary for the elongation of the fatty acid at "birth".
The 7 activities of this enzyme can be listed as follows:
- ACP: acyl group carrier protein
- 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)
- Enoyl-ACP reductase (ER)
In some organisms such as bacteria, for example, the fatty acid synthase complex is made up of independent proteins that associate with each other, but are encoded by different genes (type II fatty acid synthase system).
Yeast fatty acid synthase enzyme (Source: Xiong, Y., Lomakin, IB, Steitz, TA / Public domain, via Wikimedia Commons)
However, in many eukaryotes and some bacteria the multienzyme contains several catalytic activities that are separated into different functional domains, in one or more polypeptides, but that can be encoded by the same gene (type I fatty acid synthase system).
Stages and reactions
Most of the studies carried out regarding the synthesis of fatty acids involve the findings made in the bacterial model, however, the synthesis mechanisms of eukaryotic organisms have also been studied in some depth.
It is important to mention that the type II fatty acid synthase system is characterized in that all fatty acyl intermediates are covalently linked to a small acidic protein known as the acyl transporter protein (ACP), which transports them from one enzyme to the next.
In eukaryotes, on the contrary, ACP activity is part of the same molecule, it being understood that the same enzyme has a special site for the binding of intermediates and their transport through the different catalytic domains.
The union between the protein or the ACP portion and the fatty acyl groups occurs through thioester bonds between these molecules and the prosthetic group 4'-phosphopantetheine (pantothenic acid) of the ACP, which is fused with the carboxyl group of the fatty acyl.
- Initially, the enzyme acetyl-CoA carboxylase (ACC) is responsible for catalyzing the first step of "commitment" in the synthesis of fatty acids that, as mentioned, involves the carboxylation of an acetyl-CoA molecule to form the intermediate of 3 carbon atoms known as malonyl-CoA.
The fatty acid synthase complex receives the acetyl and malonyl groups, which must correctly "fill in" the "thiol" sites of it.
This occurs initially by the transfer of acetyl-CoA to the SH group of cysteine in the enzyme β-ketoacyl-ACP synthase, a reaction catalyzed by acetyl-CoA-ACP transacetylase.
The malonyl group is transferred from the malonyl-CoA to the SH group of the ACP protein, an event mediated by the malonyl-CoA-ACP transferase enzyme, forming malonyl-ACP.
- The step of initiation of fatty acid elongation at birth consists of the condensation of malonyl-ACP with an acetyl-CoA molecule, a reaction directed by an enzyme with β-ketoacyl-ACP synthase activity. In this reaction, acetoacetyl-ACP is then formed and a CO2 molecule is released.
- Elongation reactions occur in cycles where 2 carbon atoms are added at a time, each cycle consisting of a condensation, a reduction, a dehydration and a second reduction event:
- Condensation: acetyl and malonyl groups condense to form acetoacetyl-ACP
- Reduction of the carbonyl group: the carbonyl group of carbon 3 of acetoacetyl-ACP is reduced, forming D-β-hydroxybutyryl-ACP, a reaction catalyzed by β-ketoacyl-ACP-reductase, which uses NADPH as an electron donor.
- Dehydration: the hydrogens between carbons 2 and 3 of the previous molecule are removed, forming a double bond that ends with the production of trans -∆2-butenoyl-ACP. The reaction is catalyzed by β-hydroxyacyl-ACP dehydratase.
- Double bond reduction: the trans-del2-butenoyl-ACP double bond is reduced to form butyryl-ACP by the action of enoyl-ACP reductase, which also uses NADPH as a reducing agent.
To continue elongation, a new malonyl molecule must bind again to the ACP portion of the fatty acid synthase complex and begins with the condensation of this with the butyryl group formed in the first synthesis cycle.
Structure of palmitate (Source: Edgar181 / Public domain, via Wikimedia Commons)
At each elongation step, a new malonyl-CoA molecule is used to grow the chain onto 2 carbon atoms and these reactions are repeated until the proper length (16 carbon atoms) is reached, after which a thioesterase enzyme releases the complete fatty acid by hydration.
Palmitate can be further processed by different types of enzymes that modify its chemical characteristics, that is, they can introduce unsaturations, prolong its length, etc.
Regulation
Like many biosynthetic or degradation pathways, fatty acid synthesis is regulated by different factors:
- It depends on the presence of bicarbonate ions (HCO3-), vitamin B (biotin) and acetyl-CoA (during the initial step of the pathway, which involves the carboxylation of an acetyl-CoA molecule by means of a carboxylated intermediate of biotin to form malonyl-CoA).
- It is a path that occurs in response to cellular energy characteristics, because when there is a sufficient amount of "metabolic fuel", the excess is converted into fatty acids that are stored for subsequent oxidation in times of energy deficit.
In terms of the regulation of the enzyme acetyl-CoA carboxylase, which represents the limiting step of the entire pathway, it is inhibited by palmitoyl-CoA, the main product of synthesis.
Its allosteric activator, on the other hand, is citrate, which directs the metabolism from oxidation to synthesis for storage.
When mitochondrial acetyl-CoA and ATP concentrations increase, citrate is transported into the cytosol, where it is both a precursor for cytosolic acetyl-CoA synthesis and an allosteric activation signal for acetyl-CoA carboxylase.
This enzyme can also be regulated by phosphorylation, an event triggered by the hormonal action of glucagon and epinephrine.
References
- McGenity, T., Van Der Meer, JR, & de Lorenzo, V. (2010). Handbook of hydrocarbon and lipid microbiology (p. 4716). KN Timmis (Ed.). Berlin: Springer.
- Murray, RK, Granner, DK, Mayes, PA, & Rodwell, VW (2014). Harper's illustrated biochemistry. Mcgraw-hill.
- Nelson, DL, & Cox, MM (2009). Lehninger principles of biochemistry (pp. 71-85). New York: WH Freeman.
- Numa, S. (1984). Fatty acid metabolism and its regulation. Elsevier.
- Rawn, JD (1989). Biochemistry-International edition. North Carolina: Neil Patterson Publishers, 5.