The process cycles with the addition of another malonyl-ACP to the growing chain until ultimately an intermediate with 16 carbons is produced palmitoyl-CoA. At this point, the cytoplasmic synthesis ceases. Enzymes of Fatty Acid Synthesis Acetyl-CoA carboxylase, which catalyzes synthesis of malonyl-CoA, is the only regulated enzyme in fatty acid synthesis.
Its regulation involves both allosteric control and covalent modification. Dephosphorylation is stimulated by phosphatases activated by insulin binding. Dephosphorylation activates the enzyme and favors its assembly into a long polymer, while phosphorylation reverses the process. Citrate acts as an allosteric activator and may also favor polymerization.
Palmitoyl-CoA allosterically inactivates it. Note that FAS is only active as a homodimer rather than the monomer pictured. These include transacylases for swapping CoA with ACP on acetyl-CoA and malonyl-CoA; a synthase to catalyze addition of the two carbon unit from the three carbon malonyl-ACP in the first step of the elongation process; a reductase to reduce the ketone; a dehydrase to catalyze removal of water, and a reductase to reduce the trans double bond.
The placement of the biotin carboxylase, biotin carboxyl carrier protein, and carboxyl transferase domains is very complex. In most eukaryotes, acetyl-CoA carboxylases occur as biotin carboxylase-biotin carboxyl carrier protein-fused carboxyl transferase chains.
In archaeal biotin-dependent carboxylases specific for acetyl-CoA and propionyl-CoA, biotin carboxyl carrier protein is separate from the biotin carboxylase and fused carboxyl transferase domains . Acyltransferases The acyltransferases are made up of one very large family Table 1 whose members are produced by bacteria, eukaryota, and a few archaea.
The specific task of the acyltransferases is to exchange the CoA moiety on the malonyl-CoA entering the fatty acid synthesis cycle with an acyl carrier protein Figure 1. Ketoacyl synthases The general role of ketoacyl synthases, along with acyltransferases, is to add malonyl-CoA to an acyl-acyl carrier protein chain, with the loss of carbon dioxide and CoA and with the acyl chain increasing in length by two methylene groups  Figure 1.
There are five families of ketoacyl synthases, three of whose members have similar tertiary structures Figure 3. Together with the members of a fourth family somewhat related to them by primary structure and by catalytic mechanism members of all four families have a catalytic triad of Cys, His, and Asn or His , they form a single clan  Table 1.
These four families have very different functions, the members of one of them being involved in chalcone and stilbene synthesis. The fifth family, without a known tertiary structure, is made up only by eukaryotic enzymes involved in the elongation of already very long fatty acid chains. Figure 3. Superimposed ketoacyl synthase KS crystal structures.
Copyright , The Protein Society. In this pathway the ketoacyl reductase-, hydroxyacyl dehydratase-, and enoyl reductase-catalyzed steps operate in reverse, so these enzymes are given names characteristic of the reverse reactions. Hydration of 2-enoyl-CoA yielding 3-hydroxyacyl-CoA is catalyzed by 2-enoyl hydratase equivalent to hydroxyacyl dehydratase. A final step, with addition of CoA, removes an acetyl-CoA molecule and leaves an acyl-CoA molecule two carbon atoms shorter than before.
It is catalyzed by 3-ketoacyl-CoA thiolase, which is not a member of the standard fatty acid synthesis cycle. Polyketide synthesis A short paragraph can serve to describe the difference between fatty acid synthesis and polyketide synthesis. In the latter, the ketoacyl reductase-, hydroxyacyl dehydratase-, and enoyl reductase-catalyzed steps do not necessarily occur during each turn around the cycle, so keto and hydroxy groups and double bonds may remain in the lengthening chain.
Furthermore, the chain can be elongated by substances other than malonyl-CoA, therefore leading to chains with odd numbers of carbon atoms or different functional groups. Finally, if chain growth is terminated not by water but by a hydroxy group, chain cyclization can occur. Ketoacyl reductases The ketoacyl reductases are divided into four families Table 1 , with family KR1 having the largest number of tabulated primary structures in the ThYme database Table 1.
It also includes the former family ER1, as all the amino acid sequences of these enoyl reductases were found also in family KR1. Those in family KR2 have histidine and glutamate catalytic residues, but also NAD P -binding Rossmann folds along with C-terminal 6-phosphogluconate dehydrogenase folds.
Members of families KR1 and KR2 are freestanding, while those of families KR3 and KR4 are parts of multi-enzyme chains carrying out fatty acid and polyketide synthesis. No tertiary structures are yet known for members of families HD7 and HD8.
Although tertiary structures of members of families HD1, HD5, and HD6 can be closely superimposed on each other, the catalytic aspartate and histidine residues of HD1 are not in the same location as the catalytic aspartate and histidine residues of HD5 or the glutamate and histidine residues of HD6 . Separately, HD3 and HD4 members are part of multi-enzyme fatty acid and polyketide synthases. Figure 4. B Superimposed active-site side chains of the same HD family representatives, with colors as in A.
Enoyl reductases As previously noted, family ER1 has been merged into family KR1 because all of its entries are also found there. Furthermore, all members of each family catalyze the same types of reductive reactions.
The remaining enoyl reductases fall into five families, of which those in families ER3 and ER4 are part of larger fatty acid and polyketide synthase complexes  Table 1. A superimposition of a ER2 tertiary structure upon the structures of KR1, KR3, and KR4, members of clan KR-A, is extremely close, suggesting that ER2 members and members of the three ketoacyl reductase families have a distant common ancestor . Thioesterases The thioesterases are the most varied of the eight enzyme groups making up the fatty acid synthesis cycle.
Twelve of these families can be gathered into clans. The mechanisms of those thioesterases with HotDog tertiary structures are much less known . They may well have different mechanisms from each other, as their experimentally identified catalytic residues vary. Figure 5. Most acyl carrier proteins have 70 to amino acid residues, but members of family ACP2 have longer chains. Members of some families are freestanding, while others are part of longer fatty acid synthase and polyketide synthase chains Table 1.
The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, citrate produced by the condensation of acetyl CoA with oxaloacetate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol.
The oxaloacetate can be used for gluconeogenesis in the liver , or it can be returned into mitochondrion as malate. The two pathways are distinct, not only in where they occur, but also in the reactions that occur, and the substrates that are used.
The two pathways are mutually inhibitory, preventing the acetyl-CoA produced by beta-oxidation from entering the synthetic pathway via the acetyl-CoA carboxylase reaction. During each turn of the cycle, two carbon atoms leave the cycle as CO2 in the decarboxylation reactions catalyzed by isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. Thus each turn of the citric acid cycle oxidizes an acetyl-CoA unit while regenerating the oxaloacetate molecule with which the acetyl-CoA had originally combined to form citric acid.
The decarboxylation reactions occur before malate is formed in the cycle. This is the only substance that can be removed from the mitochondrion to enter the gluconeogenic pathway to form glucose or glycogen in the liver or any other tissue.
Only plants possess the enzymes to convert acetyl-CoA into oxaloacetate from which malate can be formed to ultimately be converted to glucose. Acetyl-CoA carboxylase is the point of regulation in saturated straight-chain fatty acid synthesis, and is subject to both phosphorylation and allosteric regulation.
In contrast to the hydroxylated intermediate of beta oxidation, the beta intermediate here is in the D-configuration. This system is intra-mitochondrial. Enzymes of Fatty Acid Synthesis Acetyl-CoA carboxylase, which catalyzes synthesis of malonyl-CoA, is the only regulated enzyme in fatty acid synthesis.
Another turn of the helix will produce a chain of fatty acid lengthened by two carbon atoms i. The biosynthesis of fatty acids requires NADPH which is mainly provided by the oxidation of glucose in the pentose-phosphates cycle. A superimposition of a ER2 tertiary structure upon the structures of KR1, KR3, and KR4, members of clan KR-A, is extremely close, suggesting that ER2 members and members of the three ketoacyl reductase families have a distant common ancestor . Palmitoyl-CoA allosterically inactivates it. Trivial names of fatty acids-Part 1.
These enzymes allow molecular oxygen, O2, to interact with the saturated fatty acyl-CoA chain, forming a double bond and two molecules of water, H2O. Regulation by phosphorylation occurs mostly in mammals, while allosteric regulation occurs in most organisms. Members of the very large KS3 family are both freestanding and are parts of polyketide and fatty acid synthases produced by bacteria, animals, fungi, and slime molds.
Joining of a fatty acyl-ACP in this case, acetyl-ACP with malonyl-ACP splits out the carboxyl that was added and creates the intermediate at the upper right in the figure at left. Members of three families have similar tertiary structures folds , while two have yet no known folds.
Dephosphorylation is stimulated by phosphatases activated by insulin binding. The placement of the biotin carboxylase, biotin carboxyl carrier protein, and carboxyl transferase domains is very complex. In the latter, the ketoacyl reductase-, hydroxyacyl dehydratase-, and enoyl reductase-catalyzed steps do not necessarily occur during each turn around the cycle, so keto and hydroxy groups and double bonds may remain in the lengthening chain. The latter is lengthened probably in the endoplasmic reticulum by a system requiring malonyl coA.
Reproduced with permission from ref. To produce fatty acids from the precursor which is acetyl-coA, the cells must be able to reduce the ketone groups: this will be achieved thanks to NADPH; they must also be able to form C— C bonds in order to condense acetyl radicals: although the methyl group of acetyl-coA is capable of binding to a carbonyl, this is not the reaction used for obtaining chains of fatty acids; the cells use a more reactive intermediate, malonyl-coA. Furthermore, archaeal chains are branched with methyl groups at regular intervals, based on isoprenoid chemistry, while bacterial and eukaryotic organisms have aryl chains with straight-chain fatty acids. Members of families KR1 and KR2 are freestanding, while those of families KR3 and KR4 are parts of multi-enzyme chains carrying out fatty acid and polyketide synthesis.
Chen used the ThYme database in to find that of the archaeal species tabulated then, 33 had one cycle member, 28 had two, 22 had three, 17 had four, 26 had five, 27 had six, one had eight, and one had all nine . More specifically, these complexes, found in some bacteria, fungi, animals, and slime molds, allow growing fatty acid chains, activated by acyl carrier protein, to be passed sequentially from one fatty acid synthesis enzyme to the next without randomly diffusing among them. Although not all enzyme groups have been analyzed, one clan of ketoacyl synthases encompasses four of its five families , one clan of ketoacyl reductases covers three of its four families , one clan of hydroxyacyl dehydratases takes in two of its eight families , and four clans of thioesterases cover four, three, three, and two of its 25 families .
A reduction of crotonyl-Enz. DesK is a membrane-associated kinase and DesR is a transcriptional regulator of the des gene. In contrast to the hydroxylated intermediate of beta oxidation, the beta intermediate here is in the D-configuration. This second pathway is regulated by repressor protein DesT. Computation has established that ACP4 members have folds similar to those of other acyl carrier protein families whose folds have been experimentally determined . Most eukaryotic members are produced by some combination of fungi, animals, and plants, as well as sometimes by algae and occasionally by other simple life forms.
Members of individual acyl carrier protein families are more likely than members of the eight enzyme groups that are part of the fatty acid synthesis cycle to be made by members of single life kingdoms, usually bacterial but sometimes eukaryotic. The fifth family, without a known tertiary structure, is made up only by eukaryotic enzymes involved in the elongation of already very long fatty acid chains. Structural classification of biotin carboxyl carrier proteins.