Amino acid synthesis

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Amino acid biosynthesis overview. The drawn molecules are in their neutral forms and do not fully correspond to their presented names. Humans can not synthesize all of these amino acids.

Amino acid synthesis is the set of biochemical processes (metabolic pathways) by which the various amino acids are produced from other compounds. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. Humans are an excellent example of this, since humans can only synthesize 11 of the 20 standard amino acids (a.k.a. non-essential amino acid), and in time of accelerated growth, histidine, can be considered an essential amino acid.[1]

A fundamental problem for biological systems is to obtain nitrogen in an easily usable form. This problem is solved by certain microorganisms capable of reducing the inert N≡N molecule (nitrogen gas) to two molecules of ammonia in one of the most remarkable reactions in biochemistry. Ammonia is the source of nitrogen for all the amino acids. The carbon backbones come from the glycolytic pathway, the pentose phosphate pathway, or the citric acid cycle.

In amino acid production, one encounters an important problem in biosynthesis, namely stereochemical control. Because all amino acids except glycine are chiral, biosynthetic pathways must generate the correct isomer with high fidelity. In each of the 19 pathways for the generation of chiral amino acids, the stereochemistry at the α-carbon atom is established by a transamination reaction that involves pyridoxal phosphate. Almost all the transaminases that catalyze these reactions descend from a common ancestor, illustrating once again that effective solutions to biochemical problems are retained throughout evolution.

Biosynthetic pathways are often highly regulated such that building-blocks are synthesized only when supplies are low. Very often, a high concentration of the final product of a pathway inhibits the activity of enzymes that function early in the pathway. Often present are allosteric enzymes capable of sensing and responding to concentrations of regulatory species. These enzymes are similar in functional properties to aspartate transcarbamoylase and its regulators. Feedback and allosteric mechanisms ensure that all twenty amino acids are maintained in sufficient amounts for protein synthesis and other processes.

Nitrogen fixation[edit]

Microorganisms use ATP and reduced ferredoxin, a powerful reductant, to reduce atmospheric nitrogen (N2) to ammonia (NH3). An iron-molybdenum cluster in nitrogenase deftly catalyzes the fixation of N2, a very inert molecule. Higher organisms consume the fixed nitrogen to synthesize amino acids, nucleotides, and other nitrogen-containing biomolecules. The major points of entry of ammonia into metabolism are glutamine or glutamate.


Most amino acids are synthesized from α-ketoacids, and later transaminated from another amino acid, usually glutamate. The enzyme involved in this reaction is an aminotransferase.

α-ketoacid + glutamate ⇄ amino acid + α-ketoglutarate

Glutamate itself is formed by amination of α-ketoglutarate:

α-ketoglutarate + NH+
⇄ glutamate

From intermediates of the citric acid cycle and other pathways[edit]

Of the basic set of twenty amino acids (not counting selenocysteine), there are eight that human beings cannot synthesize. In addition, the amino acids arginine, cysteine, glycine, glutamine, histidine, proline, serine, and tyrosine are considered conditionally essential, meaning they are not normally required in the diet, but must be supplied exogenously to specific populations that do not synthesize it in adequate amounts.[2][3] For example, enough arginine is synthesized by the urea cycle to meet the needs of an adult but perhaps not those of a growing child. Amino acids that must be obtained from the diet are called essential amino acids. Nonessential amino acids are produced in the body. The pathways for the synthesis of nonessential amino acids are quite simple. Glutamate dehydrogenase catalyzes the reductive amination of α-ketoglutarate to glutamate. A transamination reaction takes place in the synthesis of most amino acids. At this step, the chirality of the amino acid is established. Alanine and aspartate are synthesized by the transamination of pyruvate and oxaloacetate, respectively. Glutamine is synthesized from NH4+ and glutamate, and asparagine is synthesized similarly. Proline and arginine are derived from glutamate. Serine, formed from 3-phosphoglycerate, is the precursor of glycine and cysteine. Tyrosine is synthesized by the hydroxylation of phenylalanine, an essential amino acid. The pathways for the biosynthesis of essential amino acids are much more complex than those for the nonessential ones. Activated Tetrahydrofolate, a carrier of one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible: most reduced—methyl; intermediate—methylene; and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is S-adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. S-Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle.

Cortisol inhibits protein synthesis.[4]

Regulation by feedback inhibition[edit]

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from E. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications.


The α-ketoglutarate family of amino acid synthesis (synthesis of glutamate, glutamine, proline and arginine) begins with α-ketoglutarate, an intermediate in the Citric Acid Cycle. The concentration of α-ketoglutarate is dependent on the activity and metabolism within the cell along with the regulation of enzymatic activity. In E. coli citrate synthase, the enzyme involved in the condensation reaction initiating the Citric Acid Cycle is strongly inhibited by α-ketoglutarate feedback inhibition and can be inhibited by DPNH as well high concentrations of ATP.[5] This is one of the initial regulations of the α-ketoglutarate family of amino acid synthesis.

The regulation of the synthesis of glutamate from α-ketoglutarate is subject to regulatory control of the Citric Acid Cycle as well as mass action dependent on the concentrations of reactants involved due to the reversible nature of the transamination and glutamate dehydrogenase reactions.[5]

The conversion of glutamate to glutamine is regulated by glutamine synthetase (GS) and is a highly significant step in nitrogen metabolism.[5] This enzyme is regulated by at least four different mechanisms: 1. Repression and depression due to nitrogen levels; 2. Activation and inactivation due to enzymatic forms (taut and relaxed); 3. Cumulative feedback inhibition through end product metabolites; and 4. Alterations of the enzyme due to adenylation and deadenylation.[5] In rich nitrogenous media or growth conditions containing high quantities of ammonia there is a low level of GS, whereas in limiting quantities of ammonia the specific activity of the enzyme is 20-fold higher.[5] The confirmation of the enzyme plays a role in regulation depending on if GS is in the taut or relaxed form. The taut form of GS is fully active but, the removal of manganese converts the enzyme to the relaxed state. The specific conformational state occurs based on the binding of specific divalent cations and is also related to adenylation.[5] The feedback inhibition of GS is due to a cumulative feedback due to several metabolites including L-tryptophan, L-histidine, AMP, CTP, glucosamine-6-phosphate and carbamyl phosphate, alanine, and glycine.[5] An excess of any one product does not individually inhibit the enzyme but a combination or accumulation of all the end products have a strong inhibitory effect on the synthesis of glutamine.[5] Glutamine synthase activity is also inhibited via adenylation. The adenylation activity is catalyzed by the bifunctional adenylyltransferase/adenylyl removal (AT/AR) enzyme. Glutamine and a regulatory protein called PII act together to stimulate adenylation.[6]

The regulation of proline biosynthesis can be dependent on the initial controlling step through negative feedback inhibition.[7] In E. coli, proline allosterically inhibits Glutamate 5-kinase which catalyzes the reaction from L-glutamate to an unstable intermediate L-γ-Glutamyl phosphate.[7]

Arginine synthesis also utilizes negative feedback as well as repression through a repressor encoded by the gene argR. The gene product of argR, ArgR an aporepressor, and arginine as a corepressor affect the operon of arginine biosynthesis. The degree of repression is determined by the concentrations of the repressor protein and corepressor level.[8]

Erythrose 4-phosphate and phosphoenolpyruvate[edit]

Phenylalanine, tyrosine, and tryptophan are known as the aromatic amino acids. The synthesis of all three share a common beginning to their pathways; the formation of chorismate from phosphoenolpyruvate (PEP) and erythrose 4- phosphate (E4P). The first step, condensation of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) from PEP/E4P, uses three isoenzymes AroF, AroG, and AroH. Each one of these has its synthesis regulated from tyrosine, phenylalanine, and tryptophan, respectively. These isoenzymes all have the ability to help regulate synthesis of DAHP by the method of feedback inhibition. This acts in the cell by monitoring the concentrations of each of the three aromatic amino acids. When there is too much of any one of them, that one will allosterically control the DAHP synthetase by “turning it off”. With the first step of the common pathway shut off, synthesis of the three amino acids can not proceed. The rest of the enzymes in the common pathway (conversion of DAHP to chorismate) appear to be synthesized constitutively, except for shikimate kinase which can be inhibited by shikimate through linear mixed-type inhibition. If too much shikimate has been produced then it can bind to shikimate kinase to stop further production.

Besides the regulations described above, each amino acids terminal pathway can be regulated. These terminal pathways progress from chorismate to the final end product, either tyrosine, phenylalanine, or tryptophan. Each one of these pathways is regulated in a similar fashion to the common pathway; with feedback inhibition on the first committed step of the pathway.

Tyrosine and phenylalanine share the same initial step in their terminal pathways, chorismate converted to prephenate which is converted to an amino acid-specific intermediate. This process is mediated by a phenylalanine (PheA) or tyrosine (TyrA) specific chorismate mutase-prephenate dehydrogenase. The reason for the amino acid-specific enzymes is because PheA uses a simple dehydrogenase to convert prephenate to phenylpyruvate, while TyrA uses a NAD-dependent dehydrogenase to make 4-hydroxylphenylpyruvate. Both PheA and TyrA are feedback inhibited by their respective amino acids. Tyrosine can also be inhibited at the transcriptional level by the TyrR repressor. TyrR binds to the TyrR boxes on the operon near the promoter of the gene that it wants to repress.

In the terminal-tryptophan synthesis pathway, the initial step converts chorismate to anthranilate using anthranilate synthase. This enzyme requires either ammonia or glutamine as the amino group donor. Anthranilate synthase is regulated by the gene products of trpE and trpG. trpE encodes the first subunit, which binds to chorismate and moves the amino group from the donor to chorismate. trpG encodes the second subunit, which binds glutamine and uses it as the amino group donor so that the amine group can transfer to the chorismate. Anthranilate synthase is also regulated by feedback inhibition. The finished product of tryptophan, once produced in great enough quantities, is able to act as the co-repressor to the TrpR repressor which represses expression of the trp operon.


The oxaloacetate/aspartate family of amino acids is composed of lysine, asparagine, methionine, threonine, and isoleucine. Aspartate can be converted into lysine, asparagine, methionine and threonine. Threonine also gives rise to isoleucine. All of these amino acids contain different mechanisms for their regulation, some being more complex than others. All the enzymes in this biosynthetic pathway are subject to regulation via feedback inhibition and/or repression at the genetic level. As is typical in highly branched metabolic pathways, there is additional regulation at each branch point of the pathway. This type of regulatory scheme allows control over the total flux of the aspartate pathway in addition to the total flux of individual amino acids. The aspartate pathway uses L-aspartic acid as the precursor for the biosynthesis of one fourth of the building block amino acids. Without this pathway, protein synthesis would not be possible.


The enzyme aspartokinase, which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, can be broken up into 3 isozymes, AK-I, II and III. AK-I is feed-back inhibited by threonine, while AK-II and III are inhibited by lysine. As a sidenote, AK-III catalyzes the phosphorylation of aspartic acid that is the commitment step in this biosynthetic pathway. The higher the concentration of threonine or lysine, the more aspartate kinase becomes downregulated.


Lysine is synthesized from aspartate via the diaminopimelate (DAP) pathway. The initial two stages of the DAP pathway are catalyzed by aspartokinase and aspartate semialdehyde dehydrogenase and play a key role in the biosynthesis of lysine, threonine and methionine. There are two bifunctional aspartokinase/homoserine dehydrogenases, ThrA and MetL, in addition to a monofunctional aspartokinase, LysC. Transcription of aspartokinase genes is regulated by concentrations of the subsequently produced amino acids, lysine, threonine and methionine. The higher these amino acids concentrations, the less the gene is transcribed. ThrA and LysC are also feed-back inhibited by threonine and lysine. Finally, DAP decarboxylase LysA mediates the last step of the lysine synthesis and is common for all studied bacterial species. The formation of aspartate kinase (AK), which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is also inhibited by both lysine and threonine, which prevents the formation of the amino acids derived from aspartate. Additionally, high lysine concentrations inhibit the activity of dihydrodipicolinate synthase (DHPS). So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, lysine also inhibits the activity of the first enzyme after the branch point, i.e. the enzyme that is specific for lysine’s own synthesis.


There are two different asparagine synthetases found in bacterial species. These two synthetases, which are both referred to as the AsnC protein, are coded for by two genes: AsnA and AsnB. AsnC is autogenously regulated, which is where the product of a structural gene regulates the expression of the operon in which the genes reside. The stimulating effect of AsnC on AsnA transcription is downregulated by asparagine. However, the autoregulation of AsnC is not affected by asparagine.


Methionine synthesis is under tight regulation. The repressor protein MetJ, in cooperation with the corepressor protein S-adenosyl-methionine, mediates the repression of methionine’s biosynthetic pathway. Recently, a new regulator focus, MetR has been identified. The MetR protein is required for MetE and MetH gene expression and functions as a transactivator of transcription for these genes. MetR transcriptional activity is regulated by homocystein, which is the metabolic precursor of methionine. It is also known that vitamin B12 can repress MetE gene expression, which is mediated by the MetH holoenzyme.


The biosynthesis of threonine is regulated via allosteric regulation of its precursor, homoserine, by structurally altering the enzyme homoserine dehydrogenase. This reaction occurs at a key branch point in the pathway, with the substrate homoserine serving as the precursor for the biosynthesis of lysine, methionine, threonin and isoleucine. High levels of threonine result in low levels of homoserine synthesis. The synthesis of aspartate kinase (AK), which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is feed-back inhibited by lysine, isoleucine, and threonine, which prevents the synthesis of the amino acids derived from aspartate. So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, threonine also inhibits the activity of the first enzyme after the branch point, i.e. the enzyme that is specific for threonine’s own synthesis.


The enzymes threonine deaminase, dihydroxy acid dehydrase and transaminase are controlled by end-product regulation. I.e. the presence of isoleucine will downregulate the formation of all three enzymes, resulting in the downregulation of threonine biosynthesis. High concentrations of isoleucine also result in the downregulation of aspartate’s conversion into the aspartyl-phosphate intermediate, hence halting further biosynthesis of lysine, methionine, threonine, and isoleucine.

Ribose 5-phosphates[edit]

The synthesis of histidine in E. coli is a complex pathway involving 10 reactions and 10 enzymes. Synthesis begins with 5-phosphoribosyl-pyrophosphate (PRPP) and finishes with histidine and occurs through the reactions of the following enzymes:[9]

HisG-> HisE/HisI-> HisA-> HisH-> HisF-> HisB-> HisC-> HisB-> HisD (HisE/I and HisB are both bifunctional enzymes)

All of the enzymes are coded for on the his operon. This operon has a distinct block of the leader sequence, called block 1:


This leader sequence is very important for the regulation of histidine in "E. coli". The his operon operates under a system of coordinated regulation where all the gene products will be repressed or depressed equally. The main factor in the repression or derepression of histidine synthesis is the concentration of histidine charged tRNAs. The regulation of histidine is actually quite simple considering the complexity of its biosynthesis pathway and, it closely resembles regulation of tryptophan. In this system the full leader sequence has 4 blocks of complementary strands that can form hairpin loops structures.[9] Block one, shown above, is the key to regulation. When histidine charged tRNA levels are low in the cell the ribosome will stall at the string of His residues in block 1. This stalling of the ribosome will allow complementary strands 2 and 3 to form a hairpin loop. The loop formed by strands 2 and 3 forms an anti-terminator and translation of the his genes will continue and histidine will be produced. However, when histidine charged tRNA levels are high the ribosome will not stall at block 1, this will not allow strands 2 and 3 to form a hairpin. Instead strands 3 and 4 will form a hairpin loop further downstream of the ribosome. The hairpin loop formed by strands 3 and 4 is a terminating loop, when the ribosome comes into contact with the loop, it will be “knocked off” the transcript. When the ribosome is removed the his genes will not be translated and histidine will not be produced by the cell.[10]



Serine is the first amino acid in this family to be produced; it is then modified to produce both glycine and cysteine (and many other biologically important molecules). Serine is formed from 3-phosphoglycerate in the following pathway:

3-phosphoglycerate-> phosphohydroxyl-pyruvate-> phosphoserine-> serine

The conversion from 3-phosphoglycerate to phosphohydroxyl-pyruvate is achieved by the enzyme phosphoglycerate dehydrogenase. This enzyme is the key regulatory step in this pathway. Phosphoglycerate dehydrogenase is regulated by the concentration of serine in the cell. At high concentrations this enzyme will be inactive and serine will not be produced. At low concentrations of serine the enzyme will be fully active and serine will be produced by the bacterium.[11] Since serine is the first amino acid produced in this family both glycine and cysteine will be regulated by the available concentration of serine in the cell.[12]


Glycine is synthesized from serine using the enzyme serine hydromethyltransferase (SHMT), which is coded by the gene glyA. The enzyme effectively removes a hydroxyl group from serine and replaces it with a methyl group to yield glycine. This reaction is the only way E. coli can produce glycine. The regulation of glyA is very complex and is known to incorporate serine, glycine, methionine, purines, thymine, and folates however, the full mechanism has yet to be elucidated.[13] The methionine gene product MetR and the methionine intermediate homocysteine are known to positively regulate glyA. Homocysteine is a coactivator of glyA and must act in concert with MetR.[13][14] On the other hand, PurR, a protein which plays a role in purine synthesis and S-adeno-sylmethionine are known to down regulate glyA. PurR binds directly to the control region of glyA and effectively turns the gene off so that glycine will not be produced by the bacterium.


Cysteine is a very important molecule for a bacterium’s survival. This amino acid harbors a sulfur atom and can actively participate in disulfide bond formation. The genes required for the synthesis of cysteine are coded for on the cys regulon. The integration of sulfur into the molecule is positively regulated by CysB. CysB is the main focus of cysteine regulation. Effective inducers of this regulon are N-acetyl-serine (NAS) and very small amounts of reduced sulfur. CysB functions by binding to DNA half sites on the cys regulon. These half sites differ in quantity and arrangement depending on the promoter of interest. There is however one half site that is conserved. It lies just upstream of the -35 site of the promoter. There are also multiple accessory sites depending on the promoter. In the absence of the inducer, NAS, CysB will bind the DNA and cover many of the accessory half sites. Without the accessory half sites the regulon cannot be transcribed and cysteine will not be produced. It is believed that the presence of NAS causes CysB to undergo a conformational change. This conformational change allows CysB to bind properly to all the half sites and causes the recruitment of the RNA polymerase. The RNA polymerase will then transcribe the cys regulon and cysteine will be produced.

Further regulation is required for this pathway, however. CysB can actually down regulate its own transcription by binding to its own DNA sequence and blocking the RNA polymerase. In this case NAS will act to disallow the binding of CysB to its own DNA sequence. OAS is a precursor of NAS, cysteine itself can inhibit CysE which functions to create OAS. Without the necessary OAS, NAS will not be produced and cysteine will not be produced. There are two other negative regulators of cysteine. These are the molecules sulfide and thiosulfate, they act to bind to CysB and they compete with NAS for the binding of CysB.[15]


Pyruvate is the end result of glycolysis and can feed into both the TCA cycle and fermentation processes.[16] Reactions beginning with either one or two molecules of pyruvate cause the synthesis of alanine, valine, and leucine. Feedback inhibition of final products is the main method of inhibition, and, in E. coli, the ilvEDA operon also plays a part in this regulation.


Alanine is produced by the transamination of one molecule of pyruvate using two alternate steps: 1) conversion of glutamate to α-ketoglutarate using a glutamate-alanine transaminase, and 2) conversion of valine to α-ketoisovalerate via Transaminase C.

Not much is known about the regulation of alanine synthesis. The only definite method is the bacterium’s ability to repress Transaminase C activity by either valine or leucine (see ilvEDA operon). Other than that, alanine biosynthesis does not seem to be regulated.[17]


Valine is produced by a four-enzyme pathway. It begins with the reaction of two pyruvate molecules catalyzed by Acetohydroxy acid synthase yielding α-acetolactate. Step two is the NADPH+ + H+ - dependent reduction of α-acetolactate and migration of the methane groups to produce α, β-dihydroxyisovalerate. This is catalyzed by Acetohydroxy isomeroreductase. The third reaction is the dehydration reaction of α, β-dihydroxyisovalerate catalyzed by Dihydroxy acid dehydrase resulting in α-ketoisovalerate. Finally, a transamination catalyzed either by an alanine-valine transaminase or a glutamate-valine transaminase results in valine.

Valine performs feedback inhibition to inhibit the Acetohydroxy acid synthase used to combine the first two pyruvate molecules.[17]


The leucine synthesis pathway diverges from the valine pathway beginning with α-ketoisovalerate. α-Isopropylmalate synthase reacts with this substrate and Acetyl CoA to produce α-isopropylmalate. An isomerase then isomerizes α-isopropylmalate to β-isopropylmalate. The third step is the NAD+-dependent oxidation of β-isopropylmalate via the action of a dehydrogenase to yield α-ketoisocaproate. Finally is the transamination via the action of a glutamate-leucine transaminase to result in leucine.

Leucine, like valine, regulates the first step of its pathway by inhibiting the action of the α-Isopropylmalate synthase.[17] Because leucine is synthesized by a diversion from the valine synthetic pathway, the feedback inhibition of valine on its pathway also can inhibit the synthesis of leucine.

ilvEDA operon[edit]

The genes that encode both the Dihydroxy acid dehydrase used in the creation of α-ketoisovalerate and Transaminase E, as well as other enzymes are encoded on the ilvEDA operon. This operon is bound and inactivated by valine, leucine, and isoleucine. (Isoleucine is not a direct derivative of pyruvate, but is produced by the use of many of the same enzymes used to produce valine and, indirectly, leucine.) When one of these amino acids is limited, the gene furthest from the amino-acid binding site of this operon can be transcribed. When a second of these amino acids is limited, the next-closest gene to the binding site can be transcribed, and so forth.[17]

Amino acids as precursors to other biomolecules[edit]

Amino acids are precursors of a variety of biomolecules. Glutathione (γ-Glu-Cys-Gly) serves as a sulfhydryl buffer and detoxifying agent. Glutathione peroxidase, a selenoenzyme, catalyzes the reduction of hydrogen peroxide and organic peroxides by glutathione. Nitric oxide, a short-lived messenger, is formed from arginine. Porphyrins are synthesized from glycine and succinyl CoA, which condense to give δ-aminolevulinate. Two molecules of this intermediate become linked to form porphobilinogen. Four molecules of porphobilinogen combine to form a linear tetrapyrrole, which cyclizes to uroporphyrinogen III. Oxidation and side-chain modifications lead to the synthesis of protoporphyrin IX, which acquires an iron atom to form heme.[18]


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