Amino acids synthesis
From Molecularwiki
In organisms, Amino acids are synthesised from intermediates of the glycolysis, the pentose phosphate pathway and the citric acid cycle. While most (known) bacteria and plants can synthesise all 20 standard amino acids, mammals can only synthesise about half. The amino acids that cannot be synthesised are called essential amino acids, because they are essential in the organism's diet.
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The Synthetic Pathways
The 20 standard amino acids can be split into 6 groups, depending on their common metabolic presursor. These groups are not definitive. The synthetic pathways are complex and intertwined. It is important to note that Lysine derives from both oxaloacetate as pyruvate. Isoleucine is derived from pyruvate and Threonine. The pathways and categories have been simplified for clarity.
Pentose Phosphate Pathway;
- Ribose 5-Phosphate (R-5P);
Glycolysis;
- 3-Phosphoglycerate (3-Pg);
- Pyruvate (Pyr);
Pentose Phosphate Pathway and Glycolysis;
- Erythrose 4-Phosphate (E4-P) and Phosphoenolpyruvate (Pep);
Citric Acid Cycle;
- α-Ketoglutarate (α-Kg);
- Oxaloacetate (Oaa);
Optimality of the genetic code with respect to the biosynthesis of amino acids
The genetic code has essentially evolved to counter the effects of mutations, transcription and translation errors. An error in any stage will not lead to the amino acid in question being replaced by another random amino acid, but instead it will be replaced by one that is of similar nature. This feature is not exclusive to the protein structure and function, but it also affects the biosynthesis of the amino acids. The table below will illustrate how the amino acids are grouped not only by simple structural similarities, but also by occurrence, cost, frequency, etc. By making sure that a mutation is more likely to cause an amino acid being replaced by one in the same metabolic group, the code prevents the possibility of a mutation exhausting a pathway or simply wasting unnecessary amounts of energy.
| Metabolic Precursor | Amino AcidAminozuur/nl | Number of EnzymesAantal Enzymen/nl | ATP Cost | NADH Cost | NADPH Cost | N Cost | C Cost | Hydrophobicity | Structural Preference | Occurrence | Number of Codons |
|---|---|---|---|---|---|---|---|---|---|---|---|
| R5-P | Histidine | 1 | 6 | -3 | 1 | 3 | 6 | philic | - | 2.3% | 2 |
| E4-P & Pep | Phenylalanine | 9 | 1 | 0 | 2 | 1 | 9 | phobic | β-strand, α-helix | 3.9% | 2 |
| E4-P & Pep | Tryptophan | 12 | 5 | -2 | 3 | 2 | 11 | phobic | β-strand | 1.4% | 1 |
| E4-P & Pep | Tyrosine | 9 | 1 | -1 | 2 | 1 | 9 | - | β-strand | 3.2% | 2 |
| 3-Pg | Serine | 3 | -1 | 0 | 1 | 1 | 3 | - | β-turn | 6.8% | 6 |
| 3-Pg | Glycine | 4 | 0 | -1 | 1 | 1 | 2 | - | β-turn | 7.2% | 4 |
| 3-Pg | Cysteine | 9 | 4 | -1 | 5 | 1 | 3 | phobic | β-turn, β-strand | 1.9% | 2 |
| Pyr | Alanine | 1 | 0 | 0 | 1 | 1 | 3 | phobic | α-helix | 7.8% | 4 |
| Pyr | Leucine | 7 | 0 | -1 | 2 | 1 | 6 | phobic | α-helix, β-strand | 9.1% | 6 |
| Pyr | Valine | 4 | 0 | 0 | 2 | 1 | 5 | phobic | β-strand, α-helix | 6.6% | 4 |
| Pyr | Isoleucine | 11 | 2 | 0 | 5 | 1 | 6 | phobic | β-strand, α-helix | 5.3% | 3 |
| Oaa | Lysine | 10 | 2 | 0 | 4 | 2 | 6 | philic | α-helix, β-turn | 5.9% | 2 |
| Oaa | Aspartate | 1 | 0 | 0 | 1 | 1 | 4 | philic | α-helix | 5.3% | 2 |
| Oaa | Asparagine | 1 | 3 | 0 | 1 | 2 | 4 | philic | β-turn | 4.3% | 2 |
| Oaa | Methionine | 9 | 7 | 0 | 8 | 1 | 5 | phobic | α-helix | 2.3% | 1 |
| Oaa | Threonine | 6 | 2 | 0 | 3 | 1 | 4 | - | β-strand, α-helix | 5.9% | 4 |
| α-Kg | Glutamate | 1 | 0 | 0 | 1 | 1 | 5 | philic | α-helix | 6.3% | 2 |
| α-Kg | Arginine | 10 | 7 | -1 | 4 | 4 | 6 | philic | - | 5.1% | 6 |
| α-Kg | Glutamine | 2 | 1 | 0 | 1 | 2 | 5 | philic | - | 4.2% | 2 |
| α-Kg | Proline | 4 | 1 | 0 | 3 | 1 | 5 | phobic | β-turn | 5.2% | 4 |
The costs listed in the table are from the biosynthesis of amino acids in Escherichia Coli 1,2. The costs not only list the amount of molecules used by turning one of the 6 common precursors into an amino acid, but also the cost of any additional steps, such as the preparation of sulfide in the synthesis of Serine.
Notable similarities and differences in metabolic groups
- Ribose 5-Phosphate;
This metabolite only leads to histidine, it is therefore not possible to discuss notable similarities and differences.
- 3-Phosphoglycerate;
The amino acids in this group are similar in their carbon usage (between 2 and 3), Nitrogen usage (1), their hydrophobicity (generally intermediate) and their structural preference (β-turn). Cysteine is notably different in occurrence and synthetic energy costs. This can be explained by Cysteine's unique property of forming disulfide bonds, an important feature in the stability of protein structure.
- Pyruvate;
The amino acids that are derived from Pyruvate are generally very similar in most properties. Their synthetic energy costs are differ one molecule at most, they all only use 1 Nitrogen atom, they are all hydrophobic and they prefer the same secondary structure. The occurrence of these amino acids is also similarly high, ranging from 5.3% to 9.1% and the number of codons is also above average for all 4 molecules. The only notable difference is the amount of enzymes involved in their synthesis.
- Erythrose 4-Phosphate and Phosphoenolpyruvate;
This is again a group with many similarities. All three amino acids here are large, expensive (many enzymes required), hydrophobic, β-strand loving molecules. Their occurrences are also generally low, ranging from 1.4% to 3.9% and only using 1 or 2 codons. Between these three, trypophan is clearly more expensive and less frequent.
- α-Ketoglutarate;
The amino acids in this group are similar in their carbon usage (5 and 6) and occurance (between 4.2% and 6.3%), but quite different in other areas. Proline stands out, because it is a hydrophobic molecule with a clear preference for the β-turn. Arginine also stands out quite clearly, because of it's high costs.
- Oxaloacetate;
This group is also similar in some aspects, but different in others. All five amino acids here use between 4 and 6 carbon atoms, prefer the α-helix secondary structure and, with the exception of methionine, all have a similar occurrence (ranging from 4.3% to 5.9%) and number of codons (between 2 and 4). The synthetic costs are quite different, with aspartate and asparagine being relatively cheap and lysine, methionine and threonine being relatively expensive.
A quantitative analysis
| Amino Acid/nl | Total average | Group averageGemiddelde groep/nl |
|---|---|---|
| Alanine | -0.26 | -1.33 |
| Cysteine | -3.21 | -3.00 |
| Aspartate | -0.32 | +1.00 |
| Glutamate | -0.68 | +1.00 |
| Phenylalanine | -1.16 | +0.50 |
| Glycine | -1.95 | -2.00 |
| Histidine | +0.21 | N/A |
| Isoleucine | -2.05 | -0.33 |
| Lysine | -0.05 | +0.20 |
| Leucine | -1.63 | -0.33 |
| Methionine | -0.53 | -0.75 |
| Asparagine | +0.00 | +1.00 |
| Proline | -2.84 | -2.00 |
| Glutamine | +0.26 | +1.00 |
| Arginine | -0.05 | +0.67 |
| Serine | +0.53 | -1.00 |
| Threonine | +0.21 | +0.75 |
| Valine | -1.68 | +0.00 |
| Tryptophan | -0.32 | +0.50 |
| Tyrosine | -0.37 | +1.00 |
To add further weight to these arguments it is possible to analyse the similarities between metabolic groups quantitatively using a substitution matrix. Such a substitution matrix assigns values to the substitution of one amino acid in a protein by another. Common matrices are PAM and BLOSUM, but since they rely on comparing actually existing proteins these cannot be used to discuss the optimality of the genetic code, as they are influenced by it. Instead it is better to use a matrix that is independent of the code, such as the Mutation Matrix by Gilis et al 3. used in this example. This matrix was derived by mutating all amino acids on all positions of 141 not related proteins and comparing folding free energies. As a result, it incorporates hydrophobicity, preferred secondary structure, etc., but is entirely unaffected by the constraints of the biosynthesis.
In the table to the right all amino acids are listed with the average mutation value (compared to all other 19 amino acids) and the average group mutation value (compared to the other amino acids with the same metabolic precursor). The lower the value, the more impact the mutation has on the folding free energy of the protein. From this it can be concluded that the lower the value the less the two amino acids have in common.
It should be expected that amino acids in the same metabolic group should be similar and thus have a higher average substitution rating than the average over all amino acids. In general, the table to the right is in agreement with this expectation, however there are a couple of exceptions. Alanine, glycine, methionine and especially serine have lower group averages than total averages.
Alanine is grouped with isoleucine, leucine and valine under pyruvate. It is in many ways the odd one out. It is much smaller than the others and doesn't fit well in a β-strand. The reason Alanine is in this group is most likely the fact that the biosynthesis from pyruvate is easiest. Afterall, alanine and pyruvate are only one transamination apart.
Glycine is grouped with cysteine and serine under 3-phosphoglycerate. Much like alanine it is a very small amino acid (the smallest in fact) and because of that it can fulfill special structural roles in proteins, such as form the start of a β-turn. It does not like being replaced by any other amino acid in such a position, so it scores very low on all accounts. In its group the score is only slightly lower. The most likely reason for it being in this group is the same as with alanine, the synthesis from serine to glycine takes only one step.
Methionine is grouped with asparagine, aspartate, lysine and threonine under oxaloacetate. Although the average substitution value for its group is only slightly lower, there is no immediate and obvious reason why. The amino acids in the oxaloacetate group are very diverse and Methionine doesn't stand out in any particular way, other than being uncommon.
Serine is grouped with cysteine and glycine under 3-phosphoglycerate. As with alanine and glycine the reason for it scoring poorly in its group is because it is forced in there for chemical-structural reasons. Both cysteine and glycine are synthesised from serine, so it being in another group really isn't an option.
Conclusion
It can be noted that the general trend between amino acids in biosynthetic groups is that they are as similar as possible. The universal code has evolved in such a way that a mutation, transcription or translation error will result in no change at all, or at the least a different amino acid, but with similar properties. One of these properties is the synthetic cost. Comparing leucine and tryptophan one will notice that both molecules are hydrophobic amino acids that prefer to be in the β-strand. A mutation of leucine into tryptophan will, most likely, not result in any major changes in the structure and function of the proteine, yet of leucine's six codons, only a specific mutation on the second position of one of these six codons results in a tryptophan. This second position is least likely to change in a translation error. The major difference between these two amino acids is, of course, their synthetic costs. Where as leucine uses 7 enzymes, no ATP and only 2 NADPH tryptophan uses 12 enzyms, 5 ATP and 3 NADPH. Such a mutation in a frequently occurring proteine then, would cause the organism to waste a large amount of energy.
Notes & References
3 Gilis D, Massar S, Cerf NJ, Rooman M (2001) Optimality of the genetic code with respect to protein stability and amino-acid frequencies. Genome Biology 2 (11): 1-12.
DL Nelson, MM Cox; Lehninger Principles of Biochemistry; 4th ed, 2005; W.H. Freeman and Company, New York
