The synthesis of serine begins with the metabolic intermediate 3-phosphoglycerate glycolysis. Phosphoglycerate dehydrogenase oxidizes it to 3-phosphohydroxypyruvate.

An amino group is donated by glutamate in a reaction catalyzed by phosphoserine transaminase, forming 3-phosphoserine, and finally the phosphate is removed by phosphoserine phosphatase to produce serine.

Serine is the immediate precursor to glycine, which is formed by serine hydroxymethyltransferase. This enzyme requires the coenzyme tetrahydrofolate THF , which is a derivative of vitamin B 9 folic acid.

Serine is also a precursor for cysteine, although the synthesis of cysteine actually begins with the essential amino acid methionine. Methionine is converted to S-adenosylmethionine by methionine adenosyltransferase.

This is then converted to S-adenosylhomocysteine by a member of the SAM-dependent methylase family. The sugar is removed by adenosylhomocysteinase, and the resultant homocysteine is connected by cystathionine synthase to the serine molecule to form cystathionine.

Finally, cystathionine-g-lyase catalyzes the production of cysteine. Tyrosine is another amino acid that depends on an essential amino acid as a precursor. In this case, phenylalanine oxygenase reduces phenylalanine to produce the tyrosine. In general, the synthesis of essential amino acids, usually in microorganisms, is much more complex than for the nonessential amino acids and is best left to a full-fledged biochemistry course.

Book: Cells - Molecules and Mechanisms Wong. Called the retrograde model, it states that after an enzyme consumes all its substrate available, another enzyme capable of producing the aforementioned substrate is required, so the last enzyme evolved to the preceding one by a gene duplication and selection mechanism.

In other words, enzymes evolve from others with similar substrate specificity, and the substrate of the last enzyme is the product of the preceding one.

Also, the active site must bind both the substrate and the product. This model became very popular, but as more genes have been sequenced and more phylogenetic analyses performed, this mechanism has become less seemingly plausible and therefore unpopular.

An alternative model, the patchwork assembly model, proposes that ancestral enzymes were generalists, so they could bind a number of substrates to carry out the same type of reaction. Gene duplication events followed by evolutionary divergence would result in enzymes with high affinity and specificity for a substrate.

In other words, enzymes are recruited from others with the same type of chemical reaction. Whole genome analysis of Escherichia coli supports the patchwork evolution model Teichmann et al. Duplication of whole pathways does not occur very often; nevertheless, examples include tryptophan to synthesize paraminobenzoate and histidine to synthesize nucleotides biosynthesis, as well as lysine, arginine, and leucine biosynthesis see aforementioned example.

Amino acids are one of the first organic molecules to appear on Earth. As the building blocks of proteins, amino acids are linked to almost every life process, but they also have key roles as precursor compounds in many physiological processes. These processes include intermediary metabolism connections between carbohydrates and lipids , signal transduction , and neurotransmission.

Recent years have seen great advances in understanding amino acid evolution, yet many questions on the subject of amino acid synthesis remain. What was the order of appearance of amino acids over evolutionary history?

How many amino acids are used in protein synthesis today? How many were present when life began? Were there initially more than twenty used for building blocks, but intense selective process streamlined them down to twenty?

Conversely, was the initial set much less than twenty, and did new amino acids successively emerge over time to fit into the protein synthesis repertoire? What are the tempo and mode of amino acid pathway evolution? These questions are waiting to be tackled — with old or new hypotheses, conceptual tools, and methodological tools — and are ripe for a new generation of scientists.

Scientists now recognize twenty-two amino acids as the building blocks of proteins: the twenty common ones and two more, selenocysteine and pyrrolysine.

Amino acids have several functions. Their primary function is to act as the monomer unit in protein synthesis. They can also be used as substrates for biosynthetic reactions; the nucleotide bases and a number of hormones and neurotransmitters are derived from amino acids.

Amino acids can be synthesized from glycolytic or Krebs cycle intermediates. The essential amino acids, those that are needed in the diet, require more steps to be synthesized. Some amino acids need to be synthesized when charged onto their corresponding tRNAs.

We have discussed only two biosynthetic routes: the Trp pathway, which appears to have evolved only once, and the Lys pathway, which seems to have evolved independently in different lineages.

Prevailing evidence suggests that metabolic pathways themselves seem to be evolving following the patchwork assembly model, which proposes that pathways originated through the recruitment of generalist enzymes that could react with a wide range of substrates. The study of the evolution of amino acid metabolism has helped us understand the evolution of metabolism in general.

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Eukaryotic Cells. Cell Energy and Cell Functions. Photosynthetic Cells. Cell Metabolism. The Two Empires and Three Domains of Life in the Postgenomic Age.

Why Are Cells Powered by Proton Gradients? The Origin of Mitochondria. Mitochondrial Fusion and Division.

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The Mystery of Vitamin C. The Sliding Filament Theory of Muscle Contraction. An Evolutionary Perspective on Amino Acids By: Ana Gutiérrez-Preciado, B. Departamento de Microbiologia Molecular, Universidad Nacional Autonoma de Mexico , Hector Romero, B.

Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana © Nature Education. Citation: Gutiérrez-Preciado, A. Nature Education 3 9 What are they made of and how have they evolved?

Aa Aa Aa. The Origins of Nutrient Biosynthesis. Figure 1: Major events in the evolution of amino acid synthesis. The way amino acids are synthesized has changed during the history of Earth. Figure Detail. What Is an Amino Acid Made Of?

Amino Acid Precursors and Biosynthesis Pathways. Figure 2. What Makes an Amino Acid Essential? Tryptophan Synthesis: Only Created Once. Lysine Synthesis: Created Multiple Times. Synthesis on the tRNA molecule.

How Do Metabolic Pathways Evolve? Two Different Models. Other mechanisms, such as gene fusion, might occur in the process of pathway evolution. When gene fusions occur between the genes for different proteins of the same pathway, a mechanism that facilitates ligand binding is provided because the substrate of one domain is the product of the other; thus, passive diffusion becomes unnecessary.

Fusions can also result in the tight regulation of fused domains. Histidine biosynthesis is a good example of gene fusion; at least seven genes of this pathway underwent fusion events in different phylogenetic lineages. This assertion means that fusions must be relatively recent because they occurred after the lineages arose Fani et al.

Another important pathway evolution mechanism is horizontal gene transfer , which allows the rapid acquisition of fully functional enzymes and pathways.

Open Questions about Amino Acid Evolution. References and Recommended Reading Baumann, P. Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel.

If tyrosine is low, phenylalanine is used to replace it. For this chapter subsection, we will provide only the basic synthetic pathways in abbreviated form without going into mechanistic or structural details.

Ala can easily be synthesized from the alpha-keto acid pyruvate by a transamination reaction, so we will focus our attention on the others, the branched-chain nonpolar amino acids Val, Leu, and Ile.

Since amino acid metabolism is so complex, it's important to constantly review past learning. As is evident from the figure, glutamic acid can be made directly through the transamination of α-ketoglutarate by an ammonia donor, while glutamine can be made by the action of glutamine synthase on glutamic acid.

Arginine is synthesized in the urea cycle as we have seen before. It can be made from α-ketoglutarate through the following sequential intermediates: N-acetylglutamate, N-acetylglutamate-phosphate, N-acetylglutamate-semialdehyde, N-acetylornithine to N-acetylcitruline. The is deacetylated and enters the urea cycle.

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in Bioinformatics and Computational Biology Solutions Using R and Bioconductor eds. Gentleman, R. Benjamini, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. B 57 , — In the last step, L -histidinal is converted to L -histidine.

In general, the histidine biosynthesis is very similar in plants and microorganisms. The enzymes are coded for on the His operon. This operon has a distinct block of the leader sequence, called block This leader sequence is important for the regulation of histidine in E.

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.

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.

When the ribosome is removed the His genes will not be translated and histidine will not be produced by the cell. 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:. 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. Glycine is biosynthesized from serine, catalyzed by serine hydroxymethyltransferase SHMT.

The enzyme effectively replaces a hydroxymethyl group with a hydrogen atom. SHMT is coded by the gene glyA. The regulation of glyA is complex and is known to incorporate serine, glycine, methionine, purines, thymine, and folates, The full mechanism has yet to be elucidated.

Homocysteine is a coactivator of glyA and must act in concert with MetR. 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. The genes required for the synthesis of cysteine are coded for on the cys regulon.

The integration of sulfur is positively regulated by CysB. 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 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 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. Pyruvate, the result of glycolysis , can feed into both the TCA cycle and fermentation processes.

Reactions beginning with either one or two molecules of pyruvate lead to 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. Valine is produced by a four-enzyme pathway.

It begins with the condensation of two equivalents of pyruvate catalyzed by acetohydroxy acid synthase yielding α-acetolactate. This is catalyzed by acetohydroxy isomeroreductase.

The third step is the dehydration of α, β-dihydroxyisovalerate catalyzed by dihydroxy acid dehydrase. In the fourth and final step, the resulting α-ketoisovalerate undergoes transamination catalyzed either by an alanine-valine transaminase or a glutamate-valine transaminase.

Valine biosynthesis is subject to feedback inhibition in the production of acetohydroxy acid synthase. The leucine synthesis pathway diverges from the valine pathway beginning with α-ketoisovalerate. α-Isopropylmalate synthase catalyzes this condensation with acetyl CoA to produce α-isopropylmalate.

An isomerase converts α-isopropylmalate to β-isopropylmalate. The final step is the transamination of the α-ketoisocaproate by the action of a glutamate-leucine transaminase. Leucine, like valine, regulates the first step of its pathway by inhibiting the action of the α-Isopropylmalate synthase.

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. The commercial production of amino acids usually relies on mutant bacteria that overproduce individual amino acids using glucose as a carbon source.

Some amino acids are produced by enzymatic conversions of synthetic intermediates. Aspartic acid is produced by the addition of ammonia to fumarate using a lyase. See Template:Leucine metabolism in humans — this diagram does not include the pathway for β-leucine synthesis via leucine 2,3-aminomutase.

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Three of the essential amino acids can be made in humans but need significant supplementation. Arginine is depleted in processing through the urea cycle. When cysteine is low, methionine is used to replace it so its levels fall.

If tyrosine is low, phenylalanine is used to replace it. For this chapter subsection, we will provide only the basic synthetic pathways in abbreviated form without going into mechanistic or structural details. Ala can easily be synthesized from the alpha-keto acid pyruvate by a transamination reaction, so we will focus our attention on the others, the branched-chain nonpolar amino acids Val, Leu, and Ile.

Since amino acid metabolism is so complex, it's important to constantly review past learning. As is evident from the figure, glutamic acid can be made directly through the transamination of α-ketoglutarate by an ammonia donor, while glutamine can be made by the action of glutamine synthase on glutamic acid.

Arginine is synthesized in the urea cycle as we have seen before. It can be made from α-ketoglutarate through the following sequential intermediates: N-acetylglutamate, N-acetylglutamate-phosphate, N-acetylglutamate-semialdehyde, N-acetylornithine to N-acetylcitruline.

The is deacetylated and enters the urea cycle. Here we present just the synthesis of lysine from aspartate and pyruvate using the diaminopimelic acid DAP pathway. Fundamentals of Biochemistry Vol.

II - Bioenergetics and Metabolism. jpg" ]. Search site Search Search. Serine is the immediate precursor to glycine, which is formed by serine hydroxymethyltransferase. This enzyme requires the coenzyme tetrahydrofolate THF , which is a derivative of vitamin B 9 folic acid.

Serine is also a precursor for cysteine, although the synthesis of cysteine actually begins with the essential amino acid methionine. Methionine is converted to S-adenosylmethionine by methionine adenosyltransferase. This is then converted to S-adenosylhomocysteine by a member of the SAM-dependent methylase family.

The sugar is removed by adenosylhomocysteinase, and the resultant homocysteine is connected by cystathionine synthase to the serine molecule to form cystathionine.

Finally, cystathionine-g-lyase catalyzes the production of cysteine. Tyrosine is another amino acid that depends on an essential amino acid as a precursor. In this case, phenylalanine oxygenase reduces phenylalanine to produce the tyrosine.

In general, the synthesis of essential amino acids, usually in microorganisms, is much more complex than for the nonessential amino acids and is best left to a full-fledged biochemistry course. Book: Cells - Molecules and Mechanisms Wong. Search site Search Search. Go back to previous article.

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