Biosynthesis of the essential amino acids

Koolman, Color Atlas of Biochemistry, 2nd edition 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

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Tribenuronmethyl (Sulfonyl urea) CO.CH, OCH, n C >-SOjNHCON—< N CH- CHj Branched chain amino acid synthesis (ALS and A HAS) inhibitor. Acts by inhibiting biosynthesis of the essential amino acids valine and isoleucine, hence stopping cell division and plant growth... 

Another process of Importance to plant science Is amino acid biosynthesis. Plants and most microbes share the capacity to synthesize the twenty common amino acids from central, key metabolites (see Figure 1). In contrast animals must Ingest ten amino acids "essential to their diet they are unable to produce leucine, valine, Isoleuclne, threonine, methionine, lysine, histidine, tryptophan, tyrosine and phenylalanine. A sufficiently specific chemical Inhibiting the biosynthesis of an essential amino acid thus might control weed growth and display little toxicity towards mammals. Indeed a number of herbicides interfere with the biosynthesis of the essential amino acids (, see Table I). 

Genes for biosynthesis of the essential amino acids threonine and lysine from aspartate have been successfully introduced into mouse cells as a preliminary to their introduction into the pig genome. 

Aspartate 4-semialdehyde, seen, for example, in Scheme 12.13, which provided a pathway for the biosynthesis of the essential amino acid methionine (Met, M) and in Scheme 12.14, which holds a representation of the biosynthesis of threonine (Thr, T), is also a place to begin to describe a pathway to lysine (Lys, K). As shown in Scheme 12.19, aspartate 4-semialdehyde undergoes an aldol-type reaction with pyruvate (CHsCOCO ") in the presence of dihydropicoUnate synthase (EC 4.2.1.52) to produce a series of intermediates that, it is presumed, lead to (5)-23-dihydropyridine-2,6-dicarboxylate. Then, dihydrodipicolinate reductase (EC 1.3.1.26) working with NADPH produces the tetrahydropyridine, (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate.This heterocycle, in the presence of glutamate (Glu, E) and water, is capable of transamination directly to 2-oxoglutarate and (2S, 6S)-2,3-diaminopimelate in the presence of LL-diaminopimelate aminotransferase (EC 2.6.1.83), while the latter, in the presence of the pyridoxal dependent racemase... 

Biological examples of pericyclic reactions are relatively rare, although one much-studied example occurs during biosynthesis in bacteria of the essential amino acid phenylalanine. Phenylalanine arises from the precursor chorismate,... 

Humans can synthesize 12 of the 20 common amino acids from the amphiboHc intermediates of glycolysis and of the citric acid cycle (Table 28-1). While nutritionally nonessenrial, these 12 amino acids are not nonessential. AH 20 amino acids are biologically essential. Of the 12 nutritionally nonessential amino acids, nine are formed from amphibolic intermediates and three (cysteine, tyrosine and hydroxylysine) from nutritionally essential amino acids. Identification of the twelve amino acids that humans can synthesize rested primarily on data derived from feeding diets in which purified amino acids replaced protein. This chapter considers only the biosynthesis of the twelve amino acids that are synthesized in human tissues, not the other eight that are synthesized by plants. 

FIGURE 22-15 Biosynthesis of six essential amino acids from oxalo-acetate and pyruvate in bacteria methionine, threonine, lysine, isoleucine, valine, and leucine. Here, and in other multistep pathways, the enzymes are listed in the key. Note that L,L-a,e-diaminopimelate, the product of step (HI), is symmetric. The carbons derived from pyruvate (and the amino group derived from glutamate) are not traced beyond this point, because subsequent reactions may place them at either end of the lysine molecule. 

The 10 amino acids essential in the human diet (Arg, His, He, Leu, Lys, Met, Phe, Thr, Trp, Val) are synthesized by non-human organisms by multistep pathways starting from simple metabolic precursors. Amino acid biosynthesis is controlled by feedback inhibition and suppression of synthesis of biosynthetic enzymes. The ability of an amino acid analogue to block biosynthesis of the parent amino acid often contributes to the toxicity of the analogue. Mutants resistant to the toxic effects of the analogue can be valuable tools for studying various aspects of cellular mechanism (examples to be given below). 

Carnitine biosynthesis utilizes the essential amino acid lysine, with terminal methyl groups donated by S-adenosylmethionine. Only lysine incorporated into proteins is a substrate for the methylation reaction. In humans, the final reaction in the biosynthetic pathway, catalyzed by a cytosolic hydroxylase, occurs in liver and kidney but not in cardiac or skeletal muscle. The carnitine requirement of these tissues is met by carnitine transported to them via the plasma... 

A laboratory synthesis that is patterned after a biological synthesis. For example, the synthesis of amino acids by reductive amination resembles the biosynthesis of glutamic acid. (p. 1164) Proteins that provide all the essential amino acids in about the right proportions for human nutrition. Examples include those in meat, fish, milk, and eggs. Incomplete proteins are severely deficient in one or more of the essential amino acids. Most plant proteins are incomplete, (p. 1160)... 

The nonessential amino acids are synthesized by quite simple reactions, whereas the pathways for the formation of the essential amino acids are quite complex. For example, the nonessential amino acids alanine and aspartate are synthesized in a single step from pyruvate and oxaloacetate, respectively. In contrast, the pathways for the essential amino acids require from 5 to 16 steps (Figure 24.8). The sole exception to this pattern is arginine, inasmuch as the synthesis of this nonessential amino acid de novo requires 10 steps. Typically, though, it is made in only 3 steps from ornithine as part of the urea cycle. Tyrosine, classified as a nonessential amino acid because it can be synthesized in 1 step from phenylalanine, requires 10 steps to be synthesized from scratch and is essential if phenylalanine is not abundant. We begin with the biosynthesis of nonessential amino acids. 

The amino acid pool (600-700 g) is distributed among the musculature (80%), the liver (15%) and the plasma (5%). The proportion of free amino acids merely amounts to about 0.5% of the total amino acids contained in the body proteins. Of this amount, 300-500 g are used daily for protein synthesis, and approx. 2 g are used for the synthesis of other N-containing compounds (e. g. purines, porphyrins, pyrimidines) a further 120-130 g are degraded per day. This daily amino acid consumption is replaced from three sources, so that the amino acid pool is maintained at a constant level (7.) 70-100 g should be contained in the diet, (2.) 300-500 g derive from protein degradation, and (3.) 30-40 g are replenished from the biosynthesis of non-essential amino acids. The essential amino acids released by proteolysis are utilized as rapidly and completely as possible in the neosynthesis of proteins (= recycling of essential amino acids). 

Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the essential amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT fig. 9). 

We have described reactions from various different pathways in this chapter so far, but now we are going to look at one complete pathway in detail. It is responsible for the biosynthesis of a large number of compounds, particularly in plants. Most Important for us is the biosynthesis of the aromatic amino acids Phe (phenylalanine), Tyr (tyrosine), and Trp (tryptophan). These are essential amino acids for humans—we have to have them in our diet as we cannot make them ourselves. We get them from plants and microorganisms. 

The sulfonylurea herbicides are a new family of chemical compounds, some of which are selectively toxic to weeds but not to crops. The selectivity of the sulfonylureas results from their metabolism to non-toxic compounds by particular crops, but not by weeds. In addition to efficient weed control, the sulfonylurea herbicides provide environmentally desirable properties such as field use rates as low as two grams/hectare and very low toxicity to mammals. The high specificity of the herbicides for their molecular target contributes to both of these properties. In addition, the low toxicity to mammals results from their lack of the target enzyme for the herbicides. Sulfonylureas inhibit the enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS), which catalyzes the first common step in the biosynthesis of the branched chain amino acids leucine, isoleucine and valine. In mammals these are three of the essential amino acids which must be obtained through dietary intake because the biosynthetic pathway for the branched chain amino acids is not present. The prototype structure of a sulfonylurea herbicide is shown in Figure 1. 

Serotonin, or 5-hydroxytryptamine (5-HT), is another monoamine whose important central effects have only been recognized recently. It had previously been known as a vasoconstrictor in the plasma. Once identified chemically, it was found to be widely distributed in the body. After determination of significant brain levels in the hypothalamus, medulla, midbrain, and other areas (Table 12-3), and after establishing its biosynthetic paths, serotonin became recognized as a neurotransmitter. 5-HT is presently less well understood than are the catecholamines. Figure 12-3 outlines its biosynthesis from the essential amino acid tryptophan. Try enters the brain by active transport (as is L-dopa) and is hydroxylated there by tryptophan hydroxylase, which is an enzyme similar to if not identical to, tyrosine hydroxylase. 

Proteins are also classified as complete or incomplete. Protein derived from animal sources is generally complete protein. That is, it provides all of the essential and nonessential amino acids in approximately the correct amounts for biosynthesis. In contrast, protein derived from vegetable sources is generally incomplete protein because it lacks a sufficient amount of one or more essential amino acids. People who want to maintain a strictly vegetarian diet or for whom animal protein is often not available have the problem that no single high-protein vegetable has all of the essential amino acids to ensure a sufficient daily intake. For example, the major protein of beans contains abundant lysine and tryptophan but very little methionine, whereas corn contains considerable methionine but very little tryptophan or lysine. A mixture of com and beans, however, satisfies both requirements. This combination, called succotash, was a staple of the diet of Native Americans for centuries. 

Major enzyme reactions involved in the transfer of Cl moieties and the concomitant transformations of the cognate coenzyme forms are summarized in Table 1. Whereas animals use folate-type coenzymes predominantly for the biosynthesis of nucleotides, plants and many microorganisms require them also for the biosynthesis of several essential amino acids. A detailed description of the metabolic pathways that depend on the cooperation of folate-type coenzymes is beyond the scope of the present chapter. 

Chorismate is an intermediate in the biosynthesis of the aromatic amino acids tryptophan, phenylalanine, and tyrosine. Mammals do not synthesize these amino acids bom chorismate. Instead, they obtain the essential aromatic amino acids tryptophan and phenylalanine from the diet, and they can synthesize tyrosine from phenylalanine. Glyphosate is an effective herbicide because it prevents synthesis of aromatic amino acids in plants. But the compound has no effect on mammals because they have no active pathway for de novo aromatic amino acid synthesis. 

To give as complete an understanding of the chemical pathways of biosynthesis of all the different amino acids as is now possible, discussion of the mechanisms of the synthesis of the essential amino acids by autotrophic organisms is included in this chapter. 

The nutritional consequences of an excess protein diet are the same as those of an excess carbohydrate or excess fat diet lipid biosynthesis and fat deposition. Additionally, the protein amino groups must be detoxified and eliminated. The nutritional consequences of a diet lacking complete protein—that is, one that doesn t supply the essential amino acids in the proportions needed for synthesis of proteins and neurotransmitters—also include excess ammonia generation. In this case, muscle proteins are degraded to supply enough of the limiting essential amino acid. The other amino acids are broken down, with the carbon chains metabolized into carbohydrates (and, potentially lipid). The leftover amino groups must then be eliminated as urea. 

We turn now to the biosynthesis of essential amino acids. These amino acids are synthesized hy plants and microorganisms, and those in the human diet are ultimately derived primarily from plants. The essential amino acids are formed by much more complex routes than are the nonessential amino acids. The pathways for the synthesis of aromatic amino acids in bacteria have been selected for discussion here because they are well understood and exemplify recurring mechanistic motifs. 

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