31.2 Amino Acids Are Made from Intermediates of Major Pathways

✓ 4 Identify the sources of carbon atoms for amino acid synthesis.

Thus far, we have considered the conversion of N2 into NH4+ and the assimilation of NH4+ into glutamate and glutamine. We now turn to the biosynthesis of the other amino acids. The pathways for the biosynthesis of amino acids are diverse. However, they have an important common feature: their carbon skeletons come from only a few sources: intermediates of glycolysis, the citric acid cycle, or the pentose phosphate pathway. On the basis of these starting materials, amino acids can be grouped into six biosynthetic families (Figure 31.5).

Figure 31.5: Biosynthetic families of amino acids in bacteria and plants. Major metabolic precursors are shaded blue. Amino acids that give rise to other amino acids are shaded yellow. Essential amino acids are in boldface type.

Human Beings Can Synthesize Some Amino Acids but Must Obtain Others from the Diet

NUTRITION FACTS

Pyridoxine (vitamin B6) A precursor to pyridoxal phosphate (PLP) and pyridoxamine phosphate (PMP), pyridoxine also serves as a cofactor in a host of enzymes including transaminases. Pyridoxine is found in plants, whereas PLP and PMP are plentiful in salmon and the white meat of poultry. A deficiency of vitamin B6, which is rare in the United States, results in fatigue, fissures at the corners of the mouth (cheilosis), inflammation of the tongue (glossitis), and inflammation of the lining of the mouth (stomatitis).

Most microorganisms such as E. coli can synthesize the entire basic set of 20 amino acids, but human beings can make only 11 of them. The amino acids that must be supplied in the diet are called essential amino acids, whereas the others, which can be synthesized if dietary content is insufficient, are termed nonessential amino acids (Table 3.2). A deficiency of even one amino acid compromises the ability of an organism to synthesize all of the proteins required for life.

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 31.6). The sole exception to this pattern is arginine, inasmuch as the synthesis of this nonessential amino acid de novo requires 10 steps. Typically, though, arginine 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 will examine some important features of amino acid synthesis.

Figure 31.6: Essential and nonessential amino acids. Some amino acids are nonessential to human beings because they can be biosynthesized in a small number of steps. Amino acids requiring a large number of steps for their synthesis are essential in the diet because some of the enzymes for these steps have been lost in the course of evolution.

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Some Amino Acids Can Be Made by Simple Transamination Reactions

Three α-ketoacids—α-ketoglutarate, oxaloacetate, and pyruvate—can be converted into amino acids in one step through the addition of an amino group. We have seen that α-ketoglutarate can be converted into glutamate by reductive amination. The amino group from glutamate can be transferred to other α-ketoacids by transamination reactions. Thus, aspartate and alanine can be made from the addition of an amino group to oxaloacetate and pyruvate, respectively:

Transaminations are carried out by pyridoxal phosphate-dependent aminotransferases. Transamination reactions participate in the synthesis of most amino acids. All aminotransferases contain the prosthetic group pyridoxal phosphate (PLP), which is derived from pyridoxine (vitamin B6). In transamination, pyridoxal phosphate accepts an amino group to form a cofactor prominent in many enzymes, pyridoxamine phosphate (PMP).

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Serine, Cysteine, and Glycine Are Formed from 3-Phosphoglycerate

Serine is synthesized from 3-phosphoglycerate, an intermediate in glycolysis. The first step is an oxidation to 3-phosphohydroxypyruvate. This α-ketoacid is transaminated to 3-phosphoserine, which is then hydrolyzed to serine. Serine is the precursor of glycine and cysteine. In the formation of glycine, the side-chain methylene group of serine is transferred to tetrahydrofolate, a carrier of one-carbon units.

NUTRITION FACTS

Folic acid (vitamin B9) Another of the B vitamins, folic acid is especially important for growth, and a lack of folic acid during prenatal development results in spinal-cord defects. Folic acid deficiency can result in megaloblastic anemia, characterized by the release of large immature red blood cells into the blood. Green vegetables, such as spinach and broccoli, are good sources of folic acid.

!clinic! CLINICAL INSIGHT: Tetrahydrofolate Carries Activated One-Carbon Units

Tetrahydrofolate is a coenzyme essential for the synthesis of many amino acids and nucleotides. This coenzyme, a highly versatile carrier of activated one-carbon units, consists of three groups: a substituted pteridine, p-aminobenzoate, and a chain of one or more glutamate residues (Figure 31.7). Mammals can synthesize the pteridine ring, but they are unable to conjugate it to the other two units and so must obtain tetrahydrofolate from their diets or from microorganisms in their intestinal tracts.

Figure 31.7: Tetrahydrofolate. This cofactor includes three components: a pteridine ring, p-aminobenzoate, and one or more glutamate residues.

The one-carbon group carried by tetrahydrofolate is bonded to its N-5 or N-10 nitrogen atom (denoted as N5 or N10) or to both (Figure 31.8). This unit can exist in three oxidation states (Table 31.1). The most reduced form carries a methyl group, whereas the intermediate form carries a methylene group.

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Figure 31.8: Conversions of one-carbon units attached to tetrahydrofolate.
Table 31.1 One-carbon groups carried by tetrahydrofolate

More oxidized forms carry a formyl, formimino, or methenyl group. The fully oxidized one-carbon unit, CO2, is carried by biotin rather than by tetrahydrofolate. The importance of tetrahydrofolate to DNA replication and cell growth is attested to by the fact that drugs that inhibit the regeneration of tetrahydrofolate are effective in the inhibition of cancer-cell growth (Chapter 32).

Tetrahydrofolate, derived from folic acid (vitamin B9), plays an especially important role in the development of the fetal nervous system during early pregnancy. Folic acid deficiency can result in failure of the neural tube to close, which results in conditions such as spina bifida (defective closure of the vertebral column) and anencephaly (lack of a brain). The neural tube closes by about the 28th day of pregnancy, usually before a woman knows that she is pregnant. Consequently, some physicians recommend that all women of childbearing age take folic acid supplements.

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S-Adenosylmethionine Is the Major Donor of Methyl Groups

Tetrahydrofolate can carry a methyl group on its N-5 atom, but its transfer potential is not sufficiently high for most biosynthetic methylations. Rather, the activated methyl donor in such reactions is usually S-adenosylmethionine (SAM), which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine.

The methyl group of the methionine unit is activated by the positive charge on the adjacent sulfur atom, which makes the molecule much more reactive than N5-methyltetrahydrofolate. Recall that S-adenosylmethionine is an activated methyl donor in the synthesis of phosphatidylcholine from phosphatidylethanolamine.

The synthesis of S-adenosylmethionine is unusual in that the triphosphate group of ATP is split into pyrophosphate and orthophosphate; the pyrophosphate is subsequently hydrolyzed to two molecules of Pi. S-Adenosylhomocysteine is formed when the methyl group of S-adenosylmethionine is transferred to an acceptor. S-Adenosylhomocysteine is then hydrolyzed to homocysteine and adenosine:

Figure 31.9: The activated methyl cycle. The methyl group of methionine is activated by the formation of S-adenosylmethionine.

Methionine can be regenerated by the transfer of a methyl group to homocysteine from N5-methyltetrahydrofolate, a reaction catalyzed by methionine synthase (also known as homocysteine methyltransferase). The coenzyme that mediates this transfer of a methyl group is methylcobalamin, derived from vitamin B12.

These reactions constitute the activated methyl cycle (Figure 31.9). Methyl groups enter the cycle in the conversion of homocysteine into methionine and are then made highly reactive by the addition of an adenosyl group. The high transfer potential of the methyl group of S-adenosylmethionine enables it to be transferred to a wide variety of acceptors.

!quickquiz! QUICK QUIZ 2

Identify the six biosynthetic families of amino acids.

!clinic! CLINICAL INSIGHT: High Homocysteine Levels Correlate with Vascular Disease

People with elevated serum levels of homocysteine (homocysteinemia) or the disulfide-linked dimer homocystine (homocystinuria) have an unusually high risk for coronary heart disease and arteriosclerosis. The most common genetic cause of high homocysteine levels is a mutation within the gene encoding cystathionine β-synthase, the enzyme that combines homocysteine and serine to form cystathionine, an intermediate in the synthesis of cysteine:

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High levels of homocysteine appear to damage cells lining blood vessels and to increase the growth of vascular smooth muscle. The amino acid raises oxidative stress as well and has also been implicated in the development of type 2 diabetes. The molecular basis of homocysteine’s action has not been clearly identified, but may result from stimulation of the inflammatory response. Vitamin treatments are sometimes effective in reducing homocysteine levels in some people. These treatments maximize the activity of the two major metabolic pathways processing homocysteine. Pyridoxal phosphate, a vitamin B6 derivative, is necessary for the activity of cystathionine β-synthase, and tetrahydrofolate, as well as vitamin B12, are required for the methylation of homocysteine to methionine.