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Biosynthesis of Amino Acids • Plants and bacteria synthesize all twenty amino acids, whereas, most other organisms obtain at least some of the required amino acids from their diet. Humans can only synthesize about half of the twenty amino acids. • In general, the more complex amino acids are essential amino acids in humans as they require enzymes that have been lost from the human genome over evolutionary time. • Most animals are much more restricted in their ability to synthesize amino acids de novo because they lack many of the required enzymes. Biosynthesis of Amino Acids The carbon skeletons of all twenty amino acids are derived from just seven metabolic intermediates, that together, are found in three metabolic pathways. These include: 1) three glycolytic pathway intermediates; 3phosphoglycerate, phosphoenolypyruvate, and pyruvate, 2) two pentose phosphate pathway intermediates; ribose 5phosphate and erythrose 4-phosphate 3) two citrate cycle intermediates; α-ketoglutarate and oxaloacetate. Overview of Amino Acid Biosynthesis The carbon skeleton precursors derive from three sources: glycolysis (pink), the citric acid cycle (blue), and the pentose phosphate pathway (purple). Biosynthesis of amino acids (AA) Humans can synthesize only 10 of the 20 AA. Essential AA : AA that cannot be synthesized „de novo“. They must be obtained from diet. Nonessential AA: Can be synthesized in the human. • The 20 a.a. do not include hydroxy proline and hydroxy lysine. • Arginine is essential in young children not in adults. • Thus mammals can synthesize only 13 a.a ( 10 non-essential +arginine + hydroxy proline + hydroxy lysine ) • Liver is the main site for biosynthesis of non-essential a.a. Overview of Amino Acid Biosynthesis Arginine is listed as an essential amino acid because humans require arginine in their diet to support rapid growth during childhood and pregnancy. However, arginine is actually generated from argininosuccinate in the urea cycle, which means that a small amount of this "essential" amino acid is made available for protein synthesis through this route. Tyrosine is also a conditional nonessential amino acid is made in humans from the essential amino acid phenylalanine by the enzyme phenylalanine hydroxylase. Therefore, as long as we have enough phenylalanine in our diets we can generate tyrosine, although in fact, much of the tyrosine in our bodies actually comes directly from dietary tyrosine. Amino Acid Biosynthetic Families, Grouped by Metabolic Precursors • Amino acids are grouped into six families according to their metabolic precursors. α-Ketoglutarate as a Precursor • 4 amino acids are synthesized from α-Ketoglutarate . • 3 non-essential: glutamate, glutamine and proline. • One essential: Arginine. - Glutamate biosynthesis: • Glutamate is synthesized by transfer of an amino group to α-ketoglutarate. • Glutamate can also be synthesized by the reverse of oxidative deamination, catalyzed by glutamate dehydrogenase ( reductive amination of αketoglutarate). - Glutamine biosynthesis: • Glutamine is formed from glutamate by glutamine synthetase. • The reaction is driven by the hydrolysis of ATP. • Glutmine synthetase is a mitochondrial enzyme found in many tissues mainly brain and kidney. Proline biosynthesis: • Proline is synthesized through 2 pathways, both occur in mammals. • Proline Glutamate is converted to proline by cyclization and reduction reactions. • In the first step of proline synthesis, ATP reacts with the -carboxyl group of glutamate to form an acyl phosphate, which is reduced by NADPH or NADH to glutamate γ-semialdehyde. • This intermediate undergoes rapid spontaneous cyclization and is then reduced further to yield proline. Proline biosynthesis from glutamate • The second pathway for proline biosynthesis from arginine by reversible pathway of proline catabolism. (proline oxidase reaction is reversible) Arginine biosynthesis: • In mammals arginine is synthesized from glutamate via urea cycle. • In bacteria, arginine is synthesized from glutamate in pathway different from urea cycle in mammals because most bacteria do not have arginase; not form ornithine from arginine . • Ornithine could also be synthesized from glutamate γ-semialdehyde by transamination, but the spontaneous cyclization of the semialdehyde in the proline pathway precludes a sufficient supply of this intermediate for ornithine synthesis. • Bacteria have a de novo biosynthetic pathway for ornithine (and thus arginine) that parallels some steps of the proline pathway but includes two additional steps that avoid the problem of the spontaneous cyclization of glutamate γ –semialdehyde. 3-Phosphoglycerate as a Precursor • 3-Phosphoglycerate is an intermediate of glycolysis. • 3 non-essential a.a. are synthesized from 3phosphoglycerate: serine, glycine and cystein. Serine biosynthesis: • The major pathway for the formation of serine is the same in all organisms. • 3-phosphoglycerate is first oxidized to 3 phosphopyruvate, and then transaminated to 3-phosphoserine. • In the first step, the hydroxyl group of 3-phosphoglycerate is oxidized by adehydrogenase (using NAD) to yield 3phosphohydroxypyruvate. • Transamination from glutamate yields 3-phosphoserine, which is hydrolyzed to free serine by phosphoserine phosphatase. • Biosynthesis of serine from 3phosphoglycerate and of glycine from serine in all organisms. • Glycine is also made from CO2 and NH4 by the action of glycine synthase, with N5,N10methylenetetrahydrofolate as methyl group donor. Glycine biosynthesis: • Serine (three carbons) is the precursor of glycine (two carbons) through removal of a carbon atom by serine hydroxymethyltransferase . • Tetrahydrofolate accepts the carbon (C-3) of serine, which forms a methylene bridge between N-5 and N10 to yield N5,N10-methylenetetrahydrofolate. • The overall reaction, which is reversible, also requires pyridoxal phosphate. • In the liver of vertebrates, glycine can be made by another route catalyzed by glycine synthase (also called glycinecleavage enzyme): Biosynthesis of cysteine: • Biosynthesis of cysteine from homocysteine and serine in mammals. •The homocysteine is formed from methionine, as described befor. • Homocysteine gives the sulfur atom and serine gives the carbon skeleton. Biosynthesis of cysteine: • In plants and bacteria cysteine is synthesized from serine by different pathway. • Plants and bacteria produce the reduced sulfur required for the synthesis of cysteine from environmental sulfates. • The sulfide is then used in formation of cysteine from serine in a two-step pathway • Two molecules of ATP are used for each molecule of cysteine synthesized.