• 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

Biosynthesis of Amino Acids

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.

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; 3-

phosphoglycerate, phosphoenolypyruvate, and pyruvate,

Biosynthesis of Amino Acids

phosphoglycerate, phosphoenolypyruvate, and pyruvate,

2) two pentose phosphate pathway intermediates; ribose 5-

phosphate 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 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.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.

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

Overview of Amino Acid Biosynthesis

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 synthesized by the reverse

of oxidative deamination,

catalyzed by glutamate

dehydrogenase ( reductive

amination of α-

ketoglutarate).

- Glutamine biosynthesis:

• Glutamine is formed from glutamate by glutamine synthetase.

• The reaction is driven by the hydrolysis of ATP.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 • 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 spontaneousγ-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 3-

phosphoglycerate: 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 • In the first step, the hydroxyl group of 3-phosphoglycerate

is oxidized by adehydrogenase (using NAD) to yield 3-

phosphohydroxypyruvate.

• Transamination from glutamate yields 3-phosphoserine,

which is hydrolyzed to free serine by phosphoserine

phosphatase.

• Biosynthesis of serine from 3-

phosphoglycerate and

of glycine from serine in all organisms.

• Glycine is also made from

CO2 and NH4 by the action of glycine

synthase, with N5,N10-

methylenetetrahydrofolate

as methyl group donor.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 N-10 to yield N5,N10-methylenetetrahydrofolate. 10 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 from

homocysteine and serine in

mammals.

•The homocysteine is formed from

Biosynthesis of cysteine:

•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 cysteinesulfur required for the synthesis of cysteinefrom 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.