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CHAPTER 27: BIOSYNTHESIS OF THE Lengthy Metabolic Pathways Form the Nutritionally Essential Amino
NUTRITIONALLY NONESSENTIAL Acids
AMINO ACIDS The existence of nutritional requirements suggests that dependence on
an external supply of a given nutrient can be of greater survival value
BIOMEDICAL IMPORTANCE than the ability to biosynthesize it. Why?
AMINO ACID DEFICIENCY If a specific nutrient is present in the food, an organism that
states can result if nutritionally essential amino acids are can synthesize it will transfer to its progeny genetic
absent from the diet, or are present in inadequate amount information of negative survival value.
KWASHIORKOR The survival value is negative rather than nil because:
results when a child is weaned onto a starchy diet poor in ATP and
protein
MARASMUS
both caloric intake and specific amino acids are deficient
SHORT BOWEL SYNDROME
unable to absorb sufficient quantities of calories and
nutrients suffer from significant nutritional and metabolic
abnormalities
SCURVY
a dietary deficiency of vitamin C, and specific genetic
disorders are associated with an impaired ability of
connective tissue to form hydroxyproline and hydroxylysine
The resulting conformational instability of collagen results in
bleeding gums, swelling joints, poor wound healing, and
ultimately in death.
MENKES SYNDROME
nutrients are required to synthesize unnecessary DNA
characterized by kinky hair and growth retardation
even if specific encoded genes are no longer expressed
results from a dietary deficiency of copper
The number of enzymes required by prokaryotic cells to
an essential cofactor for the enzyme lysyl oxidase that
synthesize the nutritionally essential amino acids is large
functions in formation of the covalent cross-links that
relative to the number of enzymes required to synthesize the
strengthen collagen fibers
nutritionally nonessential amino acids (Table 272).
GENETIC DISORDERS OF COLLAGEN BIOSYNTHESIS
This suggests a survival advantage in retaining the ability
include several forms of osteogenesis imperfecta
to manufacture easy amino acids while losing the ability
characterized by fragile bones
to make difficult amino acids.
EHLERS-DANLOS SYNDROME
The metabolic pathways that form the nutritionally essential
a group of connective tissue disorders that result in mobile
amino acids occur in plants and bacteria, but not in humans.
joints and skin abnormalities due to defects in the genes that
encode enzymes including lysyl hydroxylase.
BIOSYNTHESIS OF THE NUTRITIONALLY NONESSENTIAL
AMINO ACIDS
NUTRITIONALLY ESSENTIAL &
NUTRITIONALLY NONESSENTIAL AMINO ACIDS
GLUTAMATE
20 Amino Acid Requirements of Humans
common amino acids
Nutritionally Essential Nutritionally the precursor of the so-called glutamate family of amino
are Nonessential essential to ensure
Arginine a
Alanine acids
Histidine Asparagine health.
formed by the reductive amidation of the citric acid cycle -
8 must be present in
Isoleucine Aspartate
Leucine Cysteine
ketoglutarate a reaction catalyzed by:
Lysine Glutamate the human diet, and
Methionine Glutamine mitochondrial glutamate dehydrogenase
thus are best
The reaction strongly favors glutamate synthesis, which
Phenylalanine Glycine

Threonine Hydroxyproline
termed
b

Tryptophan Hydroxylysine
b
lowers the concentration of cytotoxic ammonium ion.
Valine Proline nutritionally
Serine GLUTAMINE
essential.
Tyrosine
The amidation of glutamate to glutamine catalyzed by:
12 amino acids are
glutamine synthetase, involves the intermediate
nutritionally nonessential since they need not be
formation of -glutamyl phosphate
present in the diet.
Following the ordered binding of glutamate and ATP:
The distinction between these two classes of amino acids was
glutamate attacks the -phosphorus of ATP, forming -
established in the 1930s by:
glutamyl phosphate and ADP. NH4+ then binds, and
feeding human subjects purified amino acids in place of
uncharged NH3 attacks -glutamyl phosphate.
protein
Release of Pi and of a proton from the -amino group of
Amino acid deficiency disorders are endemic in certain regions
the tetrahedral intermediate then allows release of the
of West Africa where diets rely heavily on grains that are
product, glutamine.
poor sources of tryptophan and lysine.
ALANINE & ASPARTATE
Nutritional disorders include:
ALANINE: transamination of pyruvate
Kwashiorkor
The amino group may be glutamate or aspartate
Marasmus
The other product thus is, -ketoglutarate or
ARGININE: Nutritionally semiessential. Synthesized at
oxaloacetate
rates inadequate to support growth of children
ASPARTATE: transamination of oxaloacetate
HYDROXYPROLINE&HYDROXYLYSINE: Not necessary for
protein synthesis, but is formed during post-translational
processing of collagen.

BIOCHEMISTRY|CHAPTER 27: BIOSYNTHESIS OF NUTRITIONALLY NONESSENTIAL AMINO ACIDS

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GLUTAMATE DEHYDROGENASE, GLUTAMINE SYNTHETASE &
AMINOTRANSFERASES PLAY CENTRAL ROLES IN AMINO ACID
BIOSYNTHESIS
The combined action of the enzymes glutamate
dehydrogenase, glutamine synthetase, and the
aminotransferase converts:
inorganic ammonium ion into the -amino nitrogen of
amino acids
ASPARAGINE
The conversion of aspartate to asparagine, catalyzed by:
Asparagine synthetase, resembles the glutamine
synthetase reaction, but glutamine, rather than
ammonium ion, provides the nitrogen.
Bacterial asparagine synthetases can, however, also use
ammonium ion.
The reaction involves the intermediate formation of aspartyl
phosphate
The coupled hydrolysis of PPi to Pi by pyrophosphatase, EC
3.6.1.1, ensures that the reaction is strongly favored.
SERINE
Oxidation of the -hydroxyl group of the glycolytic
intermediate 3-phosphoglycerate, catalyzed by:
3-phosphoglycerate dehydrogenase, converts it to 3-
phosphohydroxypyruvate
Transamination and subsequent dephosphorylation then form
serine.
GLYCINE
Glycine aminotransferases can catalyze the synthesis of
glycine from glyoxylate and glutamate or alanine.
Unlike most aminotransferase reactions, these strongly favor
glycine synthesis.
Additional important mammalian routes for glycine formation
are from choline and from serine.
PROLINE
The initial reaction of proline biosynthesis converts the -
carboxyl group of glutamate to the mixed acid anhydride of
glutamate -phosphat.
Subsequent reduction forms glutamate -semialdehyde, which
following spontaneous cyclization is reduced to l-proline.
CYSTEINE
not nutritionally essential
cysteine is formed from methionine which is nutritionally
essential
Following conversion of methionine to homocysteine:
homocysteine and serine form: cystathionine
hydrolysis of cystathionine: forms cysteine and
homoserine
TYROSINE
Phenylalanine hydroxylase converts phenylalanine to tyrosine.
If the diet contains adequate quantities of the nutritionally
essential amino acid phenylalanine, tyrosine is nutritionally
nonessential.
However, since the phenylalanine hydroxylase reaction is
irreversible:
dietary tyrosine cannot replace phenylalanine
Catalysis by this mixed-function oxidase incorporates one
atom of O2 into the para position of phenylalanine and reduces
the other atom to water.
Reducing power, provided as tetrahydrobiopterin derives
ultimately from NADPH.
HYDROXYPROLINE & HYDROXYLYSINE
Hydroxyproline and hydroxylysine occur principally in collagen.
Since there is no tRNA for either hydroxylated amino acid:
neither dietary hydroxyproline nor dietary hydroxylysine
is incorporated during protein synthesis.
BIOCHEMISTRY|CHAPTER 27: BIOSYNTHESIS OF NUTRITIONALLY NONESSENTIAL AMINO ACIDS
Peptidyl hydroxyproline and hydroxylysine arise from proline
and lysine, but only after these amino acids have been
incorporated into peptides.
Hydroxylation of peptidyl prolyl and peptidyl lysyl residues,
catalyzed by prolyl hydroxylase and lysyl hydroxylase of skin,
skeletal muscle, and granulating wounds requires, in addition
to the substrate, molecular O2, ascorbate, Fe2+, and -
ketoglutarate.
For every mole of proline or lysine hydroxylated, one mole of
-ketoglutarate is decarboxylated to succinate.
The hydroxylases are mixedfunction oxidases.
One atom of O2 is incorporated into proline or lysine, the
other into succinate.
A deficiency of the vitamin C required for these two
hydroxylases results in scurvy, in which bleeding gums,
swelling joints, and impaired wound healing result from the
impaired stability of collagen
VALINE, LEUCINE, & ISOLEUCINE
While leucine, valine, and isoleucine are all nutritionally
essential amino acids, tissue aminotransferases reversibly
interconvert all three amino acids and their corresponding -
keto acids.
These -keto acids thus can replace their amino acids in the
diet.
SELENOCYSTEINE, THE 21ST AMINO ACID
While the occurrence of selenocysteine in proteins is
uncommon, at least 25 human selenoproteins are known.
Selenocysteine is present at the active site of several human
enzymes that catalyze redox reactions.
Examples include:
thioredoxin reductase,
glutathione peroxidase
deiodinase: converts thyroxine to triiodothyronine
Where present, selenocysteine participates in the catalytic
mechanism of these enzymes.
Significantly, the replacement of selenocysteine by cysteine
can actually impair catalytic activity.
Impairments in human selenoproteins have been implicated in:
Tumorigenesis
Atherosclerosis
Keshan disease: selenium deficiency cardiomyopathy
Biosynthesis of selenocysteine requires:
Cysteine
selenite (SeO4 2)
ATP
a specific tRNA
several enzymes
Serine provides the carbon skeleton of selenocysteine.
SELENOPHOSPHATE:
formed from ATP and selenate, serves as the selenium
donor.
Unlike hydroxyproline or hydroxylysine, selenocysteine arises
cotranslationally during its incorporation into peptides.
The UGA anticodon of the unusual tRNA called tRNASec
normally signals STOP.
The ability of the protein synthetic apparatus to identify a
selenocysteinespecific UGA codon involves the selenocysteine
insertion element, a stem-loop structure in the untranslated
region of the mRNA.
tRNASec is first charged with serine by the ligase that
charges tRNASer.
Subsequent replacement of the serine oxygen by selenium
involves selenophosphate formed by selenophosphate
synthetase.
Successive enzyme-catalyzed reactions convert cysteyl-
tRNASec to aminoacrylyl-tRNASec and then to selenocysteyl-
tRNASec.
In the presence of a specific elongation factor that
recognizes
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selenocysteyl-tRNASec, selenocysteine can then be
incorporated into proteins.

BIOCHEMISTRY|CHAPTER 27: BIOSYNTHESIS OF NUTRITIONALLY NONESSENTIAL AMINO ACIDS