Serine and threonine are often phosphorylated in proteins that participate in cell-cell

communication. This modification is reversible and serves as a chemical, signal transduction tag.
The two amino acids may also function as nucleophiles in enzymatic catalysis, thanks to the hydroxyl
group in their side chain.

Serine and threonine on the surface of membrane/secreted proteins may also

be glycosylated (attached with sugar groups). This protects the protein and increases its
water solubility. In some cases, the attached sugar groups serve also as a recognition code for other
extra-cellular elements.

Cysteine, despite being polar, tends to appear in core of water-soluble proteins. Under oxidizing
conditions, its thiol side chain deprotonates and tends to form a (covalent) disulfide bond with a thiol
group of a neighboring cysteine. These bonds are important for stabilizing proteins that are secreted
from cells (hormones, antibodies, some enzymes). Cysteine also serves as anucleophile and
an electron-transfer agent in enzymatic catalysis. Both are the result of the non-bonding electrons of
cysteines sulfur atom, conferring it high chemical reactivity and the ability to exist in different
oxidation states.

The carboxamide group of glutamine and asparagine can serve as both hydrogen bond donor and
acceptor. As a result, these amino acids are commonly involved in hydrogen bond networks within
proteins. This group in asparagine is also glycosylated in membrane/secreted proteins (see above for
the benfits of glycosylation).

III. Polar-charged amino acids

These include the following (Fig. 4):

Aspartate (asp, D) and glutamate (glu, E) have a carboxyl group in their side chains. As explained
above, this group has a low pKa and therefore tends to become deprotonated and negatively charged at
physiological pH. For this reason, aspartate and glutamate are referred to as acidic. In proteins, they
tend to interact electrostatically with positively charged groups in other amino acids or in the proteins
ligand/substrate.

Lysine (lys, K) and arginine (arg, R) have nitrogen-containing groups in their side chains
(amino group in lysine and guanidine group in arginine). These groups have high pKa and therefore
tend to become protonated and positively charged at physiological pH. For this reason, lysine and
arginine are referred to as basic. In proteins, they tend to interact electrostatically with negatively
charged groups in other amino acids or in the proteins ligand/substrate.

Histidine (his, H) has an imidazole group in its side chain. This group has a pKa of ~6, and therefore
has a 50% chance of being protonated (positively charged) or deprotonated (neutral) at physiological
pH. This allows histidine to function in hydrogen-transfer enzymatic catalysis, where it may functions
as the hydrogen donor, acceptor, or both.

Here are interesting facts on some polar-uncharged amino acids:

Carboxylation of glutamate on its carbon (see Fig. 6 below) allows it to bind efficiently cations, such
as divalent calcium. This is very useful in clotting proteins, such as prothrombin, the activity of which
is regulated by blood calcium levels.

The amino group of lysines side chain is able to form Schiff base with aldehydes. This helps some
proteins bind aldehyde-containing prosthetic groups (e.g. the pyridoxal phosphate coenzyme of
aminotranferase enzyme).

Oxidation of lysines side chain in structural proteins like collagen allows it to participate in crosslinking reactions that stabilize these proteins.

As explained above, the imidazole side chain of histidine can serve as both acid and base thanks to
its pKa, which is close to the physiological pH. This is important, for example, for the catalytic
mechanism of the enzyme acetylcholine esterase, which inactivates the
neurotransmitter acetylcholine. The inactivation is important for preventing our nervous system from
going into paralysis and death, which is what happens when the enzyme is attacked and inactivated by
toxic nerve agents. Acetylcholine is an ester, and it is hydrolyzed to choline and acetate by the
enzyme, via nucleophilic attack of a catalytic serine residue on the ester bond. To do that, the serine
must deprotonate, and this is made possible by a nearby histidine which acts as a base, abstracting
serines proton:

IV. Aromatic amino acids

These includes the following (Fig. 5):

Phenylalanine (phe, F) has a phenyl group in its side chain.

Tyrosine (tyr, Y) has a phenol group in its side chain.

Tryptophan (trp, W) has an indole group in its side chain

In contrast to the other amino acids groups, this one is considered not according the polarity of the side chain but
rather on its aromatic nature (in the chemical sense, not the olfactory one). Aromatic groups
contain delocalized electrons which can interact with similar electrons in other aromatic groups, as well as
with positively-charged groups. Indeed, all of these interactions are observed in proteins between aromatic side
chains. The aromatic amino acids are important in forming closed scaffolds within proteins, especially binding
sites for ligands and substrates.
Here are interesting facts on some aromatic amino acids:

Like serine and threonine, tyrosine may also become phosphorylated on proteins involved in cellular
communications. A well-known example is the membrane-bound receptors which respond to growth
factors. Binding of the latter to these receptors results in their phosphorylation, which in turn conveys
the signal into the cell and results in cellular division. Genetic defects that allows for hormoneindependent phosphoryaltion of these proteins often lead to cancer.

The phenol group of tyrosine also participates in differnt mechanisms of enzymatic catalysis
(e.g. nucleophilic attack, acid-base catalysis and stabilization of reaction intermediates).

The indole group in tryptophans side chain is capable of participating in different polar and
nonpolar non-covalent interactions with other chemical fspecies. Therefore, it is common in
protein binding sites. It also participates inenzymatic catalysis and electron transfer.

Tryptophans side chain fluoresce when absorbing UV light. This allows biochemists to identify
proteins or study changes in their structure by UV-irradiating them and then recording the
fluorescence of their tryptophan amino acids.

. Selenocysteine and pyrrolysine

Selenocysteine and pyrrolysine are two amino acids derivatives that evolution found a way to genetically
incorporate into certain proteins. For this reason they are often referred to as the 21st & 22nd amino acids.
Protein incorporation is achieved by loading these amino acids on a specialized tRNA molecule, which binds
inside the ribosome to a mRNA stop codon (UGA in the case of selenocysteine and UAG in the case of
pyrrolysine). A stop codon normally signals the translation machinery to stop translation, but in the case of
selenocysteine and pyrrolysine the codon also contains an addition sequence motif which prevents termination.
Selenocysteine is very similar to cysteine, with the sulfur atom replaced by selenium. However, it is created
enzymatically from serine rather than from cysteine. The replacement of sulfur with selenium turns
(seleno)cysteine into a better nucleophile, which is an advantage in enzymatic catalysis. Indeed,
selenocysteine appears in certain oxidation-reduction enzymes. Some selenocysteine-containing enzymes,
like glutathione peroxidase and some forms of thioredoxin reductase, act as antioxidants. That is, they are
part of the bodys built-in system that fights and reverses oxidative damage, caused by free radicals. In
addition, selenocysteine appears in enzymes that form T3, the most potent thyroid hormone. This is why
selenium in the diet is important for the function of the thyroid gland.
Pyrrolysine appears in an enzyme (methyltransferase) of methane-producing Archaea and 0ne Eubacterium.
It is enzymatically created from the natural amino acid lysine.
dd

II. Amino acids that are formed post-translationally

In some cases, a natural amino acid already present in a protein can be enzymatically modified to form a
chemical derivative. For example, collagen, a protein that is widespread in animal connective tissues,
contains hydroxyproline and hydroxylysine. These are produced by attachment of a hydroxyl group to the
natural amino acids proline and lysine, respectively. Another non-natural amino acid, -carboxyglutamate, is
form ed by attachment of a carboxyl group to the amino acid glutamate in blood-clotting proteins.

Figure 6a. Some

examples of non-natural amino acids.
ff

III.D-amino acids
Amino acids with the opposite configuration (D-amino acids), can be found in some proteins and peptides. Most
of the latter are bacterial proteins/peptides. For example, the bacterial cell wall (peptidoglycan) contains Dalanine, while the bacterial antibiotic valinomycin contains D-valine. However, D-amino acids can also be found
in multicellular organisms. For example, a peptide called dermorphin, which is produced by a South American
frog to repel predators, contains D-alanine.

Figure 6b. Two peptides containing D-amino acids.

sd

5. AMINO ACIDS AS A SOURCE OF OTHER COMPOUNDS

Some amino acids, such as tyrosine, tryptophan, histidine and glutamate serve as precursors of biogenic
amines, compounds that are non-proteogenic (do not appear in proteins), yet have different cellular &
physiological roles. Many biogenic amines act as neurotransmitters, hormones, or local mediators. Here are
some examples:

Tyrosine is the source of a group of excitatory neurotransmitters and hormones called

catecholamines, which include epinephrine (adrenaline), norepinephrine (noradrenaline)
and dopamine. They are called that because each of them contains the catechol (aromatic) ring that is
part of the tyrosine side chain. Tyrosine is also the source for the pigment melanin and the thyroid
hormones thyroxine (T4) and thriiodothyronine (T3).

Figure 7. Catecholamines biosynthesis from tyrosine (source)

d

Tryptophan is the source of indolamines (a.k.a. tryptamines). That is, biogenic amines containing
the indole ring of tryptophans side chain. The most well-known indolamine is the
neurotransmitter serotonin, involved in the regulation of mood, appetite, and sleep. Indeed, the
serotonergic mechanism in the brain is the target of the popular antidepressant/anxiolytic drugs called
selective serotonin reuptake inhibitors (SSRIs). These increase serotonin levels in the brain, which
has anti-depression and anti-anxiety effects. Serotonergic neuro-transmission is also targeted by other
types of drugs, such as antipsychotics, antiemetics, and antimigraine drugs, as well as
the psychedelic drugs and empathogens.

Figure 8. Serotonin
biosynthesis from tryptophan (source)
d

Another well-known indolamine is melatonin, which regulates the sleep-wake cycle (circadian rhythm)
in humans.

Histidine is the source of histamine, local mediator of inflammation and the immune response to
certain pathogens. As such, histamine also mediates allergy, and its receptors are targeted by antihistamines (allergy-fighting drugs).

Figure 9. Histamine biosynthesis from histidine (source)

f

Glutamate is the source of gamma-amino-butyric-acid (GABA), a major inhibitory brain

neurotransmitter.

Figure 10a. GABA biosynthesis from glutamate (source)

f
Glutamate, along with glycine and cysteine, also creates the tri-peptideglutathione a compound that fights
oxidative stress caused in our body by free radicals.

Figure 10b. The structure of glutathione

f
When glutathione is depleted by external agents, our body is exposed to oxidative damage. This happens, for
example, in cases of acetaminophen (paracetamol) overdose. This common painkiller is normally metabolized
in the liver to different metabolites. When consumed in large quantities, one of these metabolites depletes liver
cells glutathione, leading to acute liver failure. The treatment in such cases involves restoration of glutathione
levels in the liver, by administering its precursor, N-acetylcysteine. The latter, which is a chemical derivative of
the amino acid cysteine, is also used for treating other cases of glutathione depletion, such as naphthalene
toxicity.

Serine is used to build phosphatidylserine and phosphatidylethanolamine,two phospholipids

building the membranes of our cells. serine is also the precursor of ceramide, a waxy molecule from a
group of other membrane lipids, sphingolipids, are built.

Arginine is the precursor of creatine (an energy reservoir in our muscles, see more below), nitrogen
oxide (a mediator of blood vessel constriction),citrulline (an antioxidant, see more below), and a group
of polyamines that have various physiological and cellular roles.

f
Other amines created from amino acids have other functions. Here are some examples:
Ornithine is involved in (i) ammonia detoxification (urea cycle) (ii) syntheses of proline, glutamate, and
polyamines (iii) mitochondrial integrity and (iv) wound healing. It is built from the amino acid glutamate, and also
as an intermediate in the urea cycle.
Citrulline is an antioxidant. It also functions in (i) arginine synthesis (ii) osmo-regulation (iii) ammonia
detoxification. Finally, it constitute a reservoir of nitrogen. It is built from the amino acid arginine, and also as an
intermediate during the urea cycle.
Theanine is a glutamine analog found in tea leaves. Besides acting as an antioxidant, it is involved in increasing
GABA, dopamine and serotonin levels in the in brain, and thought to have a neuro-protective effect.
Carnitine facilitates the transport of long-chain fatty acids into mitochondria. It is build from the amino acid lysine.

Taurine is a sulfonic acid and a major constituent of bile. It is important for conjugation of bile acid, antioxidation,
osmoregulation, membrane stabilization and calcium signalling. It is built from the amino acid cysteine.
Coenzyme A is important for central metabolism in all life forms. It is crucial to their ability to derive energy for
foodstuff, as well as to build fatty acid, cholesterol and the neurotransmitter acetylcholine. It is made from the
amino acid cysteine and from pantothenic acid (vitamin B5).
Creatine is a molecule in our skeletal muscles that binds a high-energy phosphate groups. During the first
seconds of strenuous muscle action, ATP is consumed and there is no time to recreate it from glucose. The
phosphorylated creatine is then used to replenish ATP from ADP, which is particularly important for fight-or-flight
cases. Creatine is degraded in muscle to creatinine, which is secreted by the kidneys, and therefore considered
a measure for renal function. Creatine is constructed from arginine, glycine and methionine.
S-adenosylmethionine is a molecule built from the amino acid methionine and the adenosyl group of ATP. It is a
common and important enzymatic cofactor, needed for numerous biochemical reactions that involve methylation.

AMINO ACIDS METABOLISM & NUTRITIONAL VALUE

Amino acids are synthesized by all living organisms. They are built from other amino acids or from different
metabolites (e.g. -keto acids):

Pyruvate alanine

Pyruvate valine, leucine, isoleucine (only in bacteria & plants)

Branched keto acids valine, leucine, isoleucine

-ketoglutarate glutamate

Histidine glutamate

Glutamate glutamine, proline, arginine

Oxoaloacetate aspartate

Aspartate asparagine

Aspartate methionine, threonine, lysine (only in bacteria & plants)

Ribose 5-phosphate + glutamine histidine

3-phosphoglycerate serine

hydroxypuruvate serine

Glycine serine (in humans)

Glutathione serine (in humans)

Serine glycine, cysteine

Glyoxylate glycine

Isocitrate glycine

Ascorbic acid glycine

phosphoenolpyruvate + erythrose 4phosphate chorismate tryptophan,phenylalanine, tyrosine (only in bacteria & plants)

Phenylalanine tyrosine

Methionine cysteine

While the carbon skeleton of amino acids may come from different metabolites via different biochemical
reactions, the amino group ultimately comes from atmospheric nitrogen. The latter is assimilated to its
usable forms (ammonia/ammonium) by certain bacteria termed collectively diazotrophs. These include
free cyanobacteria, as well as rhizobia, which are bacteria existing inside the root nodules of legumes.
The fixation of nitrogen is possible thanks to an enzyme called nitrogenase, which these bacteria
possess.

Whereas bacteria and plants can synthesize all 20 types of amino acids, humans can synthesize only
5 of them in sufficient quantities, and at any condition. These are referred to as non-essential amino
acids (Figure 11a). All tissues in our body are capable of synthesizing amino acids, but the major
sources for newly synthesized amino acids are the liver and (to a lesser extent) the intestines.
Nine amino acids cannot be synthesized by our body at all, and must therefore be obtained from the
diet. These amino acids are referred to as essential. The remaining 6 amino acids,
termedconditionally essential, can be synthesized, but need to be supplemented from the diet under
certain conditions or situations (e.g. when the body is growing or ill). Notice that this distinction does not
refer to the importance of the two types of amino acids; all 20 are important to cellular and physiological
function

In some cases, ammonia may build up in the body (hyperammonemia). This happens due to:

Liver damage e.g. in cirrhosis.

Low blood supply to the kidneys e.g. as a result of dehydration or congestive heart failure.

Acute renal insufficiency.

Lower urinary track disease (tumor, stones).

The buildup of ammonia is dangerous; it disrupts the Krebs cycle by aminating -ketoglutarate to glutamate,
thus steeling the important intermediate from the cycle. As a result, energy production in the brain is severely
damaged, causing harsh neurological symptoms which may lead to coma (coma hepatica) or even death.

Urea may also build up in the blood (uremia), as a result of kidney damage. Indeed, a lab test of urea buildup,
called blood nitrogen urea (B.U.N), is used as a diagnostic tool for kidney failure.
g
The carbon skeleton left after removal of ammonia from the amino acid is a keto acid.These carbon
skeletons may be further degraded for energy production via glycolysisand/or the citric acid cycle. As
mentioned above, protein degradation yields less ATP compared to carbohydrates or fat, on a molar basis. The
efficiency of energy transfer from amino acids to ATP ranges from 29% for methionine to 59% for isoleucine
(Amino Acids (2009) 37 :117). Still, for rapidly dividing cells (e.g. enterocytes, lymphocytes, macrophages, and
tumors), glutamine is a preferred fuel.
Alternatively, they may be used as a building block for different metabolites (see Figure 16 below) or biogenic
amines (see section 5 above). All amino acids except leucine and lysine can be degraded to form metabolic
intermediates that can be converted toglucose via gluconeogenesis. These amino acids are therefore called
glucogenic. Amino acids whose degradation forms intermediates that can be converted to ketone
bodies (acetoacetate, -hydroxybutyrate or acetone) are called ketogenic. Lysine and leucine are purely
ketogenic (mnemonic: LL), whereas phenylalanine, isoleucine, threonine, tyrosine and tryptophan are both
glucogenic and ketogenic (mnemonic: PITTT, where P stands for phenyalanine, not proline)

Genetic defects in enzymes participating in amino acid degradation pathways lead to various diseases, such
as Maple Syrup Disease and Phenylketonuria (PKU). In the latter, a defect in the enzyme phenylalanine
hydroxylase prevents the conversion of phenylalanine to tyrosine. The accumulation of the former inhibits the
transfer of other amino acids into the brain, which impairs the synthesis of proteins and myelin. This results in
severe mental and developmental retardation in infants, as well as toshorter life expectancy. Thus, to avoid
these severe outcomes, individuals with PKU must keep a low-protein diet and avoid drinking soda beverages
which containaspartam (has phenylalanine in its structure).
ff