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Chemical Classification of Amino Acids

Chemical classification of amino acids can be considered as major basis of classification. The different chemical properties of amino acids are actually based on the properties of their R groups, which are the basis for categorizing amino acids as nonpolar, polar, aromatic, positively charged, or negatively charged as given in Figure below. We will go through each type one by one


We will go through each type one by one

Table of Contents

Non-Polar Amino Acids (ALIPHATIC)

Non polar amino acids are neutral (no charge). The number of amino and carboxyl group are equal in them. As discussed earlier ‘R’ group give them their properties, thus these amino acids have side chain or ‘R’ group with hydrophobic (no interaction with water) nature  and bears no charge. The amino acids in this group are glycine, alanine, valine, leucine, isoleucine, methionine and proline. The two others phenylalanine, tryptophan which will be discussed in aromatic category can also be included in this group.

Non-polar-amino acids

Glycine (Gly; G)

  • Glycine is the smallest as well as simplest amino acid
  • It lacks a side chain (contains only hydrogen).
  • Glycine is not optically active (or optically inactive); thus α-C is a symmetrical molecule.
  • Glycine does not favor helix formation in particular therefore termed as helix breaker.
  • Glycine is most often found in turns and loops.
  • Glycine is easily adjustable into hydrophilic or hydrophobic environments, because of presence of two hydrogen atom side chain.
Glycine – has no Beta carbon atom, i.e. no side chain. Therefore it is the least sterically hindered and is more flexible as compared to other amino acids. This fact permits it to cover a large range of area in the Ramachandran plot.
  • Glycine is the most abundant amino acid in proteins like collagen triple helices, gelatin and silk fibroin.
  • Substitution of glycine with bulkier amino acid in collagen leads to osteogenesis imperfecta.
  • Glycine is an inhibitory neurotransmitter in the CNS, mainly in the spinal cord and brainstem.
  • Glycine is released from the Renshaw cell which acts as an inhibitory neurotransmitter especially in the anterior horn of the spinal cord.
  • Strychnine is a competitive antagonist at the site of inhibitory neurotransmitter glycine receptors in the spinal cord, brain stem, and higher centers.
  • Importantly, the NMDA receptor which is a glutamate and ion channel protein receptor and is activated when glycine and glutamate bind to it and thus glycine in this case acts to mediate excitatory neurotransmission in the mammalian central nervous system (CNS).
  • Glycine acts as precursor for several key metabolites of low molecular weight such as creatine (glycine, arginine), glutathione, haem (an oxygen carrying molecule), purines ring (C4, C5, N7 atoms), porphyrins and S- adenosyl methionine.
  • Glycine and sarcosine are interconvertible through transmethylation. Sarcosine dehydrogenase has vital role in glycine-sarcosine cycle, because this enzyme regulates the ratio of S-adenosylhomocysteine to S-adenosylmethionine.
  • Glycine is synthesized from amino acid threonine (through threonine dehydrogenase pathway), essential nutrientcholine (via formation of sarcosine), and amino acid serine (through serine hydroxymethyltransferase [SHMT]).
  • Glycine also play vital roles such as antioxidant, anti-inflammatory, cryoprotective, and immunomodulatory in peripheral and nervous tissues.
  • Glycine is the main substrate of respiration in the mitochondria from mesophyll cells of illuminated leaves undergoing photorespiration.

Alanine (Ala; A)

  • Alanine is also the simplest amino acid after glycine and has only a single methyl group (CH3) on its side chain.
  • Alanine is slightly non-polar.
  • D-alanine are present in bacterial cell walls.
  • Alanine can be used for gluconeogenesis in Liver, via glucose-alanine cycle.
  • Alanine is a source of energy for muscles and the central nervous system. It also strengthens the immune system and helps the body use sugars.
  • Transamination (amino group from glutamate transferred to pyruvate) of pyruvate forms alanine which is the transported to liver, thus helping in lowering energy load on muscles.
  • β-Alanine is also found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A.

Valine (Val; V)

  • Valine a 3-carbon branched-chain essential amino acid (BCAA). Thus is extremely non-polar.
  •  Valine is isolated from herb, valeria hence named, Valine.
  •  Valine tends to be present in β strands and interior side of globular proteins.
  • Valine promotes muscle growth and tissue repair.

The point mutation, which is relatively frequent, leads to replacement of a glutamate residue in position 6 of the β-chain by valine (GAGà GTG). As a consequence, the mutated hemoglobin tends to aggregate in the deoxygenated form that leads to sickle-cell anemia

Sickle-Cell Anaemia (SCA) is also termed as Drepanocytosis. It is an autosomal recessive genetic blood disorder and is caused by the substitution of one amino acid (valine) for the normal one (glutamic acid) at a 6th  position in the primary structure of β globin gene, the protein that carries oxygen in red blood cells. Normal red blood cells are disk-shaped, but in sickle-cell disease the abnormal hemoglobin HbS (β6Glu--> Val) polymerizes reversibly when in deoxygenated state and forms a fibrous polymer, this stiffens the RBC membrane, increases cell viscosity and cause dehydration due to potassium leakage and calcium influx. These changes produce the sickle shape which leads to the distortion of RBC and disturbances of oxygen transport.

Leucine (Leu; L)

  • Leucine contains large hydrocarbon chain (BCAA) and are frequently present in α- helices.
  • Leucine in responsible for the activation of mTOR (the mammalian target of rapamycin kinase that regulates cell growth).

Isoleucine (Ile)

  • Contains an additional asymmetric (chiral) center. therefore can occur in 4 stereoisomeric forms
  • Only one isomer of isoleucine is present in proteins.
  • Isoleucine tends to be present in β strands.
  • Vitamin B7 (Biotin) or H, is an absolute requirement for the complete catabolism of isoleucine and leucine.
           Branched Chain Amino Acids(BCAA-Valine, Leucine, Isoleucine)
 Arrangement of carbon atoms of BCAA cannot be made by humans, thus, these amino acids are an essential element in the diet. When these amino acids are catabolized in muscle they yields NADH and FADH2 which can further results in formation of ATP. 
Interestingly, when these amino acids are catabolized they uses the same enzymes in the first two steps. Transamination is the first step in each case using a single BCAA aminotransferase, with α-ketoglutarate as amine acceptor. This results in the formation of three different α-keto acids that are oxidized using a common branched-chain α-keto acid dehydrogenase, yielding the three different CoA derivatives. Subsequently the metabolic pathways diverge, producing many intermediates. 
The principal product formed from 
Valine is propionylCoA, the glucogenic precursor of succinyl-CoA. 
Isoleucine catabolism terminates with production of acetylCoA and propionylCoA; thus isoleucine is both glucogenic and ketogenic. 
Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as strictly ketogenic.
 There are a number of genetic diseases associated with faulty catabolism of the BCAAs. The most common defect is in the branched-chain a-keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all three amino acids, all three α-keto acids accumulate and are excreted in the urine. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet; ultimately, the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS

Methionine (Met; M)

  • Methionine contains a large aliphatic side chain that includes a thioether (-S-) group.
  • Occurs much frequently in α-helices.
  • Methionine, is one of the two sulfur-containing amino acid and is part of S-adenosylmethionine (SAM), a methyl donor in biochemical pathways.
  •  Methionine play important role in myelination of neurons.
  •  High levels of methionine can be found in cereal grains, eggs, sesame seeds, Brazil nuts, fish, meats and some other plant seeds. Most fruits, vegetables and most legumes are also low in methionine. 
  •  Improper conversion of methionine can lead to atherosclerosis.

Proline (Pro; P)

  • Proline is considered as an “imino acid”.
  • It differs from other amino acids in that the side chain of proline is bonded to both the nitrogen and the α-carbon atom. Thus conformations of proline are even more restricted due to the absence of free rotation of the N–Cα bond.
  • Proline is the only amino acid that is commonly found to form a cis peptide bond between itself and the residue that precedes it in the polypeptide chain.
  • Proline disrupts the conformation of the α helix, producing a bend (helix breaker). It most frequently occurs in turns of beta helices, as it has restricted set of torsion angles regions. Collagen is rich in proline.
  • Proline is the only amino acid that does not form a blue/purple color with ninhydrin instead it produces an orange/yellow color.
  • L-Proline is an important osmoprotectant.

Polar Uncharged Amino Acids

These amino acids do not carry any charge on the ‘R’ group and therefore readily participate in hydrogen bonding of protein structure. The amino acids in this group are – serine, threonine, tyrosine (aromatic), cysteine, glutamine and asparagine.


Serine (Ser; S)

  • The oxygen in Serine contains two pairs of nonbonding electrons, as water does, and the hydrogen is correspondingly a focus of partial positive charge. Thus, can act as hydrogen bond donor and acceptor.
  • Sugars or oligosaccharides can be added to the side chain oxygen of serine (O-linked glycosylation), a posttranslational modification that should be associated with the Golgi apparatus.
  • Serine is alanine with a hydroxyl (–OH) group. And can be easily phosphorylated; this process is often important in cellular regulation.
  • Generally found on the outside surface of  protein or on the active sites of enzymes like trypsin, chymotrypsin etc.,
  • Participates in biosynthesis of purines and pyrimidines.
  • D-Serine is a non-essential amino acid and dextro isomer of serine with antipsychotic activity. D-serine is a selective full agonist at the glycine site of N-methyl-D-aspartate (NMDA)-type glutamate receptor.
  • Serine can be decarboxylated to ethanolamine, which can further be methylated in choline formation.

Threonine (Thr; T)

  • Threonine resembles valine. Threonine, like isoleucine, contains an additional asymmetric (chiral) center. As, two asymmetric carbon, therefore occurs in 4 stereoisomeric forms.
  • Threonine has four carbons, with a hydroxyl group on the beta carbon.
  • The presence of the hydroxyl group on threonine means that the beta carbon of threonine is optically active, in addition to the alpha carbon.
  • Threonine is also a sites for O-linked glycosylation of proteins, and phosphorylation.
  • Threonine is synthesized from aspartic acid via α-aspartyl semialdehyde and homoserine and is converted to pyruvate via threonine dehydrogenase.

Cysteine (Cys; C)

  • Cysteine is alanine with a sulfhydryl (–SH) group, excellent nucleophiles but its hydropathy value is 2.5 (thus considered non polar according to hydropathy index.
  • Two cysteine residues can be oxidized to form a disulfide bond that can increase the overall stability of the protein.
cystine-formation from oxidation of two cysteines
  • Proteins found outside the cell are more likely to have disulfides (extracellular proteins) than are proteins found inside the cell, because of the more reducing environment in the cell. Thus, for example, digestive enzymes found in the small intestine have disulfides, while many enzymes involved in cell metabolism have free (reduced) cysteine –SH groups.
  • Cysteine with an extra carbon is termed homocysteine; homocysteine is also an intermediate in the biosynthesis of methionine.
  • Cysteine prenylation serves to anchor proteins in membranes.
  • Cysteine is the sulfur source for Fe-S cluster biogenesis in prokaryotes and eukaryotic mitochondria and chloroplasts.
  • The classical C2H2 zinc finger typically contains a repeated 28–30 amino acid sequence, including two conserved cysteines and two conserved histidine residues.
  • Glutathione (tripeptide of glycine, cysteine, and glutamic acid) and N-acetyl-cysteine (NAC) are antioxidants 

Asparagine (Asn; N)

  • Asparagine was the first discovered amino acid and contains a terminal carboxamide in place of a carboxylic acid.
  • Asparagine is a site for N-linked glycosylation of proteins, a posttranslational modification that should be associated with the endoplasmic reticulum.
  • Its side chain can form hydrogen bond interactions with the peptide backbone, thus they are often found near the beginning or at the end of alpha helices and also in turns and motifs. Oxaloacetate is the precursor of asparagine.

Glutamine (Glu; Q)

  • It also contains a terminal carboxamide in place of a carboxylic acid.
  • In the blood, glutamine (most abundant free amino acid) is the most important transport molecule for amino nitrogen. Hydrolytic deamination of glutamine in the liver also supplies the urea cycle with NH3.

Cysteine and Tyrosine are uncharged but they may become ionized or negatively charged at pH above 8.18 and 10 respectively.

Aromatic Amino Acids

Phenylalanine, tyrosine, and tryptophan contain ring systems. Amino acids usually are colorless as they do not absorb visible light. However, tyrosine, phenylalanine, and especially tryptophan absorb high-wavelength (250–290 nm) i.e., near UV range (i.e., 230 nm to 310 nm). Tryptophan and tyrosine contain delocalized π electrons that strongly absorb ultraviolet light.  Tryptophan therefore makes the major contribution to the ability of most proteins to absorb light in the region of 280 nm. These strong absorptions can be used for spectroscopic determinations of protein concentration.

In contrast, nucleic acids absorb light with a maximum around 260 nm due to the nucleotides. The extinction coefficients of the nucleotides are larger than those for the aromatic amino acids. In general, if a protein sample is contaminated with nucleic acid the sample will contribute to UV absorption at 260 nm. Thus, often the 260/280 ratio is used as a criterion for purity.

Importantly, nucleic acids (DNA and RNA) absorb more strongly at 260 nm than 280 nm such that the ratio A260 : A280 ranges from 1.6 to 2.0. While, if a solution of nucleic acid contaminated with protein then A260 : A280 ratio may be lower.

Phenylalanine (Phe; F)

  • Phenylalanine has only a benzyl group therefore is purely hydrophobic.
  • Phenylalanine absorbs light less strongly and at shorter wavelengths.
  • L-Phenylalanine is biologically converted into L-tyrosine. L-tyrosine in turn is converted into L-DOPA (Figure below), which is further converted into  skin  pigment melanin, dopaminenorepinephrine (noradrenaline), and  epinephrine (adrenaline). The latter three are known as the catecholamines.
  • Hepatic enzyme phenylalanine hydroxylase (PAH) converts phenylalanine into the tyrosine. If PAH becomes nonfunctional, phenylalanine accumulates and excessive phenylalanine gets metabolized into phenylketones (through the transaminase pathway with glutamate). Metabolites which are formed include phenylacetatephenylpyruvate and phenyllactate.  These phenylketones can cross blood brain barrier and affects brain.
  • Tyrosine also becomes deficient and can lead to a disease Phenylketonuria (PKU, autosomal recessive genetic disorder) that cause problems with brain development, leading to progressive mental retardationbrain damage, and seizures.
  • Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic.
  • Treatment involves a diet that is extremely low in phenyalanine. Also, tyrosine a non essential amino acid becomes essential in a patient having PKU, as phenylalanine which is a precursor of tyrosine fails to metabolize.
  • The majority of cases of cystic fibrosis result from deletion of phenylalanine at position 508, which interferes with proper protein folding.
Phenylalanine is sold as a nutritional supplement (food and drink products), for its reputed  analgesic  and  antidepressant  effects  as it is a direct precursor to the neuromodulator phenylethylamine.  A non-food source of phenylalanine is the artificial sweetener aspartame which is metabolized by the body into some chemical byproducts including phenylalanine. Therefore, aspartame must be avoided by people with phenylketonuria (PKU).

Tyrosine (Tyr, Y)

  • Tyrosine is phenylalanine with an added hydroxyl group.
  • Tyrosine is less hydrophobic because of their hydroxyl groups. Easily phosporylated.
  • DOPA (an acronym of 3,4-dihydroxyphenylalanine) is synthesized by hydroxylation of tyrosine. Tyrosine iodination results in Throxine and its oxidation in Melanin.
  • Defects in tyrosine metabolism results in alkatonuria (blackurine disease), albinism (tyrosinase deficiency), generalized hypopigmentation due to decreased melanin.
  • Tyrosine also plays vital role in photosynthesis in photosystem II (refer photosynthesis).

Tryptophan (Trp, W)

  • Tryptophan has an indole ring joined to a methylene (-CH2-) group; the indole group comprises two fused rings and an NH group.
  •  It is also less hydrophobic because of their NH groups. Tryptophan is a precursor of auxin, serotonin (neurotransmitter), melatonin (neurohormone) and niacin (Vitamin B3).
  •  Deficiency of tryptophan in blood results in Hartnup’s disease.
Hartnup disease (also known as "pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder which cause defect in the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into serotonin, melatonin and niacin).

Polar Charged Amino Acids

Polar and Positively Charged Amino Acids

Polar amino acids have positive charge on the ‘R’ group (have more amino groups) are placed in this category. They are lysine, arginine and histidine.


Lysine (Lys; K)

  • Contains a protonated alkyl amino group. It is almost fully ionized at the pH values found (7.4) in the cell.
  •  Lysine’s pKa is greater than 9; therefore, it will be > 99% protonated in the cell.
  •  The ε-amino group of lysine residues is subject to a particularly large number of modifications like methylation, acetylation, sumoylation, ubiquitination.  These modifications play an important role in controlling gene expression. 
  • Many coenzymes and cofactors are covalently linked to lysine residues, these include biotin, lipoic acid, and pyridoxal phosphate, as well as retinal.
  •  Lysine also plays an important role in coordinating negatively charged ligands; however, it functions as nucleophiles in some enzyme catalyzed reactions are vital.
  •  L-Lysine helps in calcium absorption, building muscle protein, production of hormones, enzymes and antibodies.

Arginine (Arg; R)

  • Arginine’s side chain is even more basic as its pKa is > 12. The ionized group of arginine is a guanidinium.
  • Arginine is the immediate precursor of nitric oxide (NO), ureaornithine, and agmatine; is necessary for the synthesis of creatine; and can also be used for the synthesis of polyamines,  citrulline, and glutamate.
  •  Arginine and lysine side chains, which are protonated under physiological conditions, participate in electrostatic interactions in proteins.
  •  Histones are rich in lysine and arginine, which confer a positive charge on the proteins, therefore helps in wrapping of negatively charged DNA.
Arginine plays an important role in cell division, the healing of wounds, removing ammonia from the body, immune function, and the release of hormones. As a precursor of nitric oxide (acts as an second messenger), arginine may have a role in the treatment of some conditions where vasodilation is required.

Histidine (His; H)

  • Histidine has a 5-member imidazole ring. One of the two nitrogen ions has a pKa near 7.0. This means that, at the neutral pH values found in cells, about half of the histidine molecules will have their side chains protonated (that is, with a positive charge) and about half will have their side chains unprotonated and uncharged.
  • Histidine is often used in enzymes to bind and release protons during the enzymatic reaction, thus they are the most common and versatile catalytic residue in proteins.
  •  Histidine-containing peptides are important biological buffers, also has the ability to form covalent intermediates during catalysis such as phosphohistidine.
  •  In addition, it is often a ligand for transition metal ions such as iron and zinc.
  •  Histidine is a precursor for histamine (act as mediator of allergies and inflammation) synthesized by decarboxylation of histidine and carnosine biosynthesis.
  • Diphenylhydramine is an inhibitor of histamine use in treatment of cough and cold
Histamine binds to histamine receptors for the cellular actions. The four histamine receptors that have been discovered in humans are designated H1 through H4, and are all G protein-coupled receptors (GPCR). Histamine receptors are primarily involved in vasodilation and also stimulate gastric acid secretion

Polar and Negatively Charged Amino Acids

Polar amino acids that have negative charge on the ‘R’ group (have more carboxy groups) are placed in this category. Thus, they are called as dicarboxylic mono-amino acids. They are aspartic acid and glutamic acid.


Aspartate (Asp; D)

  • Aspartic acid is negatively charged amino acids.
  • Aspartate is produced from oxaloacetate by transamination.
  • In proteins aspartate sidechains are often hydrogen bonded to form asx turns or asx motifs, which frequently occur at the N-termini of alpha helices.

Glutamate (Glu; E)

  • Glutamate is the most abundant excitatory neuro-transmitter in the vertebrate nervous system.
  • γ-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter.

All the above described twenty amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino acids and are encoded by the universal genetic code. The other two proteinogenic  amino acids, selenocysteine (Sec; U) and pyrrolysine (Pyl; O), are incorporated into proteins by unique synthetic mechanisms.

Classification-of-L-α-amino acids-found-in-proteins

Selenocysteine and Pyrrolysine


Selenocysteine, considered as 21st amino acid. It is incorporated when the mRNA being translated includes a SECIS element (selenocysteine insertion sequence), which causes the UGA codon to encode selenocysteine instead of a stop codon. Its application in biotechnology includes use of 73Se-labeled in positron emission tomography (PET) studies and 75 Se-labeled in specific radiolabeling. Half-life of 73Se is 7.2 hrs and half-life of 75 Se is 118.5 days.

Pyrrolysine considered as 22nd amino acid. It is used by some methanogenic archaea in enzymes that they use to produce methane. It is coded for with the codon UAG, which is normally a stop codon in other organisms. This UAG codon is followed by a PYLIS (pyrrolysine insertion sequence) downstream sequence. It is similar to lysine with an added pyrroline ring linked to the end of lysine side chain. The extra pyrroline ring is incorporated into the active site of several methyltransferases.

Pyrrolysine is present in some archaebacterial species and is not yet discovered in human proteins.