Amino Acids (continued)
Amino Acids with hydroxyl
group: Refer previous lecture notes for structure:
IA. General Properties:
- Serine and Threonine
have hydroxyl groups attached to the
aliphatic side chains that impart hydrophilic character and make them more
reactive than their structural relative’s alanine and valine, whereas
- Phenylalanine and Tyrosine
are aromatic aminoacids have hydrophobic character.
note that the hydroxyl group of the tyrosine
is reactive when compared with the sidechains of other aliphatic amino acids.
These OH- groups can be
phosphorylated by reactions
catalyzed by enzymes called kinases, which involves ATP molecules as a source
The Phosphorylation of the hydroxyl group is necessary for a
cascade of reactions called as signal transduction.
II. Why amino acids are so essential?
- The answer lies in understanding the role they play
in the different cellular processes.
- Any slight defect in their synthesis, modification or
incorporation of amino acids into proteins can lead to devastating
- To site a few examples of diseases those are caused
by either due to improper modification of aminoacid functional groups or
due to mutation in genes that carry the information for incorporating
aminoacids in proper sequence during protein synthesis.
The following examples would explain how these aminoacids
play an crucial role in cellular processes.
- Cancer is caused due to aberrations in the growth
- The aberration results in uncontrollable growth of
- In normal cases such as in wound healing the cells
stop growing when they contact adjacent cells. This phenomenon is called contact inhibition.
cancerous cells the ability to sense the own kind adjacent to it is lost
resulting in cancerous growth.
- This is due to the mutations that occur in the DNA
that carries all the information regarding the protein that is responsible
for contact inhibition.
- These mutations can be caused by various factors. One
such factor is viruses such as AIDS virus or
Human Pappiloma Virus.
III. Initially Central Dogma was:
DNA RNA Protein
However, in viruses:
IIIA. How viruses cause cancer and
how is serine and tyrosine involved in this?
1. Viral genome is made of RNA.
2. The viruses that can make DNA from RNA are called
an enzyme called reverse transcriptase.
- These viruses carry a typical gene called oncogene that transforms the normal cells
into cancerous cells by affecting the contact inhibition of cell growth.
- Normal cells grow as a monolayer whereas the
cancerous cells grow haphazardly and form a lump.
- In addition the cancerous cells can become mobile in
some cases called metastasis
resulting in malignancy.
- All cells communicate
with each other by means of many chemicals that are released in the medium
that bind to the receptors (proteins that are present on cell membranes)
of the other cells and elicit a response. Example: EGFR (Endodermal
growth factor receptor), platelet receptor etc.
- These proteins have specific structure and shape.
- The cells synthesize growth factors that tell other
cells near it to grow by binding to these EGFR, which then signal pathways
- The binding of growth factor causes conformational changes in the EGFR, which
triggers its kinase activity.
- Kinases are enzymes that phosphorylate
some functional groups of amino acids.
Protein-OH + ATP Protein-OPO3H2
11. The functional
groups that typically get phosphorylated are the hydroxyl groups of serine, threonine, phenylalanine and tyrosine.
phosphorylation reaction triggers a cascade of reactions involving many
proteins that induces cells division.
- The activation involves conformational changes of the proteins.
- In the case of cancer, the normal gene involved is
mutated in the EGFR cascade and thus is constantly activated to induce
cell growth and division.
- This results in cell growth even in the absence of
endodermal growth factor (EGF).
IIIB. Which amino acid is mutated in
the kinase that causes uncontrollable growth of cells?
In most cases it is the Serine that
is mutated into tyrosine.
IV. Swapping of parts of chromosomes
can cause serious abnormalities due to overproduction of protein kinases:
- Leukemia is type of
cancer that is a result of aberrations in chromosomes 9 and 22.
- During replication the DNA polymerase jumps from one
chromosome to another resulting in translocation of genetic material
between chromosome 9 and 22. This is called as Philadelphia
- This is due to the insertion of a gene called c-abl in chromosome 9, which encodes
tyrosine kinase into the Bcr-gene of the chromosome 22.
- This results in bcr-abl
- This fusion protein is not regulated properly and in
turn phosphorylates every tyrosine, serine and threonine residues of the
proteins involved in the growth-promoting pathway.
- Remedy: A
specific inhibitor of the bcr-abl kinase inhibits both the
serine-threonine and tyrosine side of the kinase and prevents
IVA. Where is phenylalanine involved?
accumulation in the body causes phenylketonuria (PKU).
- In this case the phenylalanine is not converted into
tyrosine due to absence or deficiency of
phenylalanine hydroxylase, which attaches OH-group on the
phenyl group of phenylalanine to convert it into tyrosine.
- Symptoms of phenylketonuria include mental
retardation and demyelination.
- Normally newborn babies are tested for
phenylketonuria so that giving a low phenyalanine diet can prevent the
onset of the disease.