Fenomena biomedik

dari transkripsi gen

hingga metabolisme
Dra. Lusia Hayati, MSc.
Biologi Kedokteran FK Unsri
 Gene Function

> DNA sequence

AATTCATGAAAATCGTATACTGGTCTGGTACCGGCAACAC
TGAGAAAATGGCAGAGCTCATCGCTAAAGGTATCATCGAA
TCTGGTAAAGACGTCAACACCATCAACGTGTCTGACGTTA
ACATCGATGAACTGCTGAACGAAGATATCCTGATCCTGGG
TTGCTCTGCCATGGGCGATGAAGTTCTCGAGGAAAGCGAA > Protein sequence
TTTGAACCGTTCATCGAAGAGATCTCTACCAAAATCTCTG MKIVYWSGTGNTEKMAELIAKGIIESGKDVNTINVSDVNI
GTAAGAAGGTTGCGCTGTTCGGTTCTTACGGTTGGGGCGA DELLNEDILILGCSAMGDEVLEESEFEPFIEEISTKISGK
CGGTAAGTGGATGCGTGACTTCGAAGAACGTATGAACGGC KVALFGSYGWGDGKWMRDFEERMNGYGCVVVETPLIVQNE
TACGGTTGCGTTGTTGTTGAGACCCCGCTGATCGTTCAGA PDEAEQDCIEFGKKIANI
ACGAGCCGGACGAAGCTGAGCAGGACTGCATCGAATTTGG
TAAGAAGATCGCGAACATCTAGTAGA
What are genes and why are they important in
clinical medicine?
• Gene expression:
– General mechanism of transcription
– Components involved in transcription
– General mechanism of splicing
– General mechanism of translation
– Components involved in translation
• DNA Replication:
– General mechanism of DNA replication
– Components involved in DNA replication
• DNA mutation & repair
– Types of mutation
– Types of DNA repair
– The effect of mutation on gene function and disease
 Function of Genes

• Control the physical development,

behavior, and being of organisms
(look, size, health, etc)

• Genes encode the information

necessary to construct the proteins
needed for the organism to function
TRANSCRIPTION
5’ 3’
DNA Sense strand  A T T G C C A T T

Template Strand  T A A C G G T A A
Anti – Sense Strand 3’ 5’

RNA A U U G C C A U U
5’ 3’
5’ 3’
Direction of Transcription
TRANSLATION 5’
A U U G C C A U U
Ile Ala Ile
N
N C
Direction of Translation
 Transcription
Transcription occurs in the nucleus
Factors involved in transcription:
 DNA template
 Transcription factors
 RNA polymerase
 ATP
 Nucleotides: ATP, UTP, GTP, CTP
RNA synthesis is in 5’ to 3’ direction
RNA strand is complementary to DNA template
 Promoters in Eukaryote

Enhance the activity of a promoter due to its association

with proteins called transcription factors
 The Eukaryotic Message

Mature mRNA
Post transcriptional
processing
a single pre-mRNA molecule could yield different functional
mRNAs
 Gene 1 Gene 3

DNA molecule

Gene 2

DNA strand

TRANSCRIPTION

RNA

Codon
TRANSLATION

Polypeptide
Amino acid
Codon table
Note the degeneracy of the genetic
code. Each amino acid might have
up to six codons that specify it.
• Different organisms have
different frequencies of codon
usage.
•A handful of species vary from
the codon association described
above, and use different codons fo
different amino acids.

How do tRNAs recognize to which

codon to bring an amino acid? The
tRNA has an anticodon on its
mRNA-binding end that is
complementary to the codon on the
mRNA. Each tRNA only binds the
appropriate amino acid for its
anticodon.
An initiation codon marks the start
of an mRNA message

AUG = methionine

Start of genetic message

End
• mRNA, a specific tRNA, and the ribosome
subunits assemble during initiation

Large
Initiator tRNA ribosomal
subunit
P site
A site

Start
codon Small ribosomal
mRNA subunit

1 2

Figure 10.13B
• Summary of DNA
TRANSCRIPTION

transcription
Stage 1 mRNA is
and mRNA
RNA
transcribed from a
DNA template.
translation Amino acid
polymerase

TRANSLATION
Stage 2 Each amino
Enzyme acid attaches to its
proper tRNA with the
help of a specific
enzyme and ATP.
tRNA

Initiator Anticodon
tRNA Stage 3 Initiation of
Large polypeptide synthesis
ribosomal
subunit The mRNA, the first
tRNA, and the
ribosomal subunits
Start Small
Codon ribosomal come together.
mRNA
subunit

Figure 10.15
 New
peptide
Growing bond Stage 4 Elongation
polypeptide forming
A succession of tRNAs
add their amino acids to
the polypeptide chain as
the mRNA is moved
through the ribosome,
one codon at a time.
Codons
mRNA
Polypeptide

Stage 5 Termination
The ribosome recognizes
a stop codon. The poly-
peptide is terminated and
Stop Codon released.

Figure 10.15 (continued)

 Source of Protein

• Animal Sources:  Plant Sources:

(Complete Proteins) (Incomplete
– Meat Proteins) *
– Poultry – Dry Beans
– Fish – Peas
– Eggs – Nuts
– Dairy Products – Tofu
 Grain Products

* (low in one or more of the essential amino acids)

Complete and incomplete proteins

• Bodies produce some amino acids

referred to as “nonessenial amino acids”

• The other amino acids that bodies need

are called “essential amino acids” and
must come from the foods we eat
 Classification of Protein
by Their Function
• Enzymes - proteins that catalyze chemical and
biochemical reactions within living cell and outside
(RNA-polymerases, dehydrogenases, etc)
• Hormones - proteins that are responsible for the
regulation of many processes in organisms (insulin,
grows factor, lipotropin, prolactin etc)
• Transport proteins -proteins are transporting or
store some other chemical compounds and ions (
cytochrome C - electron transport; haemoglobin and
myoglobin - oxygen transport, etc)
• Immunoglobulin or Antibodies - proteins that
involved into immune response of the organism to
neutralize large foreign molecules (tumor necrosis
factor (TNF), IgG)
• Structural proteins - These proteins are maintain
structures of other biological components, like cells
and tissues (collagen, elastin, α-keratin etc)
• Motor proteins. These proteins can convert
chemical energy into mechanical energy (actin and
myosin are responsible for muscular motion)
• Receptors. These proteins are responsible for
signal detection and translation into other type of
signal (receptor protein, rhodopsin, etc)
• Signalling proteins. This group of proteins is
involved into signalling translation process
(GTPases, etc)
• Storage proteins. These proteins contain energy,
which can be released during metabolism
processes in the organism (Egg ovalbumin and
milk casein)
 Protein Deficiency

Protein-Calorie Malnutrition (PCM)

Marasmus
Kwashiorkor
 Kwashiorkor

Inadequate protein intake

Disease of weaning (typically about age 2)
Edema, fatty liver
Body proteins broken down --> decreased
antibodies
The edema and enlarged liver
characteristic of kwashiorkor
are apparent in this child’s
swollen belly, enlarged
abdomen from parasites as
well.
 Marasmus

Deficiency of kcals, protein, vitamins,

minerals
“Skin and bones” appearance
Infancy to 6 - 18 months; also adults w/
extremely poor intake over time
Impaired brain development
Child may never “catch up”
 Protein Excess

If a person consumes over

Kidney/liver hypertrophy 15% protein in
his diet (beef typically has 26% protein, the
Colon and rectum cancer
rest is fat and chicken has 61% protein, the
Osteoporosis
rest is fat), then the body must get rid of
Arthritis and Gout
that protein.
 Kidney/liver hypertrophy
The body stores very little protein. Certain organs are
responsible for getting rid of the protein—namely the
kidneys and liver. The more protein we eat, the harder
the kidneys and liver have to work to excrete the protein.

Colon and rectum cancer

Animal protein is hard to digest so it is hard on the
digestive system causing digestive problems. This could
related to the high incidence of colon and rectum cancer
 Osteoporosis
Arthritis and Gout
The animal protein makes the body more acidic,
Excess
the body protein makes the
has to neutralize thebody
acid.more acidic,
It does so by
and these
pulling calciumacids accumulate
out of the bones, inandthe joints
then take
causing
out arthritis and gout
the calcium.
 Protein and Diseases

• Alzheimer's disease protein

(progressive disorder in neurons).
• Cystic fibrosis disease (inherited
disease of the secretory glands, including
the glands that make mucus and sweat)

Folding – Misfolding - Protein aggregation -

Diseases.
 Protein and Diseases
• Maintenance of the complex three-dimensional
structure in the cell is vital for protein function

• The environmental stress, genetic mutation, and

infection make the protein shape changed and
become aggregation

• In many protein aggregation diseases, incorrectly

folded proteins self-associate, forming fiber-like
aggregates that cause brain cell death and
dementia
 What is Alzheimer's

• Alzheimer's disease (AD), is the most

common form of dementia.

• This incurable, degenerative, and terminal

disease was first described by German
psychiatrist and neuropathologist Alois
Alzheimer in 1906 and was named after
him
Two abnormal structures called plaques and tangles are prime suspects in
damaging and killing nerve cells.

1. Plaques are deposits of a protein fragment called beta-amyloid that build up in the
spaces between nerve cells.

2. Tangles are twisted fibers of another protein called tau or neurofibrillary that build up
inside cells. play

Plagues and tangles play a critical role in blocking communication among nerve cells
and disrupting processes that cells need to survive.

It's the destruction and death of nerve cells that causes memory failure, personality
changes, problems carrying out daily activities and other symptoms of Alzheimer's
disease.

This damage initially appears to take place in the hippocampus, the part of the brain
essential in forming memories.

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 What is Cystic Fibrosis

• Cystic fibrosis is a heterogeneous recessive

genetic disorder with features that reflect
mutations in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene

• Classic cystic fibrosis is characterized by chronic

bacterial infection of the airways and sinuses, fat
maldigestion due to pancreatic exocrine
insufficiency, infertility in males due to obstructive
azoospermia, and elevated concentrations of
chloride in sweat
 Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR)
• CFTR is a protein ion channel that transports chloride
ions across epithelial cell membranes

• CFTR is found in the epithelial cells of many organs

including the lung, liver, pancreas, digestive tract,
reproductive tract, and skin. Normally, the protein
moves chloride ions (with a negative charge) out of an
epithelial cell to the covering mucus

• Mutations of the CFTR gene affect functioning of the

chloride ion channels, leading to cystic fibrosis and
congenital absence of the vas deferens.
 The CF gene: CFTR
CFTR (7q)

mRNA

CFTR Protein

CFTR Protein in
Cell Membrane
Cystic fibrosis
Lung function from the absence of the CTFR protein
Cl channel
 Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR)

CFTR is made up of five domains:

Two membrane-spanning domains

(MSD1 and MSD2) that form the
chloride ion channel
Two nucleotide-binding domains
(NBD1 and NBD2) that bind and
hydrolyze ATP (adenosine
triphosphate)
and a regulatory (R) domain.

Delta F508, the most common CF-causing

mutation, occurs in the DNA sequence
that codes for the first nucleotide-
binding domain (NBD1).
CFTR Protein With The Delta F508
Mutation
• When a CFTR protein with the delta
F508 mutation reaches the ER, the
cellular component recognizes that
the protein is folded incorrectly and
marks the defective protein for
degradation. As a result, delta F508
never reaches the cell membrane.
• Chloride ion can not exodus through
the CFTR protein

• The sodium and chloride ion

imbalance creates a thick, sticky
mucus layer that cannot be removed
by cilia and traps bacteria, resulting
in chronic infections (Cystic
Fibrosis).
CFTR

NBF1 R
NBF2

hydrophilic membrane-spanning domain (MSD)

Nucleotide Binding fold
Types (classes) of CFTR mutations.

Class 5: mutations altering the stability of

mature CFTR protein.

Class 4: mutations altering the conduction of Cl-

channel. Certain segments of membrane spanning
domains participate in the formation of an ionic pore.

Class 3: mutations disturbing the regulation of Cl-

channel. These mutations are frequently situated in
the ATP binding domain (NBF1 and 2).

Class 2: mutations altering the cellular

maturation of the protein.

Class 1: mutations altering the production of the

protein. These mutations result in the total or
partial absence of the protein. This class
includes the nonsense mutations and those that
produce a premature stop codon
TERIMA KASIH

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