Chapter 9 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 9 Gene...

Chapter 9Gene Expression:

From Genes to Proteins

DNA Codes for Protein

The information required to produce proteins is encoded in the nucleotide sequence of DNA

Relationship Between Genes, Proteins, and Phenotype

• Archibald Garrod (early 1900s)– Inborn errors of metabolism

• Alkaptonuria altered metabolism of alkapton (homogentisic acid)

• Urine turns black • Using pedigree analysis he determined it is an autosomal recessive trait

Metabolic Pathways

Fig. 9.1

• Chains of chemical reactions

• In a pathway, an enzyme is required to convert one compound into another

• Each reaction is controlled by a different enzyme

One Gene, One Enzyme

• Beadle and Tatum (1930s)

• Experiments on Neurospora, a common bread mold

Fig. 9.2

DNA Stores Genetic Information

• Phenotype is the result of protein function

• When the function is altered or absent, the result is a mutant phenotype

• Proteins are products of genes• Genes are made of DNA• Changes in DNA may change protein functions

Genetic Code

• Information is stored in the sequence of nucleotides in the DNA

The Genetic Code

Fig. 9.3

About the genetic code:

AAGCTTCAATTC

Lys-Leu-Gln-Phe

AAGCTTCAATTCSer-Phe-Asn

AAGCTTCAATTC

Ala-Ser-Ile

open reading frames

1. Triplet code: 3 bases encode an amino acid.

2. Continuous code.

3. Non-overlapping

About the genetic code cont’d.

5. Code is degenerate.

4. Code is universal.

Exceptions: AUG - Met UGG - Trp

7. Nonsense or STOP codons

6. Wobble hypothesis.

61 sense codons3 nonsense codons

UAAUGAUAG

Skin cell Liver cell

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5

Protein 2

Protein 4

Protein 5

Protein 1

Protein 3

Protein 4

• Messenger (mRNA) – single-stranded, complementary copy of DNA

• Transfer RNA (tRNA) contains a binding site for mRNA codon and a binding site for a specific amino acid

• Ribosomal RNA (rRNA) – component of the ribosome

Protein Synthesis

• Linear sequence of nucleotides of DNA is transferred to a linear sequence of amino acids of the protein

Two steps• Transcription

– DNA to mRNA• Translation

– mRNA to protein

Fig. 9.4

The Flow of Genetic Information

Central dogma

Transcription

• Occurs in the nucleus• One strand is used as a template to produce mRNA

• Three stages –Initiation–Elongation–Termination

Transcription

Transcription: Initiation

Fig. 9.5a,b

• RNA polymerase binds to the promoter region

• DNA unwinds

Transcription: Elongation

• 30–50 nucleotides/second• RNA nucleotides pair with DNA template A–U, T–A, G–C, and C–G

Fig. 9.5c

Transcription: Termination

• RNA polymerase reaches the terminator and mRNA is released

Fig. 9.5d

Product of Transcription: Pre-mRNA

• Large pre-mRNA molecules are composed of exons and introns

• Exons are nucleotide sequences that are transcribed and translated

• Introns are nucleotide sequences that are transcribed but not translated– 0–75 per gene– Size ranges from 100–100,000 nucleotides

Organization of an Eukaryotic Gene

Fig. 9.6

Processing Pre-mRNA

• Introns are removed• Exons are spliced together• Cap is added to the 5’ end

– The cap helps attach mRNA to the ribosome

• Poly-A tail is added to the 3’ end• The mRNA is transported out of the nucleus to the ribosome for translation

Processing Pre-mRNA

Fig. 9.7

Nobel Prize in Medicine, 1993

Introns

Phil Sharp Rich Roberts

Proteins

• Proteins are composed of amino acids joined together by peptide bonds

• 20 different amino acids can be used to produce proteins

• Amino acids have a Carboxyl (acid) group, an amino group, and an unique R group

Fig. 9.8

Amino Acids Are the Subunits of Proteins

Domains - can bring residues far apart in primary sequence in contact with each other.

Primary sequence - sequence of amino acidsin a protein.

Secondary structure - depends on primary sequence. Beta sheets and alpha helices.Can be usually predicted from sequence.

Tertiary structure - 3-D structure of how the proteinfolds.Cannot be always predicted.

Quaternary structure - multimers. Many subunits eachof which is a polypeptide.

Tertiary structure Quaternary structure

Hemoglobin

Diseases arising from defects in protein folding

• May cause changes in protein folding• Examples

– A form of Alzheimer disease– MPS VI– Cystic fibrosis– Prion diseases

Prions

Fig. 9.13

Stanley Pruisiner won the Nobel Prize in 1997 for his work with prions and their role in disease

Ribosomes• The site of protein synthesis • May be free in the cytoplasm or attached to endoplasmic reticulum

• Contains two binding sites– A (Amino) and P (peptide) site

• Composed of – Two subunits– rRNA and protein

Fig. 9.9

Transfer RNA (tRNA)

Fig. 9.10

• Adapters that bond to an amino acid and recognize specific mRNA codons

• Small, single- stranded RNA that folds back, forming a cloverleaf shape

HIV infection

Nobel Prize in Medicine, 1975

Retroviral mechanisms

Renato DulbeccoDavid Baltimore Howard Temin

Nucleotide analogs used as anti-AIDS drugs

Translation

• Converts mRNA sequence to amino acid sequence

• Occurs within the ribosomes• Requires various factors: enzymes, amino acids, energy, mRNA, rRNA and tRNA

• Three steps– Initiation– Elongation– Termination

Steps in Translation: Initiation

• Small ribosomal subunit binds to mRNA

• tRNA carrying methionine binds to the start codon (AUG) with in P site

• Forms initiation complex• Large ribosomal subunit binds to small subunit

Fig. 9.9a-d

Initiation

Steps in Translation: Elongation

• tRNA for the second amino acid binds to the mRNA within the second ribosomal binding site (A site)

• Peptide bonds forms between methionine and second amino acid

• Ribosome moves down mRNA• tRNA brings in the third amino acid

into the A site• Peptide bond forms

Termination

Steps in Translation: Termination

• Elongation continues until the ribosomes reaches a stop codon

• No tRNA binds • Synthesis is completed and mRNA, tRNA, are released from the ribosome

• Polypeptide is folded into 3-dimensional shape

• Many antibiotics interfere with steps in protein synthesis

Mechanism of antibiotic action

Specifically target protein translation in bacteria.

Since prokaryotes and eukaryotes use different proteins for translation, antibiotics can specificallyaffect bacterial, but not cellular translation.

Puromycin prevents elongation of polypeptide. Causes premature termination.

Streptomycin

Tetracycline

Chloramphenicol

Erythromycin

Binds to 30s subunit and prevents initiation of protein synthesis

Prevents elongation by preventing charged tRNA frombinding to A site.

Binds 50s subunit and blocks peptidyl transferase reaction.

Prevents translocation

Proteome

• Set of proteins present in a cell under specific environmental conditions

• It is estimated that humans can make over 100,000 proteins

• This is greater than the number of genes in the human genome

• How is this possible?

Chapter 9 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning Chapter 9 Gene...

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