Genetics
Chapter 20
• Complete carbohydrate metabolism
(catabolism and anabolism)
• Complete fat metabolism (catabolism and anabolism)
• Cholesterol metabolism (catabolism and anabolism)
• Protein (including heme) catabolism and amino acid metabolism (catabolism and non essential amino acid synthesis)
• What’s left?
• PROTEIN SYNTHESIS
– Structure and metabolism of purines, pyrimidines, nucleotides, and nucleic acids
(DNA and RNA)
– Need to make purines and pyrimidines before you can make nucleotides, which need to be made before you can make new DNA (for new cells, growth) or new RNA (protein synthesis)
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• Nucleic acids are polymers in which the individual components are nucleotides
• Two types: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)
• DNA – most is found inside the nucleus
– Storage and transfer of genetic information
– Controls most cellular functions
• RNA – occurs in most parts of the cell
– Used primarily for protein synthesis
• Class of nitrogen-containing heterocyclic bases (pyrole rings containing nitrogen)
• Require amino acids and folate (a B vitamin) for synthesis
- Purines: 1. Adenine (A)
2. Guanine (G)
2. Uracil (U)
3. Thymine (T)
• The breakdown of purines is important in the formation of uric acid
– Excreted in blood and urine
– Causes Gout and Kidney Stones in some individuals
• Disorder of increased purine catabolism due to altered enzyme activity
• Overproduction & excretion of uric acid
• Hyperuricemia: increase uric acid in blood, supersat’d solution, precipitates out of solution
• Crystallizes in joints (gout) or urine
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• Synthetic purines and pyrimidines
(leukemia and breast/colorectal cancers)
– Block DNA replication
• Consist of a purine or pyrimidine and pentose (ribose or deoxyribose) (carbon
#2 only H atom)
– Adenosine
– Guanosine
– Cytodine
– Thymidine
– Uridine
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• The term ribonucleotides or deoxyribonucleotides is based on which pentose
• Contain phosphate(s) in addition to nucleosides
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• Both DNA and RNA contain cytosine, adenine, and guanine
• DNA also contains thymine
• Whereas, RNA contains uracil instead of thymine
• Only the monophosphate molecule is used
• Four deoxynucleotides:
– Deoxyadenylate
– Deoxyguanylate
– Deoxycytidylate
– Thymidylate
• Sugar is deoxyribose
• Content of purines and pyrimidines are equal (double stranded and base pairs)
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• 3’,5’-phosphodiester linkage is the bond holding the nucleotides together within one strand
• DNA molecule is a double-stranded helix where both strands are held together by hydrogen bonds (base pairs) and go in the opposite direction
• One strand starts with a 3’-hydroxy terminal end while the other strand matches with a 5’-phosphate terminal end
• Strands are always read 5’ to 3’
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• Hydrogen bonding between both strands is
A with T and G with C (purine to pyrimidine) (complementary bases)
• Template strand: contains the genetic information (this strand is copied during mRNA synthesis, “transcription”)
• Opposite (coding) strand: matches the mRNA in sequence of bases (except U in place of T)
– Complementary strands
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• Predict the sequence of bases in the opposite strand that would be complementary to the template strand shown below:
5’ A–A–T–G–C–A–G–C–T 3’
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• DNA serves as a template for the:
– Transcription of the information into mRNA for protein synthesis (gene)
– Replication of the genetic information into daughter DNA molecules for making new cells
• DNA interacts with specific proteins
(histones) to form structurally stable units known as “chromosomes”
• Chromosomes: 15% DNA and 85% protein
– 46 chromosomes are matched into 23 homologous pairs
– One member of the pair is from dad and the other from mom
– Both code for the same trait (color of eyes) but for different forms of the trait (blue vs brown)
• Identical twins (same DNA)
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• The sugar is ribose instead of deoxyribose
• Contains uracil rather than thymine
• Exists as a single strand
• Sequence is complementary to template strand of DNA and identical to the opposite strand of DNA except U has replaced T
• DNA molecules produce exact duplicates of themselves when replicated
• Unwinding enzymes (DNA helicases) cause the double helix to open (disrupt hydrogen bonds between bases) and the strands separate
• The “leading strand” (new daughter strand) is formed continuously in a 5’ → 3’ direction
“towards the fork” by DNA polymerases
– Which also proofreads for proper base pairing
• The “lagging strand” (new daughter strand) is formed in a 5’ → 3’ direction however in short segments “from the fork”
– These are called Okazaki Fragments
– The gaps between these fragments are called
“nicks”
– DNA ligases connect the fragments forming another new daughter strand
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• Process of unwinding occurs through out the DNA molecule at multiple sites simultaneously
– This results in “replication bubbles”
– Allows DNA to be replicated very fast
• Newly synthesized daughter DNA strands have a RNA primer at the beginning
• Eventually one parent “old” strand is hydrogen bonded to one daughter “new” strand
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• Most of human DNA is not transcribed
(not used to make RNA or proteins)
– Protein coding regions are known as exons (transcription)
– The noncoding regions are called introns
• Protein synthesis is under the direction of our DNA
• Protein synthesis can be divided into two phases.
– Transcription – A process by which DNA directs the synthesis of RNA molecules
– Translation – a process in which mRNA is deciphered to synthesize a protein molecule
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1. Messenger RNA (mRNA)
- contains only exons
- Made from heterogenous nuclear RNA,
(hnRNA; primary transcript); which contains exons and introns and is formed directly from DNA
- Serves as template for protein synthesis
- 3 consecutive bases are known as codons, which specify which amino acid to be added to make protein
2. Transfer RNA (tRNA)
• Functions as intermediaries between mRNA and amino acids and delivers amino acids for protein synthesis.
• At least 1 type of tRNA exists for each amino acid.
• All tRNA molecules have the same general shape (2D “cloverleaf”), which is crucial to how they function.
• Two important features:
– The open end (stem) of the cloverleaf structure is where the amino acid covalently bonds to the tRNA.
• Known as the acceptor arm
– The loop opposite the open end of the cloverleaf is the site for a sequence of 3 bases called the anticodon arm.
• The anticodon arm reads the mRNA codon
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3. Ribosomal RNA (rRNA)
- Combines with a specific protein to form ribosomes, the physical site for protein synthesis
- Builds the protein (forms the peptide bonds)
• hnRNA is synthesized from DNA template strand
– RNA polymerases
• U replaces T in the RNA strand
• Very small portion of DNA (known as a gene) is transcribed into hnRNA
• No proofreading
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• A segment of a DNA base sequence (1 gene
= 1 protein?) responsible for the production of a specific RNA molecule
– Most human genes are ~1000–3500 nucleotides long
– “Human Genome Project”
– Genome: All of the genetic material (the total
DNA) contained in the chromosomes of an organism
– Human genome is about 20,000–25,000 genes
• Process of transcription has 3 stages:
– Initiation binds RNA polymerase to the promoter region at the beginning of the gene
– Chain elongation then occurs forming a 3'-5' phosphodiester bond, generating a new hnRNA molecule
– Termination is the final step of transcription when the RNA polymerase releases the newly formed hnRNA molecule
• The hnRNA still must be processed in post-transcriptional modification, a three step process:
– A 5' cap structure is added
– A 3' poly(A) tail (100 to 200 units) is added by poly(A) polymerase
• The 5’ cap and poly(A) tail protect the ends of the hnRNA and mRNA from enzymatic digestion
– RNA splicing removes the introns from the hnRNA
• The introns are cut out and the exons
(coding sequences) are spliced together to form mRNA
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Answers: a. 3’ GCG–GCA–UCA–ACC–GGG–CCU–CCU 5’ b. 3’ GCG–ACC–CCU–CCU 5’
• Almost universal for all organisms
• Given a specific codon, only a specific amino acid will be incorporated
(translation)
• Maybe more than one codon for an individual amino acid
– Stop codons: there are three, don’t code for any amino acid
– AUG – initiation codon (methionine)
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mRNA 5’ 3’
GCC-AUG-GUA-AAA-UGC
Translates to?
• Mutations are changes/errors in the base sequence in DNA molecules
– This error in DNA coding is then passed on each time the DNA replicates
– EVOLUTION?
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• Mutagens or carcinogens: substances that cause mutations
– Radiation: ultraviolet light, X rays,
– Chemicals: nitrates, nitrites, nitrosamines → nitrous acid
• Each time mRNA is transcribed from mutated DNA, the resulting mRNA will have an altered base sequence
• The consequences of a mutation range from insignificant (silent) to lethal
• The body has some enzymes that recognize errors in replication of new DNA and can sometimes repair the damage
• If the damage is not repaired: the mutation may remain and be present for all future new cells, or the cell stops dividing
(dormant), or the cell commits suicide
(apoptosis)
• In Sickle Cell Anemia, a replacement mutation occurs
• The amino acid glutamic acid at position #6 in the beta chain of hemoglobin is replaced by valine
– Codons for glutamic acid are GAA and GAG but for valine the codons are GUA and GUG
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• Virus: tiny disease-causing agents that are composed of an outer protein coat (capsid) and an inner nucleic acid core which contains either DNA or RNA (retroviruses), not both
• Viruses are unable to reproduce outside of the cells of living organisms (host)
• They do not possess the nucleotides, enzymes, amino acids, and other molecules necessary to replicate their nucleic acid or to synthesize proteins
• They can infect many cells including; bacteria, human, plants and animals
• Once attached they essentially inject their
DNA or RNA into the host cell
• Once inside, the viral DNA or RNA uses the host cells supply of nucleotides, ribosomes, etc. to replicate the viral DNA or RNA
(reverse transcriptase)
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• The cell becomes filled with new virus particles, undergoes lysis, which kills the cell and releases countless new virus particles into the blood that infect other cells in order to multiply thus killing many cells
• Due to their somewhat uncomplicated structure, viruses are difficult to kill
• They are resistant to many antiseptics, radiation and can survive a long time on a surface (computer keyboard, phone, toilet, etc…)
• The most effective agents are our own antibodies (immunoglobulins) that can attach their antigenic sites to the virus, attract white blood cells, which then encapsulate it and eventually destroy it
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• Additionally viruses are frequently able to change their capsid (protein coat) which then make them immune to antibody attack by the immunoglobulins already present
• In these cases new immunoglobulins would have to be synthesized to recognize the new antigenic substance
• AIDS virus – retrovirus that infects helper
T-cells (white blood cells that are an important part of the body’s immune system)
• These cells don’t work properly when infected thus the body becomes more susceptible to other infections and diseases
• Preparation containing an inactive or weakened form of a virus or bacterium
• The antibodies produced work very well against the naturally ocurring form
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• Anti-Cancer Drugs
• Interrupt DNA replication by bonding to N atoms in the purine and pyrimidine bases
• Make hydrogen bonding between incoming nucleotides impossible
• Reduces cell division and replication of mutated cells
• Unfortunately not selective for cancerous cells, therefore effect other rapidly reproducing cells like intestinal mucosal,
RBC’s and lymphocytes
• Results in anemia, decreased disease resistance and digestive disorders like diarrhea and vomiting (common symptoms of cancer treatments)
• These drugs were derived from the first poisonous gas used in warfare during World
War I
• The parent chemical is (was) called
“mustard gas”
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