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Biochemistry of Medicinals I – Nucleic Acids PowerPoint PPT Presentation


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Biochemistry of Medicinals I – Nucleic Acids. Instructor : Natalia Tretyakova, Ph.D. 760E CCRB (Cancer Center) Tel. 6-3432 e-mail [email protected] Lecture : MWF 2:30-3:20 7-135 WDH Web page : see “Web enhanced courses”. Chapter 1. DNA Structure.

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Biochemistry of Medicinals I – Nucleic Acids

Instructor: Natalia Tretyakova, Ph.D.

760E CCRB (Cancer Center)

Tel. 6-3432

e-mail [email protected]

Lecture: MWF 2:30-3:20 7-135 WDH

Web page: see “Web enhanced courses”


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Chapter 1. DNA Structure.

Required reading: Stryer 5th Edition p. 117-125, 144-146, 152, 745-750,

754-762, 875-877)

(or Stryer’s Biochemistry 4th edition p. 75-77,80-88, 119-122, 126-128,

787-799, 975-980)


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DNA Structure: Chapter outline

  • Biological roles of DNA. Flow of genetic information.

  • Primary and secondary structure of DNA.

  • Types of DNA double helix. Sequence-specific DNA recognition by proteins.

  • Biophysical properties of DNA.

  • DNA topology. Topoisomerases.

  • Restriction Endonucleases. Molecular Cloning


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(ribonucleic acids)

(deoxyribonucleic acids)

replication

transcription

translation

DNA


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Why ?

  • Questions?

    • How is genetic information transmitted to progeny cells?

    • How is DNA synthesis initiated?

    • What causes DNA defects and what are their biological an physiological consequences?

    • What causes the differences between cells containing the same genetic information?

  • Relevance:

    • •Cancer: ex. Xeroderma pigmentosum

    • •Genetic diseases: ex., cystic fibrosis, sickle cell anemia, inborn errors of metabolism

    • •Genetic typing: ex., drug metabolism

    • •Rational drug design: ex., antitumor and antimicrobial drugs

    • •Biotechnology: ex., growth hormones


  • The building blocks of dna l.jpg

    The Building Blocks of DNA

    -N-glycosidic bond


    Dna and rna nucleobases l.jpg

    DNA and RNA nucleobases

    (DNA only)

    (RNA only)


    Purine nucleotides l.jpg

    Purine Nucleotides


    Pyrimidine nucleotides l.jpg

    Pyrimidine Nucleotides


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    nucleobase

    (Deoxy)

    nucleoside

    5’-mononucleotide

    Adenine (A)

    Guanine (G)

    Thymine (T)

    Cytosine (C)

    Uracil (U)

    2’-Deoxyadenosine (dA)

    2’- Deoxyguanosine (dG)

    2’- Deoxythymidine

    (dT)

    2’- Deoxycytidine

    (dC)

    Uridine (U)

    Deoxyadenosine 5’-monophosphate

    (5’-dAMP)

    Deoxyguanosine 5’-monophosphate

    (5’-dGMP)

    Deoxythymidine 5’-monophosphate

    (5’-dTMP)

    Deoxycytidine 5’-monophosphate

    (5’-dCMP)

    Uridine 5’-monophosphate (5’-UMP)

    Nomenclature of nucleobases, nucleosides, and mononucleotides


    Structural differences between dna and rna l.jpg

    Structural differences between DNA and RNA

    DNA

    RNA


    Preferred conformations of nucleobases and sugars in dna and rna l.jpg

    Preferred conformations of nucleobases and sugars in DNA and RNA

    Sugar puckers:

    5.9 A

    7.0 A


    Nucleosides must be converted to 5 triphosphates to be part of dna and rna l.jpg

    Nucleosides Must Be Converted to5’-Triphosphates to be Part of DNA and RNA


    Dna is arranged 5 to 3 connected by phosphates l.jpg

    DNA isArranged5’ to 3’Connected byPhosphates

    Linking inDNA biopolymer: DNA primary structure


    Dna secondary structure double helix l.jpg

    DNA secondary structure – double helix

    • James Watson and Francis Crick, 1953- proposed a model for DNA structure

      • DNA is the molecule of heredity (O.Avery, 1944)

      • X-ray diffraction (R.Franklin and M. Wilkins)

      • E. Chargaff (1940s) G = C and A = T in DNA

    Francis CrickJim Watson


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    Watson-Crick model of DNA was based on X-ray

    diffraction picture of DNA fibres

    (Rosalind Franklin and Maurice Wilkins)

    Rosalind Franklin


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    Watson-Crick model of DNA was consistent with Chargaff’s base composition rules

    Erwin Chargaff (Columbia University)

    G = C and A = T in DNA


    Dna is composed of complementary strands l.jpg

    DNA is Composed of Complementary Strands


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    Base Pairing is Determined by Hydrogen Bonding

    same size


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    Base stacking: an axial view of B-DNA


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    Forces stabilizing DNA double helix

    • Hydrogen bonding (2-3 kcal/mol per base pair)

    • Stacking (hydrophobic) interactions

    • (4-15 kcal/mol per base pair)

    • 3. Electrostatic forces.


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    B-DNA

    • •Sugars are in the 2’ endo conformation.

    • •Bases are the anti conformation.

    • •Bases have a helical twist of 36º

    • (10.4 bases per helix turn)

    • Helical pitch = 34 A

    23.7 A

    right handed helix

    • helical axis passes through

    • base pairs

    7.0 A

    • planes of bases are nearly

    • perpendicular to the helix axis.

    • 3.4 A rise between base pairs

    Wide and deep

    Narrow and deep


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    DNA can deviate from the ideal Watson-Crick structure

    • Helical twist ranges from 28 to 42°

    • Propeller twisting 10 to 20°

    • Base pair roll


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    Major groove and Minor groove of DNA

    N

    NH

    O

    2

    N

    H

    N

    O

    2

    N

    NH

    N

    N

    N

    HN

    C-1’

    N

    N

    N

    N

    C-1’

    NH

    O

    O

    2

    C-1’

    Hypothetical situation: the two grooves would have similar size if dR residues

    were attached at 180° to each other

    To deoxyribose-C1’

    C1’ -To deoxyribose

    C-1’


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    N

    NH

    2

    H

    N

    O

    2

    N

    N

    HN

    C-1’

    N

    N

    NH

    O

    2

    C-1’

    Major and minor groove of the double helix

    O

    N

    NH

    N

    N

    N

    N

    C-1’

    O

    C-1’

    Wide and deep

    Narrow and deep


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    B-type duplex is not possible for RNA

    steric “clash”


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    A-form helix:dehydrated DNA; RNA-DNA hybrids

    • •Sugars are in the 3’ endo conformation.

    • •Bases are the anti conformation.

    • •11 bases per helix turn

    • Helical pitch = 25.3 A

    Right handed helix

    • planes of bases are tilted

    • 20 ° relative the helix axis.

    • 2.3 A rise between base pairs

    25.5 A

    Top View


    The sugar puckering in a dna is 3 endo l.jpg

    The sugar puckering in A-DNA is 3’-endo

    5.9 A

    7.0 A


    A dna has a shallow minor groove and a deep major groove l.jpg

    A-DNA has a shallow minor groove and a deep major groove

    Helix axis

    A-DNA

    B-DNA


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    Z-form double helix:polynucleotides of alternating purines and pyrimidines (GCGCGCGC) at high salt

    • • Backbone zig-zags because sugar puckers alternate between 2’ endo pyrimidines and 3’ endo (purines)

    • • Bases alternate between anti (pyrimidines) and syn conformation (purines).

    • •12 bases per helix turn

    • Helical pitch = 45.6 A

    Left handed helix

    • planes of the bases are

    • tilted 9° relative the helix

    • axis.

    • 3.8 A rise between base pairs

    18.4 A

    •Flat major groove

    •Narrow and deep minor groove


    Sugar and base conformations in z dna alternate l.jpg

    Sugar and base conformations in Z-DNA alternate:

    5’-GCGCGCGCGCGCG

    3’-CGCGCGCGCGCGC

    C:sugar is 2’-endo, base is anti

    G: sugar is 3’-endo, base is syn


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    Biological relevance of the minor types of DNA secondary structure

    • Although the majority of chromosomal DNA is in B-form,

    • some regions assume A- or Z-like structure

    • Runs of multiple Gs are A-like

    • The upstream sequences of some genes contain

    • 5-methylcytosine = Z-like duplex

    • Structural variations play a role in DNA-protein interactions

    • RNA-DNA hybrids and ds RNA have an A-type structure


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