Download Nucleic Acids: Structure, Properties, and Functions Bases A G C T U

Nucleic Acids: Structure, Properties, and Functions
Bases
A
N
N
H
G
NH2
N
N
N
H
N
Adenine
N
TO
NH2
NH
Guanine
Purines
C
O
N
H
Cytosine
NH
NH
N
NH2
UO
O
N
H
O
Thymine
Pyrimidines
N
H
uridine
O
NH2
Nucleotides
N
O
-O
ATP: energy currency
GTP: involved in regulation
G-proteins
ATP, GTP, CTP, UTP:
Precursors for RNA
P
O-
O
O
P
O-
N
O
O
P
O
N
N
O
O-
H
H
OH
OH
H
H
Adenosine
Adenosine 5’-monophosphate
AMP
Adenosine 5’-diphosphate
ADP
Adenosine 5’-triphosphate
ATP
Deoxynucleotides
NH2
N
O
-O
P
O-
O
O
P
O-
N
O
O
P
O
N
O
O-
H
H
OH
H
H
dATP, dGTP, dCTP, dUTP:
Precursors for DNA
N
H
Deoxyadenosine
Deoxyadenosine 5’-monophosphate
dAMP
Deoxyadenosine 5’-diphosphate
dADP
Deoxyadenosine 5’-triphosphate
dATP
Poly(deoxy)nucleotide
DNA
RNA
Base pairing
3D-structure: Watson & Crick, 1953
DNA: double helix;
RNA: usually single-stranded, secondary structure
Representation of DNA (or genes)
5’
GACGCTGAATTCCGTCACGACTCCGGTTACGAAGTTCACCAC
CTGCGACTTAAGGCAGTGCTGAGGCCAATGCTTCAAGTGGTG
3’ D A E F R H D S G Y E V H H
CAGAAACTGGTTTTCTTCGCTGAAGACGTTGGTTCCAACAAA
GTCTTTGACCAAAAGAAGCGACTTCTGCAACCAAGGTTGTTT
Q K L V F F A E D V G S N K
3’
GGTGCTATCATCGGTCTGATGGTTGGTGGTGTTGTTATCGCT
CCACGATAGTAGCCAGACTACCAACCACCACAACAATAGCGA
5’
G A I I G L M V G G V V I A
Amyloid-beta peptide 1-42
UV spectroscopic properties, DNA melting
Different forms of double-stranded DNA
Circular DNA
DNA Functions
1. Template for DNA replication----heredity
2. Codes for all proteins (genes), all forms of RNA
3. Other biological information: such as transcription
signals and regulation signals of cellular processes
Drugs targeting DNA
1. Small molecule intercalation into the base pairs
Cancer chemotherapy
Anti-malaria
2. Alkylating agents
Alkylating agent-mitomycin
3. Cisplatin: DNA chelation
Steven Lippard, MIT
Testicular and ovarian tumors
chemotherapy
4. DNA cleavage
Sequence-specific
DNA cleavage:
Peter Dervan, Caltech
Sidney Hecht, Virginia Tech
Dai, W.-M. et al. J. Med. Chem. 2002
Disadvantages of DNA-targeting Drugs
1. Low specificity leads to severe side effects
2. Too reactive, destroy anything on the road, like endiynes
3. Sequence-specific DNA cleavage agents: ability to penetrate
cell membranes
Disruption of translation at the mRNA level
Transcription
Translation
×
Binding of small complementary RNA/DNA sequences to the mRNA
×
Disruption of translation at the mRNA level
1. Antisense oligonucleotides:
single-stranded, complementary to the target gene
2. Small double-stranded RNA:
RNA interference (RNAi), double-stranded, sequence is from target.
Movement of the mobile silencing signal in a GFP-expressing tobacco plant is visualized as a red trail where GFP
has been silenced, revealing red fluorescence of chlorophyll in the background of green fluorescence from GFP.
RNAi in Drosophila
Postulated RNAi C. elegans
1.
V. Vance1,H. Vaucheret. RNA Silencing in Plants—
Defense and Counterdefense, Science 292, 2001, 2277
2.
P. Ahlquist, RNA-Dependent RNA Polymerases,
Viruses, and RNA Silencing, Science 296, 2002, 1270
3.
R. H. A. Plasterk, RNA Silencing: The Genome’s
Immune System, Science 296, 2002, 1263
4.
M. Matzke, A. J. M. Matzke, J. M. Kooter, RNA:
Guiding Gene Silencing, Science 293, 2001, 1080
5.
P. D. Zamore, Ancient Pathways Programmed by Small
RNAs, Science 296, 2002, 1265
6.
M. Boutros, A. A. Kiger, S. Armknecht, K. Kerr, M.
Hild, B. Koch, S. A. Haas, H. Fly, Array Consortium,
R. Paro, N. Perrimon. Genome-Wide RNAi Analysis of
Growth and Viability in Drosophila Cells, Science
2004, 832-835.
More reading materials:
Li BJ et al. Using siRNA in prophylactic and therapeutic regimens
against SARS coronavirus in Rhesus macaque. Nat. Med. 2005; 11:
944–951.
Chang Z, Hu J. RNAi therapeutics: Can siRNAs conquer SARS?
Gene Ther. 2005, 871-872.
Watanabe T, Umehara T, Kohara M. Therapeutic application of RNA
interference for hepatitis C virus. Adv. Drug Deliv. Rev. 2007,
59(12):1263-76.
Scherer L, Rossi JJ, Weinberg MS. Progress and prospects: RNAbased therapies for treatment of HIV infection. Gene Ther. 2007,
14(14):1057-64.
Grimm D, Kay MA. Therapeutic application of RNAi: is mRNA
targeting finally ready for prime time? J. Clin. Invest. 2007,
117(12):3633-41.
Gewirtz AM. On future's doorstep: RNA interference and the
pharmacopeia of tomorrow. J. Clin. Invest. 2007, 117(12):3612-4.