Download Incomplete handout - the Conway Group

Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
Organic Chemistry Option II: Chemical Biology Dr Stuart Conway Department of Chemistry, Chemistry Research Laboratory, University of Oxford email: [email protected] Teaching webpage (to download hand-­‐outs): http://conway.chem.ox.ac.uk/Teaching.html Recommended books: Biochemistry 4th Edition by Voet and Voet, published by Wiley, ISBN: 978-­‐0-­‐470-­‐57095-­‐1. Foundations of Chemical Biology by Dobson, Gerrard and Pratt, published by OUP (primer) ISBN: 0-­‐19-­‐924899-­‐0 1
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
Information flow in cells slide 7 •
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We must understand this process in order to harness it for exploration of biological problems. The central dogma of molecular biology slide 8 •
How does DNA in genes direct the synthesis of RNA and protein? •
How is DNA replicated? •
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Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The central dogma of molecular biology slide 9 •
• Solid lines indicate the genetic information transfers that occur in all cells. • Dotted lines indicate special transfers. •
The structure of DNA and RNA slide 10 •
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Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 12 •
Nucleotides are phosphate esters of pentose (furanose) sugars. • Deoxynucleotides lack the hydroxyl group at the 2’ position of the sugar ring. • A nitrogen-­‐containing base is linked to the 1’-­‐position of the sugar. The structure of DNA and RNA slide 13 •
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It is possible that this chemical stability is why DNA has evolved to be the store of genetic information. 4
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 14 •
The nitrogen bases are planar, aromatic and heterocyclic. • They are usually either purine or pyrimidine derivatives. The structure of DNA and RNA •
The major purine components of nucleic acids are adenine and guanine. • The purines form glycosidic bonds to ribose via their N9 atoms. The structure of DNA and RNA slide 16 •
slide 15 The major pyrimidine components of nucleic acids are cytosine, uracil and thymine (5-­‐methyluracil). • Uracil occurs mainly in RNA whereas thymine occurs mainly in DNA. • The pyrimidines form glycosidic bonds to ribose via their N1 atoms. 5
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 17 •
Some DNAs contain bases that are derivatives of the standard set. •
The structure of DNA and RNA slide 18 6
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 19 Nucleotide: adenosine monophosphate (R = OH in RNA and H in DNA) Nucleoside: adenosine (R = OH in RNA and H in DNA) Base: adenine The structure of DNA and RNA •
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The phosphate groups bridge the 3’-­‐ and 5’-­‐positions of successive sugar residues. •
The phosphate groups are deprotonated at physiological pH, hence nucleic acids are polyanions in the cell. •
slide 20 7
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 21 •
Nucleic acids were first isolated in 1869 and the presence of these molecules in cells was demonstrated a few years later. •
In the 1930s and 1940s it was widely believed that nucleic acids had a monotonously repeating sequence of all four bases = the so called “tetranucleotide hypothesis”. •
It was generally assumed that genes, known to be carriers of genetic information, were proteins. •
See Biochemistry pages 85-­‐89 to see the experiments that proved DNA is the carrier of genetic information. The structure of DNA and RNA slide 22 •
Erwin Chargaff was the first to show that DNA contains equal numbers of adenine and thymine residues (A = T) and equal numbers of cytosine and guanine residues (C = G). •
These relationships are known as “Chargaff’s rules”. •
Although not specifically stated by Chargaff, this observation suggests some form of base pairing in the (then unknown) structure of DNA. 8
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
The structure of DNA and RNA slide 25 •
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The planes of the bases are nearly perpendicular to the helix axis. •
Each base is hydrogen bonded to a base on the opposite strand to form a planar base pair. Complementary base pairing slide 26 •
The most remarkable feature of the Watson and Crick structure is that it can accommodate only two types of base pairs. •
Each adenine residue must pair with a thymine residue and vice versa. 9
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
Complementary base pairing slide 27 •
Each guanine residue must pair with a cytosine residue and vice versa. •
The geometries of these A:T and G:C pairs , the so-­‐called Watson-­‐Crick base pairs, mean that these base pairs are interchangeable in the double helix. 10
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
Hydrogen bonding slide 28 •
Hydrogen bonds are one of the most important non-­‐covalent interactions in biological systems. •
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There is a significant electrostatic component to H-­‐bonding. Hydrogen bonding slide 29 •
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Consequently, there is an optimum orientation for H-­‐ bonding. Hydrogen bonding slide 30 •
The optimum angle for H-­‐bonding is where the X-­‐H bond points directly to the lone pair, such that the angle is 180°. •
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Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
Complementary base pairing slide 31 N
X
N
H
N H donor
acceptor O
N acceptor
donor H N
N
adenine
X
acceptor N
N H donor
H
guanine
acceptor O
X
thymine
N
N
N
X
cytosine
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The H-­‐bond donor and acceptor patterns are such that A can only bind to T and G can only bind to C. •
As A can only bind to T and G can only bind to C, we can immediately understand Chargaff’s rules. •
In addition, the Watson-­‐Crick structure allows for any sequences of bases on one polynucleotide strand if the opposite strand has the complementary sequence. •
This structure also suggests that hereditary information is encoded in the sequence of bases on either strand. O
N H donor
N
CH3
N
H
O acceptor
H
donor H N
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Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
DNA structure advanced slide 32 & 33 •
DNA has three major helical forms, B-­‐DNA, A-­‐DNA and Z-­‐DNA. •
B-­‐DNA is the biologically predominant form of DNA it forms a right-­‐handed helix with major and minor grooves. •
When relative humidity is reduced to 75%, B-­‐DNA undergoes a reversible conformational change to A-­‐DNA. •
A-­‐DNA forms a wide, flatter helix than B-­‐DNA. •
The base pairs of A-­‐DNA are tilted 20 ° with respect to the helix axis. •
Certain DNA sequences can form a left-­‐handed helix that has been called Z-­‐DNA. •
It is not clear whether Z-­‐DNA has any biological significance -­‐ it may play a role in regulating DNA transcription. 13
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
RNA structure slide 34 •
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Transfer RNA (see later) resembles an “L” shape, being made up of two short helical regions connected by a hinge. •
RNA structure slide 35 •
Hydrogen bonding in helical RNA occurs between cytosine and guanine as in DNA. •
Cytosine is replaced by uracil, which forms complementary hydrogen bonds with adenine. 14
Dr Stuart Conway
Organic Option II: Chemical Biology
University of Oxford
DNA replication slide 36 “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for genetic material.” •
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In this process, mediates by DNA polymerase enzymes, each DNA strand acts as a template for the formation of its complementary strand. •
Consequently, every progeny cell contains a complete copy of the DNA from the parent cell. •
Mutations arise when, through rare copying errors, one or more wrong bases are incorporated into a daughter strand. •
DNA replication is a highly complex process. •
Translation and transcription slide 37 & 38 •
DNA directs its own replication and transcription to yield RNA, which is translated to form proteins. •
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“Translation” indicates that the “language” changes from that of the base sequence to that of the amino acid sequence. •
Individual portions of a DNA molecule provide the information for the construction of various RNA molecules and proteins. •
RNA corresponding to the region of interest id produced by transcription (the synthesis of an RNA strand from a DNA template). The RNA produced in this case is called messenger RNA or mRNA. •
This mRNA is then translated when molecules of transfer RNA (tRNA) align with the mRNA via complementary base pairing between segments of three consecutive nucleotides (codon). •
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