Dr Stuart Conway Organic Option II ... - University of Oxfordconway.chem.ox.ac.uk/Teaching_files/Handout 1.pdfDr Stuart Conway Organic Option II: Chemical Biology University of Oxford

Dr Stuart Conway Organic Option II: Chemical Biology University of Oxford

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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


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Information flow in cells

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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

• How does DNA in genes direct the synthesis of RNA and protein?

• How is DNA replicated?

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The central dogma of molecular biology

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• Solid lines indicate the genetic information transfers that occur in all cells.

• Dotted lines indicate special transfers.

• The structure of DNA and RNA

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The structure of DNA and RNA

• 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

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• It is possible that this chemical stability is why DNA has evolved to be the store of genetic information.

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• The nitrogen bases are planar, aromatic and heterocyclic.

• They are usually either purine or pyrimidine derivatives.


• The major purine components of nucleic acids are adenine and guanine.

• The purines form glycosidic bonds to ribose via their N9 atoms.


• 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.

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• Some DNAs contain bases that are derivatives of the standard set.

• The structure of DNA and RNA

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Nucleotide: adenosine monophosphate (R = OH in RNA and H in DNA)

Nucleoside: adenosine (R = OH in RNA and H in DNA)

Base: adenine


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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.

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• 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

• 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.

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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

• 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.

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Complementary base pairing

• 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.

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Hydrogen bonding

• 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

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• Consequently, there is an optimum orientation for H-‐ bonding.

Hydrogen bonding

• 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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Complementary base pairing

• 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.

NN

NH

HN

NX N

NH

O CH3

XOHN

N

ON

NX N

N

N

XON

H

HH

HHdonor

acceptor

acceptor

donor

acceptor

donor

donor acceptor

donor

acceptor

adenine thymine guanine cytosine

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DNA structure

• 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.

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RNA structure

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• Transfer RNA (see later) resembles an “L” shape, being made up of two short helical regions connected by a hinge.

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RNA structure

• 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.

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DNA replication

“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.

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Translation and transcription

• 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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Dr Stuart Conway Organic Option II ... - University of Oxfordconway.chem.ox.ac.uk/Teaching_files/Handout 1.pdfDr Stuart Conway Organic Option II: Chemical Biology University of Oxford

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