Nucleotides

BIOMEDICAL IMPORTANCE • Building blocks of nucleic acids• Part of many coenzymes • Donors of

– Phosphoryl groups (eg, ATP or GTP)– Sugars (eg,UDP- or GDP-sugars)– Lipid (eg, CDP-acylglycerol)

• Regulatory nucleotides – cAMP and cGMP

• Control of oxidative phosphorylation– by ADP

• Allosteric regulation of enzyme activity– by ATP, AMP, and CTP

BIOMEDICAL IMPORTANCE

• For therapy – Chemotherapy of cancer and AIDS– Suppressors of the immune response during organ

transplantation

Classification

• PURINES• PYRIMIDINES• NUCLEOSIDES• NUCLEOTIDES

Tautomerism of the oxo and amino

keto-enol and amine-imine tautomerism

• Nucleoside– Diphosphates – Triphosphates

• The sugar moiety – D-ribose or 2-deoxy-Dribose

• Nucleoside triphosphates– have high group transfer potential• Participate in covalent bond syntheses.

• Cyclic phosphodiesters – cAMP and cGMP • Intracellular second messengers

Ribonucleosides

Additional phosphorylgroups linked by acid anhydride bonds

The syn and anti conformers of adenosine differ with respect to orientation about the N-glycosidic bond.

Bases, nucleosides, & nucleotides.

Nucleic Acids Also Contain Additional Bases

• 5-methylcytosine • 5-hydroxymethylcytosine• Mono- and di-N-methylated adenine &

guanine – Mammalian messenger RNAs

uncommon naturally occurring pyrimidines and purines.

• Function – Oligonucleotide recognition – Regulating the half-lives of RNAs

• Free nucleotides – Hypoxanthine, xanthine, and uric acid – Intermediates in the catabolism

Posttranscriptional modification

• Pseudouridine (Ψ)

• Methylation by S-adenosylmethionine of a UMP of preformed tRNA forms TMP

Nucleotides Serve DiversePhysiologic Functions

• Protein synthesis• Nucleic acid synthesis• Regulatory cascades• Signal transduction pathways

Physiologic functions

• As precursors of nucleic acids • Transducer of free energy– ATP

• The second messenger – cAMP

• Adenosine 3 -phosphate-5 -phosphosulfate ′ ′• Methyl group donor

3 -phosphate-5 -phosphosulfate (PAPS)′ ′

S-Adenosylmethionine

Uridine diphosphate glucose (UDPGlc).

• Energy source for protein synthesis– GTP

• UDP-sugar derivatives – Sugar epimerizations– Biosynthesis of glycogen, glucosyl disaccharides,

and the oligosaccharides of glycoproteins and proteoglycans

• UDP-glucuronic acid.– Conjugation• Bilirubin • Drugs

• CTP – Biosynthesis of phosphoglycerides – Sphingomyelin

• Coenzymes

Many coenzymes and related compounds are derivatives of adenosine monophosphate.

Flavin adenine dinucleotide (FAD).

Nicotinamide adenine dinucleotide (NAD).* Shows the site of phosphorylation in NADP.

* Shows the site of acylation by fatty acids.

• Nucleotides Are Polyfunctional Acids• Nucleotides Absorb Ultraviolet Light – Close to 260 nm

SYNTHETIC NUCLEOTIDE ANALOGSARE USED IN CHEMOTHERAPY

• Altered in– Heterocyclic ring– The sugar moiety

• Inhibition of enzymes – Treatment of hyperuricemia

• Incorporation into nucleic acids

• Suppress immunologic rejection– Organ transplantation

POLYNUCLEOTIDES

• Linked by a 3 → 5 phosphodiester bond to ′ ′form the “backbone” of RNA and DNA

• RNAs are far less stable than DNA

• Polynucleotides Are Directional Macromolecule– “5 - end” or the “3 - end”′ ′– the 5 - end is at the left ′

Polynucleotides Have Primary Structure

• Base sequence– Compact notation• pGpGpApTpCpA • GGATCA

DNA Contains Four Deoxynucleotides

Double-stranded DNA

Formation of hydrogen bonds between complementary bases in double-stranded DNA

Base pairing

Supercoiling of DNA.

DNA Exists in Relaxed &Supercoiled Forms

Negative and positive supercoils.

extent of DNA packaging in metaphase chromosomes

Important structural elements of a yeast chromosome

• One of the hallmarks of living organisms is their ability to reproduce.

• DNA contains the genetic information

The interrelationship of DNA,RNA & Protein