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 phosphoryl groups 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 Diverse Physiologic 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 ANALOGS ARE 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