Nucleic Acid , its chemistry, functions and pharmaceutical importance.pptx

a presentation on discovery, chemistry, structure, metabolism, disorders of nucleic acids in human body along with its pharmaceutical importance

1. Nucleic Acids Chemistry of

2. 01. Introduction TABLE of contents 02. Synthesis of Purine Bases 03. De-Novo Synthesis 07. Functions of Nucleotides 08. Biologically Important Nucleotides 09. Structure of Nucleic Acid 04. Salvage Pathway 10. Structure of DNA 11. Structure of RNA 05. Disorders 06. Synthesis of Pyrimidine Nucleotides 12. Biological & Pharmaceutical Importance

3. Introduction Discovered by Swiss physician Friedrich Meishcher in 1868. He isolated a new compound from nuclei of pus cells. Named it Nuclein . Discovery Nucleic acids Nucleic acids are biopolymers or large biomolecules essential to all known forms of life. Present in every living cell as well as viruses. Transmit genetic information Play central role in processes like cell division, protein synthesis, inheritance.

4. Introduction Types Components Both RNA and DNA are formed by joining together of nucleotide units or mononucleotides, each of which is nitrogenous base sugar phosphoric acid complex. ● Nitrogenous base ● Sugar ● Phosphoric acid

5. Introduction Nitrogenous base Purines Six membered ring fused to five membered imidazole ring. These are aromatic heterocyclic bases. Two types of nitrogenous bases are found in all nucleic acids. Purines Pyrimidines Adenine 6-amino purines Guanine 2-amino 6-oxypurine

6. Introduction Pyrimidine Six membered ring containing 2 nitrogen atoms. Cysteine 2-oxy 4-amino pyrimidine Thymine 5-methyl 2-4 dioxy pyrimidine Found in DNA Uracil 2,4-dioxy pyrimidine Found in RNA

7. Introduction Minor bases Pseudo-Uracil 5-methylcytosine

8. Synthesis of Purine Bases It takes place in liver . The sources of atoms of purine rings are: Amino acids (aspartic acid, glycine, glutamine) CO 2 Formyltetrahydrofolate Synthesis of purine is done by two pathways. De Novo Synthesis Salvage Pathway

9. De-Novo Synthesis

10. De-Novo Synthesis

11. De-Novo Synthesis

12. Salvage Pathway

13. Disorders Lesch-Nyhan Syndrome Rare,X-linked,recessive disorder. Deficiency of HGPRT Excessive amount of uric acid produced (hyperuricemia) Gouty arthritis It is characterized by: Motor dysfunction. Coginitive deficits Self mutilation

14. Synthesis of Pyrimidine Nucleotide The sources of atoms in pyrimidine ring are: ● Aspartic acid ● Glutamine ● CO2

15. INTRODUCTION OF SUGAR Sugar One posses D-2 deoxyribose, hence named deoxyribonucleic acid. The other posses D- ribose,hence named ribonucleic acid.

16. Synthesis of Nucleoside Phosphoric acid ● 3 monovalent hydroxyl groups ● A divalent oxygen atom ● Pentavalent phosphorus atom Nucleoside Nitrogenous bases are conjugated to pentose sugar(ribose or deoxyribose) by Beta -glycosidic linkage. Purine nucleosides are N-9 glycosides. Pyrimidine nucleosides are N-1 glycosides

17. Deoxyribo Nucleosides Ribonucleosides Deoxy Adenosine   Adenosine Deoxy Guanosine Guanosine Deoxy Cytidine   Cytidine Deoxy Thymidine Thymidine Deoxy Uracil Uridine Synthesis of Nucleoside

18. Deoxyribo Nucleotides Ribonucleotides Deoxy adenosine 5- mono phosphate ( dAMP )   Adenosine 5-Mono phosphate (AMP) Deoxy Guanosine 5-mono phosphate ( dGMP ) Guanosine 5-mono phosphate (GMP) Synthesis of Nucleotide Nucleotide : Phosphoric acid esters of nucleosides.

19. Deoxyribo Nucleotides Ribonucleotides Deoxy cytidine 5-mono phosphate ( dCMP ) Cytidine 5-mono phosphate (CMP) Deoxy thymadine 5-mono phosphate (dTMP) Uridine 5-mono phosphate (UMP) Synthesis of Nucleotide

20. Functions of Nucleotide Activated precursors of DNA and RNA. Energy carriers e.g., ATP,GTP Component of enzyme cofactors e.g., adenine nucleotide. Chemical messenger e.g., cAMP and cGMP. Activator of metabolic intermediates e.g., UDP glucose is precursor of glycogen.

21. Biologically Important Nucleotide 1-ATP Source of energy in metabolic pathways as: Fatty acid synthesis, gluconeogenesis, protein synthesis, cholesterol synthesis. Physiological functions: Muscle contraction, nerve impulse transmission. 2-AMP Component of coenzymes as: NAD+,FADH, coenzyme A.

22. Biologically Important Nucleotide 3- C-AMP (cyclic adenosine 3-5 monophosphate) Formed from ATP by action of adenylate cyclase. Acts as second messenger for hormones as : Epinephrine, glucagon, calcitonin, FSH, TSH, Vasopressin. Inhibit aggregation of platelets. Increase secretion of acid by gastric mucosa 4- GDP and GTP Convert Succinyl CoA to succinate. Required for activation of adenylate cyclase by some hormones.

23. Biologically Important Nucleotide 5- UDP ● Participate in glycogenesis. ● UDP glucose and galactose take part in galactose metabolism. ● Required for synthesis of lactose and cerebrosides ● UDP glucuronic acid is required in detoxification and synthesis of mucopolysaccharides such as heparin and hyaluronic acid.

24. Structure of a Nucleic Acid Nucleic Acid structure is often divided into four different levels: Primary structure Secondary structure Tertiary structure Quaternary structure Primary Structure Primary structure consists of a linear sequence of nucleotides that are linked together by phosphodiester bond.

25. Structure of a Nucleic Acid Secondary Structure This is the set of interactions between bases. In DNA double helix, the two strands of DNA are held together by hydrogen bonds. The nucleotides on one strand base pairs with the nucleotide on the other strand. The secondary structure is responsible for the shape that the nucleic acid assumes.

26. Structure of a Nucleic Acid Tertiary structure This is the locations of atoms in three- dimensional space, taking into consideration geometrical and steric constraits . A higher order than the secondary structure in which large scale folding in a linear polymer occurs and the entire chain is folded into a specific 3-dimensional shape.

27. Structure of a Nucleic Acid Quaternary Structure Quaternary structure refers to a higher level of organization of nucleic acids moreover, it refers interactions to of nucleic acids with other molecules.

28. Structure of DNA DNA is a very long, thread like macromolecule made up of a large number of deoxyribonucleotides. Deoxyribonucleotide is composed of a nitrogenous base , a sugar and phosphate group.

29. Structure of DNA Linkage Linked covalently by 3, 5’ phosphodiester bonds. The 3-hydroxyl group of the sugar moiety of one deoxyribonucleotide is joined to the 5’-hydroxyl group of the adjacent sugar moiety of deoxyribonucleotide by a phosphodiester linkage (Sugar Phosphate Backbone)

30. Structure of DNA The Watson-Crick DNA Double Helical Structure In 1953, James Watson and Francis Crick deduced the three- dimensional structure of DNA. The important features of their model are as follows: It consists of two helical polynucleotide chains wound around the same axis to form a right handed double Helix. The chains run in opposite direction (antiparallel) The purine and pyrimidine bases are on the inside of the helix, whereas the phosphate and deoxyribose units are on the outside.(sugar phosphate backbone) The diameter of the helix is 20 A. Adjacent bases are Separated by 3.4 Å along the helix axis and the helical structure repeats after ten residues on each chain i.e., at intervals of 34° A containing grooves of alternate size, known as major and minor grooves.

31. Structure of DNA Complementary The two chains are held together by hydrogen bonds between complementary pairs of bases: Adenine always paired with thymine by of two hydrogen bonds. Guanine always paired with cytosine by three hydrogen bonds Content of Adenine equals to thymine and guanine to that of cytosine proves chargaffs rule.

32. Structure of DNA Conformation of DNA double Helix The double Helical structure of DNA exists in at least 6 different forms-A to E and Z. Among these, B, A And Z forms are important. The B-form of DNA double helix, described by Watson and Crick (discussed above), is the most Predominant form under physiological Conditions.

33. Structure of DNA Triple-stranded DNA Triple stranded DNA formation may occur due to additional hydrogen bonds between the bases. Thymine can selectively form two Hoogsteen hydrogen bonds to the adenine of A-T pair to form T-A-T. Cytosine can also form two hydrogen bonds with guanine of G-C pairs that results in C-G-C. Triple helical structure is less stable than double helix. Due to three negatively charged backbone strands in triple helix results in an increased electrostatic repulsion.

34. Structure of RNA RNA is a polymer of ribonucleotides held together by 3’,5’-phosphodiester bridges. Single strand RNA is usually a single- stranded polynucleotide. Chargaff’s rule not obeyed.

35. Types of RNA The three major types of RNAs with their respective cellular composition are given below: Messenger RNA (mRNA) : 5-10% Transfer RNA (IRNA) : 10-20% Ribosomal RNA (RNA) : 50-80%

36. Messenger RNA The eukaryotic mRNA is capped at the 5’-terminal end by 7-methylguanosine triphosphate. It is believed that this cap helps to prevent the hydrolysis of mRNA by 5’-exo- nucleases. Further, the cap may be also involved in the recognition of mRNA for protein synthesis. The 3’-terminal end of mRNA contains a polymer of adenylate residues (20-250 nucleotides) which is known as poly (A) tail. This tail may provide stability to mRNA, besides preventing it from the attack of 3’-exonucleases.

37. Transfer RNA The structure of tRNA (for alanine) was first elucidated by Holley . The structure of tRNA, resembles that of a clover leaf. tRNA contains mainly four arms, each arm with a base paired stem. 1. The acceptor arm: This arm is capped with a sequence CCA (5’ to 3’). The amino acid is attached to the acceptor arm. 2. The anticodon arm: This arm, with the three specific nucleotide bases (anticodon), is responsible for the recognition of triplet codon of mRNA. The codon and anticodon are complementary to each other. 3. The D arm: It is so named due to the presence of dihydrouridine. 4. The TwC arm: contains both ribothymidine (T) and pseudouridine (ψ, psi) 5. The extra arm: is also known as variable arm because it varies in size, is found between the anticodon and TwC arms.

38. Transfer RNA tRNAs are classified into 2 categories: Class I tRNAs: The most predominant (about 75%) form with 3-5 base pairs length. Class II tRNAs : They contain 13-20 base pair long arm. Base pairs in tRNA: The four arms with their respective base pairs are given below The acceptor arm 7 bp The TVC arm -5 bp The anticodon arm 5 bp The D arm -4 bp

39. Ribosomal RNA The RNA of Ribosomes is called rRNA The ribosome is a spheroidal particle and is composed of a large and a small nucleoprotein subunit. Each subunit is composed of one or more strand of rRNA and numerous protein molecules

40. Biological Importance Genetic information storage Nucleic acid (DNA) are the only way a cell has to store information on its own and act as blueprint for building and developing organisms providing the necessary information for growth and development To transfer that information to its off Springs Main source of Energy and Physiological Functions These nucleotides are source of energy in several metabolic pathways, e.g. fatty acid synthesis, glycolysis, cholesterol synthesis, protein synthesis, etc and are essential for the metabolism of carbohydrate, lipid and protein.

41. Biological Importance DNA Fingerprinting used by forensic experts to determine paternity identification of criminals Genetic engineering and DNA recombinant technology It is a breakthrough in the treatment of genetic disease, production of antigens, antibodies, hormones (e.g., Insulin), and many other therapeutic agents, and also diagnostic reagents. It has become possible to find out defective genes leading to serious diseases even before birth by DNA studies on fatal cells obtained from amniotic fluid.

42. Pharmaceutical Importance Analogue An analogue is prepared either by altering the heterocyclic ring or sugar moiety. Chemically, synthesized analogues of purines and pyrimidines (nucleotides and nucleosides) used in the treatment of infections or in cancer chemotherapy are: Azathioprine It is a structural analogue of thymidine used in the treatment of acquired immunodeficiency syndrome (AIDS), a disease caused by the human immunodeficiency virus (HIV). It is used during organ transplantation to suppress events involved in immunologic rejection.

43. Pharmaceutical Importance Cytarabine The nucleoside cytarabine ( arabinosyl cytosine; ara -c) in which arabinose replaces ribose, is used in the chemotherapy of cancer and viral infections. The purine analogue allopurinol used in treatment of hyperuricemia and gout. 5-iododeoxyuridine it is a nucleoside analogue that has antiviral activity and is used in the treatment of herpetic keratitis, an infection of the cornea by Herpes virus. The pharmaceutical perspectives of Nucleic acid based therapy presents a comprehensive account of gene therapy, control gene regulation, transcription, translation and replication.