nucleotide chemistry - basics

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NUCLEIC ACID CHEMISTRY Nucleic acid structure basics. Basics about DNA. How DNA is organized. RNA in detail.

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Page 1: Nucleotide Chemistry - Basics

NUCLEIC ACID CHEMISTRY• Nucleic acid structure basics.• Basics about DNA.• How DNA is organized.• RNA in detail.

Page 2: Nucleotide Chemistry - Basics

Why Nucleic acid chemistry ??

Page 3: Nucleotide Chemistry - Basics

1. Basic Nucleic acid structure1.1 Nitrogenous base1.2 Sugars1.3 Nucleoside

2. Nucleotide 2.1Properties of nucleotide2.2 Functions2.3 Synthetic Nucleotide Analogs

Page 4: Nucleotide Chemistry - Basics

1. BASIC NUCLEIC ACID STRUCTURE POLYMERS of NUCLEOTIDES

↓ Held by 5’ and 3’ SUGAR PHOSPHATE BRIDGES

Page 5: Nucleotide Chemistry - Basics

NUCLEOTIDE - SPLIT UP

Page 6: Nucleotide Chemistry - Basics

1.1 NITROGENOUS BASE - Aromatic heterocyclic compounds PURINE PYRIMIDINE

Page 7: Nucleotide Chemistry - Basics

PURINES - Pyrimidine ring + Imidazole ring.

Page 8: Nucleotide Chemistry - Basics
Page 9: Nucleotide Chemistry - Basics

PYRIMIDINES – One of the 3 isomer forms of

DIAZINE(C4H4N2).

Page 10: Nucleotide Chemistry - Basics
Page 11: Nucleotide Chemistry - Basics

Some properties of nitrogenous bases

- Weak Bases: Purines and Pyrimidines with NH2 in their structure act as weak bases.

- Planar character: facilitates the close association or stacking that stabilizes thew structure of nucleic acids.

- Tautomerism

Page 12: Nucleotide Chemistry - Basics

TAUTOMERISM• Heterocyclic rings of nitrogenous bases with oxo

groups exhibit keto(Lactam) enol(lactim) Tautomerism.

Page 13: Nucleotide Chemistry - Basics
Page 14: Nucleotide Chemistry - Basics

PROPERTY PURINE PYRIMIDINE

Numbering Counterclockwise Clockwise

Melting and Boiling points

Higher Lower

Glycosidic linkage with the sugar

N present on 9th position forms

glycosidic linkage.

N present on 1st position forms glycosidic linkage.

Biosynthesis Cytoplasm Cytoplasm+Mitochondria

End product of metabolism

Uric acid CO2, NH3

Page 15: Nucleotide Chemistry - Basics

MINOR/UNUSUAL BASES

• DNA and RNA contain small quantities of

Minor/modified bases also

- Methylation

- Hydroxymethylation

- Glycosylation

- Alteration of atoms.

Page 16: Nucleotide Chemistry - Basics

• Modification of Adenine:

N-methyladenine,

N6N6- dimethyladenine

• Modification of Guanine:

7-methylguanine

• Modification of Cytosine:

5-methylcytosine

5-hydroxymethylcytosine

Page 17: Nucleotide Chemistry - Basics

• Modification of Uracil:

Dihydroxyuracil

• Special Bases:

Hypoxanthine (6-oxopurine)

Xanthine (2,6-dioxopurine)

Uric acid (2,6,8-trioxopurine)

Page 18: Nucleotide Chemistry - Basics
Page 19: Nucleotide Chemistry - Basics
Page 20: Nucleotide Chemistry - Basics

Purine bases of plants

• Plants contain certain methylated purines.

- Caffeine (1,3,7-trimethylxanthine):

It is found in coffee, It acts as a stimulant of nervous

system.

- Theophylline (1,3-dimethylxanthine):

Present in tea leaves. It acts as a bronchial smooth

muscle relaxant.

Page 21: Nucleotide Chemistry - Basics

1.2 SUGARS - Ribose (in RNA) and Deoxyribose (in DNA). - Ribose and deoxyribose predominantly exist in

the cyclic form.

Page 22: Nucleotide Chemistry - Basics

1.3 NUCLEOSIDE

- Derivatives of sugar linked to ring Nitrogen of Purine or Pyrimidine .

- Linkage is formed by -N-glycosidic bond. SUGAR N9 of PURINE SUGAR N1 of PYRIMIDINE

Page 23: Nucleotide Chemistry - Basics

ADENOSINE

Page 24: Nucleotide Chemistry - Basics
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2. NUCLEOTIDE

• Mononucleotides are Nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar.

• Additional phosphoryl groups, ligated by acid anhydride bonds to the phosphoryl group of a mononucleotide, form nucleoside diphosphates and triphosphates.

Page 26: Nucleotide Chemistry - Basics
Page 27: Nucleotide Chemistry - Basics

BASES NUCLEOSIDES NUCLEOTIDES

Adenine (A) Adenosine Adenosine 5’-triphosphate (ATP)

Deoxyadenosine Deoxyadenosine 5’-triphosphate (dATP)

Guanine (G) Guanosine Guanosine 5’-triphosphate (GTP)

Deoxyguanosine Deoxy-guanosine 5’-triphosphate (dGTP)

Cytosine (C) Cytidine Cytidine 5’-triphosphate (CTP)

Deoxycytidine Deoxy-cytidine 5’-triphosphate (dCTP)

Uracil (U) Uridine Uridine 5’-triphosphate (UTP)

Thymine (T) Thymidine/Deoxythymidie

Thymidine/deoxythymidie 5’-triphosphate (dTTP)

Page 28: Nucleotide Chemistry - Basics

• Nucleoside bases common in DNA and RNA are highly conjugated molecules, a property with important consequences for the structure, electron distribution,and light absorption of nucleic acids.

- Polyfunctional acids. - Absorption of UV light. - Syn and Anti Conformers.

2.1 PROPERTIES OF NUCLEOTIDES

Page 29: Nucleotide Chemistry - Basics

1. POLYFUNCTIONAL ACIDS

• Phosphoryl groups of nucleosides have pKa values of 1.0, thus contribute to the negative charge at physiologic pH.

• pKa values of the secondary phosphoryl groups are about 6.2 → proton donors or acceptors at pH values approximately 2 units ± NEUTRAL pH

Page 30: Nucleotide Chemistry - Basics

2. ABSORB U-V LIGHT• Conjugated double bonds of the purine and

pyrimidine bases are characterized by a strong absorption at wavelengths near 260 nm at neutral pH.

• Concentration is expressed as molar absorptivity at 260 nm.

Importance: - Helps in identification of nucleic acids. -The mutagenic effect of ultraviolet light is due to its absorption by nucleotides in DNA that results

in chemical modifications

Page 31: Nucleotide Chemistry - Basics
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3. SYN AND ANTI CONFORMERS

• Due to Steric hindrance by the heterocyclic ring there is no freedom of rotation about the -N-glycosidic bond.

• Both therefore exist as non inter convertible Syn or Anti conformers .

• Anti Conformers have more common occurrence

• SYN & ANTI CONFORMERS interconversion - cleavage & reformation of the glycosidic bond.

Page 34: Nucleotide Chemistry - Basics
Page 35: Nucleotide Chemistry - Basics

i) Principal biologic transducer of free energy in metabolic inter conversions – ATP.

ATP ADP + Pi - Group Transfer Potential: ATP acts a donor of

phosphate group ATP + Creatinine Creatinine-P + ADP - Formation of a high energy intermediate: PPi – PYROPHOSPHATE. ATP AMP + PPi

2.2 NUCLEOTIDES – DIVERSE FUNCTIONS

Page 36: Nucleotide Chemistry - Basics

ii) Allosteric regulation and energy source for protein synthesis.

- GTP

iii) Second messenger for Hormones: - c-AMP for Glucagon - c-GMP for Nitric oxide in smooth muscle

relaxation

Page 37: Nucleotide Chemistry - Basics

c-AMP c-GMP

Page 38: Nucleotide Chemistry - Basics

iv) Carbohydrate metabolism: UDP-glucose and UDP- galactose participate in

sugar inter conversions and in the biosynthesis of - Starch, glycogen

- Glucosyl disaccharides, - Oligosaccharides of glycoproteins - Proteoglycans. UDP-Glucuronic acid forms the urinary

glucuronide conjugates of bilirubin and of many drugs like aspirin

Page 39: Nucleotide Chemistry - Basics

v) CTP participates in biosynthesis of: - Phosphoglycerides, - Sphingomyelin, - Substituted sphingosines.

vi) Lipid metabolism: Nucleoside-lipid derivatives such as CDP-acyl glycerol are intermediates in lipid biosynthesis.

Page 40: Nucleotide Chemistry - Basics

vii) Signal transduction pathways: - GTP and GDP play key roles in signal

transduction pathways.

viii) Coenzymes: - When linked to vitamins or vitamin

derivatives function as coenzymes e.g: Niacin, Pyridoxine, Pantothenic acid

derivatives, Coenzyme A.

Page 41: Nucleotide Chemistry - Basics

ix) Donor of various groups: a) 3'Phosphoadenosine -5'-phosphosulfate - Sulphate donor for proteoglycans and

sulfate conjugate of drugs.

.

Page 42: Nucleotide Chemistry - Basics

b) S-adenosylmethionine - Methyl donor in various metabolic reactions in Liver

Page 43: Nucleotide Chemistry - Basics

2.3 SYNTHETIC NUCLEOTIDE ANALOGS • Modifications in Heterocyclic ring or in the

Sugar moiety SYNTHETIC ANALOG.

Incorporation into nucleic acids with resulting disruption of base-pairing

Inhibition of enzymes essential for nucleic -

acid synthesis

Page 44: Nucleotide Chemistry - Basics

1) Cancer chemotherapy: Incorporated into DNA prior to cell division. 5-fluoro- or 5-iodouracil, 5-iodo-2’-deoxyuridine, 6-mercaptopurine, 6-thioguanine 6-azauridine,8-azaguanine, Cytarabine etc.

APPLICATIONS OF SYNTHETIC ANALOGS

Page 45: Nucleotide Chemistry - Basics
Page 46: Nucleotide Chemistry - Basics
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Page 48: Nucleotide Chemistry - Basics

2) Suppresion of Organ transplant rejection: - Azathioprine

3) Viral Diaseases: - Arabynosyladenoisine for Encephalitis. - Zidovudine for HIV infection.

Page 49: Nucleotide Chemistry - Basics

4) Metabolic diseases: Allopurinol - It is structurally similar to hypoxanthine,

inhibits the enzyme activity of XANTHINE OXIDASE.

- Used in treatment of hyper uricemia and gout.

Page 50: Nucleotide Chemistry - Basics
Page 51: Nucleotide Chemistry - Basics

POLYNUCLEOTIDE CHAINBASE SEQUENCE OF NUCLEIC ACID