nucleotide chemistry

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NUCLEOTIDE CHEMISTRYBy: Prachand Man Singh RajbhandariBSc Medical Biochemistry ( Nobel College, Pokhara University, Nepal)MSc Medical Biochemistry (JN Medical College, KLE University, Belgaum)

Contents:IntroductionHistoryGeneral features of nucleotidesNomenclatureIndividual properties of basesClassificationSynthetic analogues of biomedical importance

IntroductionNucleotides areorganic compoundsmade up of aPO4 group, nitrogenous base & asugar molecule.

These are the building blocks ofnucleic acids(DNAandRNA).

They serve as sources of chemical energy (ATP, GTP), participate in cellularsignalling (cAMP,cGMP) and function as importantcofactorsof enzymatic reactions (coA,FAD,FMN,NAD+).

HISTORYIn 1869, Miescherdiscovered "nuclein" (DNA) in the cells from pus & later he separated it into a protein and an acid molecule. It came to known as nucleic acid after 1874.1926 , Levene proposed Tetra nucleotide theory which states that Nucleic acid consists of only 4 nitrides as it gives 4 diff nucleotides on hydrolysis.

In 1950, Erwin Chargaffshows that the four nucleotides are not present in nucleic acids in stable proportions.1957, Sir Alexander R.Todd of Cambridge University gave structure of nucleotide.

General features of nucleotides

SUGARSTwo main sugars

Present in furanose form

Lacks 2-OH groupBasesPurines : Adenine (A) Guanine (G) Pyrimidines :Cytosine (C)Uracil (U)Thymine (T) The bases are abbreviated by their first letters (A, G, C, T, U).The purines (A, G) occur in both RNA & DNA.Among the pyrimidines, C occurs in both RNA & DNA, butT occurs in DNA, and U occurs in RNA.DNA: A,G,C,TRNA: A,G,C,U

Some minor bases:

Minor bases of DNAMinor bases of RNA5-Methylcytidine occurs in DNA of animals and higher plants.N6-methyladenosine occurs in bacterial DNA.Nucleosides =Ribose/Deoxyribose + Bases

The bases are covalently attached to the 1 position of a pentose sugar ring, to form a nucleoside

Nucleotides = nucleoside + phosphate

A nucleotide is a nucleoside with one or more phosphate groups bound covalently to the 3rd or 5th hydroxyl group of pentose sugar. Most of nucleoside phosphate involve in biological function are 5- phosphates. Since 5- phosphates are most often seen, they are written without any prefix.

H

HRibonucleotideDeoxy-ribonucleotideNucleosideNOMENCLATURE:-Nucleosides phosphorylated on the 3 or 5 C of ribose are termed ; nucleoside 3- monophoshate & nucleoside 5- monophoshate.5 is by convention omitted when naming nucleotide.Abbrevations such as AMP, GTP denotes the phosphate is esterified to 5 of pentose.Additional phosphate group is attached to preexisting phosphate of mononucleotide , - nucleotide diphosphate ADP - nucleotide triphosphate ATP

Nucleotide nomenclature:

Nucleotide nomenclature:

Individual properties :-PROPERTIES OF PURINE BASES:-

Sparingly soluble in water

Absorb light in UV region at 260 nm. (detection & quantitation of nucleotides)

Capable of forming hydrogen bondProperties of pyrimidine bases :-Soluble at body pH

Also absorb UV light at 260 nm

Capable of forming hydrogen bondPyrimidine base :-Aromatic base atoms are numbered 1 to 6 for pyrimidine

Atoms or group attached to base atoms have same number as the ring atom to which they are bonded

Cytosine :-Chemically is 2-oxy ,4-amino pyrimidine

Exist both lactam or lactim form

Thymine :-Chemically is 2,4 dioxy ,5-methyl pyrimidine

Occurs only in DNA

URACIL :-Chemically is 2,4 dioxy pyrimidine

Found only in RNA

PURINE BASES :-Aromatic base atoms numbered 1 to 9

Purine ring is formed by fusion of pyrimidine ring with imidazole ring

Numbering is anticlockwise

Adenine :-Chemically it is 6-aminopurine

Guanine :-Chemically is 2-amino,6-oxy purineCan be present as lactam & lactim form

CLASSIFICATION:Adenosine nucleotidesATP, ADP, AMP, Cyclic AMPGuanosine nucleotidesGTP, GDP, GMP, Cyclic GMPUridine nucleotidesUTP, UDP, UMP, UDP-GCytosine nucleotidesCTP, CDP, CMP and certain deoxy CDP derivatives of glucose, choline and ethanolamineMiscellaneous PAPS (active sulphate), SAM (active methionine), certain coenzymes like NAD+, FAD, FMN, Cobamide coenzyme, CoA ADENOSINE CONTAINING NUCLEOTIDESATP (ADENOSINE TRIPHOSPHATE)Many synthetic reactions requires energy, e.g. arginosuccinate synthetase reaction in urea cycle.ATP is required for the synthesis of Phospho creatine from creatine, synthesis of FA from acetyl CoA, formation of glucose from pyruvic acid, etc.ATP is an important source of energy for muscle contraction, transmission of nerve impulses, transport of nutrients across cell membrane, motility of spermatozoa.ATP is required for the formation of active methionine, which is required for methylation reactionATP donates phosphate for a variety of phosphotransferase reactions e.g., hexokinase reaction.ATP IN UREA CYCLE:

ATP IN FA SYNTHESIS:

ATP IN PHOSPHORYLATION REACTIONS:

ATP IN SYNTHESIS OF SAM:

ADENOSINE DI PHOSPHATE (ADP)ADP plays an important role as a primary PO4 acceptor in oxidative phosphorylation and muscle contraction, etc

ADP is also important as an activator of the enzyme glutamate dehydrogenaseACTVATION OF GLUTAMATE DEHYDROGENASE

ADENOSINE MONO PHOSPHATE (AMP)In the glycolytic pathway, the enzyme phosphofructokinase is inhibited by ATP but the inhibition is reversed by AMP.AMP can also act as an inhibitor of certain enzymes like fructose-1-6- bisphosphatase and adenylosuccinate synthetase.In resting muscles, AMP is formed from ADP, by adenylate kinase, the AMP produced activates the phosphorylase b enzyme of muscle and increase breakdown of glycogen.AMP ROLE IN REGULATION

URIDINE NUCLEOTIDES UTP also has the role of a source of energy or an activator of substrates in metabolic reactions, like that ofATP, but more specific.When UTP activates a substrate, UDP-substrate is usually formed and inorganic phosphate is released.UDP-glucoseenters the synthesis ofglycogen. UTP is used in the metabolism ofgalactose, where the activated formUDP-galactoseis converted to UDP-glucoseUDP-glucuronateis used to conjugate bilirubinto a more water-solublebilirubin diglucuronideUDP ROLE IN GLYCOGEN SYNTHESIS

CONJUGATION OF BILIRUBIN

UDP ROLE IN GALACTOSE METABOLISM

CYTIDINE NUCLEOTIDES

41Miscellaneous :-PAPS - Phospho Adenosine Phospho Sulphate(active sulphate) formed in liverSulfates enzymes which catalyze introduction of SO4 group In biosynthesis of chondroitin sulfateFormation of sulpholipids

SAM:- S- Adenosyl MethionineActive methionine

TRANSMETHYLATION REACTIONSPHOSPHO ADENOSINE PHOSPHO SULPHATE

SYNTHESIS OF GAGS FROM PAPS

C AMP

Contd.Cyclic AMP mediated activation cascade

C GMP

FUNCTIONSc-GMP is second messenger in photo transduction in the eyes.It has been claimed that c-GMP as second messengers regulate the closing and opening of Na+ channels. In the dark there are high levels of c-GMP which bind to Na+ channels causing them to open. Reverse occur in light.

INOSINE MONOPHOPHATEHypoxanthine ribonulcleotide, usually called IMP is a precursor of all purine nucleotide synthesized de-novoInosinate can also be formed by de amination of AMP, a reaction which occurs particularly in muscles as a part of purine nucleotide cycleSYNTHETIC ANALOGUES OF BIOMEDICAL IMPORTANCESynthetic analogues of nucleobases, nucleosides and nucleotides are recently of wide use in medical sciences and clinical medicine.The heterocyclic ring structure or the sugar moiety is altered in such a way as to induce toxic effects when the analogues get incorporated into cellular constituents of the body.

TheophyllineAzathiopurineAzapurineSOME IMPORTANT SYNTHETIC DERIVATIVES52

Allopurinol is a purine analogue. This drug is an inhibitor of the enzyme xanthine oxidase, which inhibit uric acid formation. The drug is widely used for the treatment of gout AZT-(azydothymidine):- thymidine analogue treatment of AIDS (terminates DNA synthesis catalysed by reverse transcriptase of retrovirus such as HIV)Uses of some Synthetic analogues of nucleotides:-NUCLEOSIDE ANALOGUES AS DRUGSANALOGUES DRUGSUSESDeoxyadenosine analogues

Didanosine, VidarabineHIVChemotherapyDeoxycytidine analogues

Cytarabine, EmtricitabineLamivudineZalcitabine

ChemothrapyHIVHepatitis BHIVDeoxyguanosine analogues

Abacavir EntecavirHIVHepatitis BDeoxy-thymidineanalogues

StavudineTelbivudine ZidovudineHIVHepatitis BHIVDeoxyuridine analogues

IdoxuridineTrifluridineHIVHIVNUCLEOTIDE ANALOGUES AS DRUGSTenofovir, also called 'prodrug. It is approved in the USA for the treatment of both HIV and hepatitis B.

Adefovir, has trade names Preveon and Hepsera. It was not approved by the FDA for treatment of HIV due to toxicity issues, but a lower dose is approved for the treatment of hepatitis B.

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