Download MBBS Chemistry of Nucleotide Lecture PPT

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? Nucleotides are organic compounds made up

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of a PO4 group, nitrogenous base & a sugar
molecule.

? These are the building blocks of nucleic acids

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(DNA and RNA).

? They serve as sources of chemical energy

(ATP, GTP), participate in cellular signalling

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(cAMP, cGMP) and function as important
cofactors of enzymatic reactions (CoA, FAD,
FMN, NAD+).
Functions of nucleotide

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1. As Nucleic Acid:- being the monomeric units

they carry the genetic code as DNA and RNA

2. In Biosynthesis of sugar:- UDP-Galactose is

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used in synthesis of lactose, UDP-Glucose in
synthesis of Glycogen.

3. As components of coenzyme:- NAD, FAD,

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CoA.

4. As biological regulators:- as second

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messenger cAMP. participate in cellular
signalling
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5. As an energy source:-ATP as universal currency

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of energy in biological system.

6. Conjugation reaction:- UDP-Glucuronic acid

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forms the urinary glucuronide conjugate of
bilirubin and of many drug including aspirin.

7. In biosynthesis of lipids:- CDP-Choline, CDP-

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Glycerol, CDP-ethonalamine are involved in
phospholipid synthesis.

8. As active donor molecule:- S-adenosyl

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methionine as methyl donor, PAPS as sulfate
donor, ATP as phosphate donor.
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9. As an allosteric regulator:- GTP in protein

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synthesis.

10. In treatment of diseases:-
5- flurouracil ? Cancer

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Allopurinol - Gout


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Nucleotide bases in nucleic acids are pyrimidines or
purines. nitrogen-containing heterocycles, structures
that contain, in addition to carbon, other (hetero)
atoms such as nitrogen

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The purine bases

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present in RNA and DNA are

the same; - adenine and guanine.

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Adenine is 6-amino purine and
Guanine is 2-amino, 6-oxopurine.
The numbering of purine ring with structure of

adenine and guanine are shown in Figure.

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? These bases may be found in small amounts in

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nucleic acids and hence called minor bases.

? These are hypoxanthine (6-oxopurine) and

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Xanthine (2, 6-di-oxopurine).


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? Uric acid (2,6,8-tri-oxopurine) is formed as the

end product of the catabolism of other purine
bases.

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? It can exist in the "enol" as well as "keto"

forms (tautomeric forms).

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PYRIMIDINE BASES
The pyrimidine bases present in nucleic acids

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are cytosine, thymine and uracil.

1. Cytosine (2 deoxy,4 amino pyrimidine) is

present in both DNA and RNA.

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MODIFIED PYRIMIDINE BASES

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? A few other modified pyrimidine bases like

dihydrouracil and 5-methyl cytosine are also
found rarely in some types of RNA.

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MODIFIED BASES
5 hydroxy methyl cytosine ? bacteriophages,

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viral nucleic acids

5-methyl cytosine ? bacteria and human DNA
Dimethylated adenine & 7- methyl guanine ?

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m RNAs

Theophylline ? 1,3 dimethyl xanthine
Theobromine ? 3,7 dimethyl xanthine
Caffeine- 1,3,7 trimethyl xanthine

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METHYLATED HETEROCYCLIC PLANT

DERIVATIVES

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NUCLEOSIDES

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? Nucleosides are formed when bases are

attached to the pentose sugar, D-ribose or 2-
deoxy-D-ribose.

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? The carbon atoms of the pentose sugar are

denoted by using a prime number to avoid
confusion with the carbon atoms of the purine
or pyrimidine ring

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? All the bases are attached to the corresponding pentose

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sugar by a beta-N-glycosidic bond between the 1st carbon
of the pentose sugar and N9 of a purine or N1 of a
pyrimidine

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NUCLEOTIDES

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? These are phosphate esters of nucleosides.

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? Base plus pentose sugar plus phosphoric acid is a

nucleotide

? Nucleotides are Polyfunctional Acids

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? The phosphoryl groups of nucleosides have pKa - 1.0.
? Bear significant negative charge at physiologic pH
? pKa values of the secondary phosphoryl groups - 6.2
? serve as proton donors or acceptors at pH values

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approximately two or more units above or below
neutrality.


NUCLEOTIDES

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? The esterification occurs at the 5th or 3rd hydroxyl group

of the pentose sugar.

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? Most of the nucleoside phosphates involved in biological

function are 5'-phosphates.

? Figure : Structure of ATP

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NUCLEOTIDES

? Since 5'-nucleotides are more often seen, they

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are simply written without any prefix.

? For example, 5'-AMP is abbreviated as AMP;

but 3' variety is always written as 3'-AMP.

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? Many co-enzymes are derivatives of adenosine

monophosphate.

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? Examples are NAD+, NADP, FAD and Co-

enzyme A.

ATP (ADENOSINE TRIPHOSPHATE)

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? Many synthetic reactions requires energy, e.g.

arginosuccinate synthetase reaction in urea cycle.

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? ATP is required for the synthesis of Phospho creatine from

creatine, synthesis of FA from acetyl CoA, formation of
glucose from pyruvic acid, etc.

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? ATP is an important source of energy for muscle

contraction, transmission of nerve impulses, transport of
nutrients across cell membrane, motility of spermatozoa.

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? ATP is required for the formation of active methionine,

which is required for methylation reaction

? ATP donates phosphate for a variety of phosphotransferase

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reactions e.g., hexokinase reaction.
ADENOSINE DI PHOSPHATE (ADP)

? ADP plays an important role as a primary PO4

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acceptor in oxidative phosphorylation and
muscle contraction, etc

? ADP is also important as an activator of the

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enzyme glutamate dehydrogenase.
ADENOSINE MONO PHOSPHATE (AMP)

? In the glycolytic pathway, the enzyme

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phosphofructokinase is inhibited by ATP but
the inhibition is reversed byAMP.

? AMP can also act as an inhibitor of certain

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enzymes like fructose-1-6- bisphosphatase and
adenylosuccinate synthetase.

? In resting muscles, AMP is formed from ADP,

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by adenylate kinase, the AMP produced
activates the phosphorylase b enzyme of
muscle and increase breakdown of glycogen.

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? cAMP act as second messenger for calcitonin,

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corticotrophin, epinephrine, FSH TSH,LH,MSH

etc.

? It enhances glycogenolysis and lipolysis

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? Increases acid secretion from gastric mucosa
? Dispersion of melanin pigment
? Aggregation of platelets
ADENOSINE 3'-PHOSPHATE-5'-

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PHOSPHOSULFATE (PAPS)

? sulfate donor for sulfated proteoglycans and for

sulfate conjugates of drugs;

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S- ADENOSYLMETHIONINE (SAM)?
METHYL DONAR
URIDINE NUCLEOTIDES

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? UTP also has the role of a source of energy or an

activator of substrates in metabolic reactions, like

that of ATP, but more specific.

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? When UTP activates a substrate, UDP-substrate is

usually formed and inorganic phosphate is released.

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UDP-glucose enters the synthesis of glycogen.

? UTP is used in the metabolism of galactose, where

the activated form UDP-galactose is converted to

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UDP-glucose

? UDP-glucuronate is used to conjugate bilirubin to a

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more water-soluble bilirubin diglucuronide


UDP ROLE IN GLYCOGEN SYNTHESIS

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CONJUGATION OF BILIRUBIN
CYTIDINE NUCLEOTIDES

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? CDP- choline, CDP-glycerol and CDP

ethanolamine are involved in the biosynthesis
of phospholipids

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? CMP-acetyl neuraminic acid is an important

precursor of cell-wall polysaccharides in
bacteria.

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C GMP

? c-GMP is second messenger in photo

transduction in the eyes.

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? 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

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of c-GMP which bind to Na+ channels causing
them to open. Reverse occur in light.

? cGMP serves as a second messenger in

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response to nitric oxide (NO) during relaxation
of smooth muscle
INOSINE MONOPHOPHATE

? Hypoxanthine ribonulcleotide, usually

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called IMP is a precursor of all purine
nucleotide synthesized de-novo

? Inosinate can also be formed by

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deamination of AMP, a reaction which
occurs particularly in muscles as a part of
purine nucleotide cycle.
SYNTHETIC ANALOGUES OF BIOMEDICAL

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IMPORTANCE

? Synthetic

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analogues

of

nucleobases,

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nucleosides and nucleotides are recently of
wide use in medical sciences and clinical
medicine.

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? 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

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body.
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? Toxic effects reflect either inhibition of

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enzymes essential for nucleic acid
synthesis or their incorporation into
nucleic acids with resulting disruption of
base-pairing
APPLICATIONS

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6- thio- guanine and 6 mercaptopurine Structural

analogues of inosine and guanine

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5-FU and 5-Iodouracil Thymine or thymidine

analogues

used in cancer chemotherapy

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Azapurine, Azacytidine, 8 Azaguanine ? cancer

chemothearpy

Allopurinol- inhibitor of xanthinine oxidase, used in

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hyperuricemia and gout
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Cytarabine (Arabinose replaces ribose)

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Vidarabine ? nucleoside analogue
cancer chemothearpy and viral infection
Azathiopurine catabolized to 6-mercaptopurine

organ transplantation

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5 iodo deoxy uridine herpes keratitis
Aminophylline and theophylline- CAMP

levels, Used as bronchodilators

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Acyclovir ? guanosine attached to incomplete

ribose herpes simplex
POLYNUCLEOTIDES

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? The 5-phosphoryl group of a mononucleotide

can esterify a second -OH group, forming a
phosphodiester.

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? The second -OH group is the 3-OH of the

pentose of a second nucleotide.

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? This forms a dinucleotide in which the pentose

moieties are linked by a 3 5
phosphodiester bond to form the "backbone"
of RNA and DNA.

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? Phosphodiesterases rapidly catalyze the

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hydrolysis of phosphodiester bonds
whose spontaneous hydrolysis is an
extremely slow process. Consequently,
DNA persists for considerable periods

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and has been detected even in fossils.
WHY UV RAYS ARE MUTAGENIC?

? Nucleotides and nucleic acids absorb light at a

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wavelength of 260 nm; this aspect is used to
quantitate them.

? As nucleic acids absorb ultraviolet light,

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chemical modifications are produced leading to
mutation and carcinogenesis.