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 importantcofactors of enzymatic reactions (CoA, FAD,
FMN, NAD+).
Functions of nucleotide
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1. As Nucleic Acid:- being the monomeric unitsthey 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 cellularsignalling
.
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 ofbilirubin and of many drug including aspirin.
7. In biosynthesis of lipids:- CDP-Choline, CDP-
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Glycerol, CDP-ethonalamine are involved inphospholipid synthesis.
8. As active donor molecule:- S-adenosyl
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methionine as methyl donor, PAPS as sulfatedonor, ATP as phosphate donor.
.
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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..
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..
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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 andGuanine 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 theend 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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.
,
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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 acids5-methyl cytosine ? bacteria and human DNA
Dimethylated adenine & 7- methyl guanine ?
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m RNAsTheophylline ? 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 areattached to the pentose sugar, D-ribose or 2-
deoxy-D-ribose.
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? The carbon atoms of the pentose sugar aredenoted 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.
? These are phosphate esters of nucleosides.
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? Base plus pentose sugar plus phosphoric acid is anucleotide
? 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 belowneutrality.
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 biologicalfunction 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 fromcreatine, 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 musclecontraction, 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,MSHetc.
? 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 anactivator 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 diglucuronideUDP 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 causingthem to open. Reverse occur in light.
? cGMP serves as a second messenger in
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response to nitric oxide (NO) during relaxationof 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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analoguesof
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 sugarmoiety 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..
? Toxic effects reflect either inhibition of
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enzymes essential for nucleic acidsynthesis 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 thymidineanalogues
used in cancer chemotherapy
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Azapurine, Azacytidine, 8 Azaguanine ? cancerchemothearpy
Allopurinol- inhibitor of xanthinine oxidase, used in
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hyperuricemia and gout
.
Cytarabine (Arabinose replaces ribose)
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Vidarabine ? nucleoside analoguecancer 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 pentosemoieties 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 toquantitate them.
? As nucleic acids absorb ultraviolet light,
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chemical modifications are produced leading tomutation and carcinogenesis.