Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Chemistry of Nucleotide Lecture PPT
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? Nucleotides are organic compounds made up
of a PO4 group, nitrogenous base & a sugar
molecule.
? These are the building blocks of nucleic acids
(DNA and RNA).
? They serve as sources of chemical energy
(ATP, GTP), participate in cellular signalling
(cAMP, cGMP) and function as important
cofactors of enzymatic reactions (CoA, FAD,
FMN, NAD+).
Functions of nucleotide
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
used in synthesis of lactose, UDP-Glucose in
synthesis of Glycogen.
3. As components of coenzyme:- NAD, FAD,
CoA.
4. As biological regulators:- as second
messenger cAMP. participate in cellular
signalling
.
5. As an energy source:-ATP as universal currency
of energy in biological system.
6. Conjugation reaction:- UDP-Glucuronic acid
forms the urinary glucuronide conjugate of
bilirubin and of many drug including aspirin.
7. In biosynthesis of lipids:- CDP-Choline, CDP-
Glycerol, CDP-ethonalamine are involved in
phospholipid synthesis.
8. As active donor molecule:- S-adenosyl
methionine as methyl donor, PAPS as sulfate
donor, ATP as phosphate donor.
.
9. As an allosteric regulator:- GTP in protein
synthesis.
10. In treatment of diseases:-
5- flurouracil ? Cancer
Allopurinol - Gout
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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
The purine bases
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present in RNA and DNA are
the same; - adenine and guanine.
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.
.
? These bases may be found in small amounts in
nucleic acids and hence called minor bases.
? These are hypoxanthine (6-oxopurine) and
Xanthine (2, 6-di-oxopurine).
.
? Uric acid (2,6,8-tri-oxopurine) is formed as the
end product of the catabolism of other purine
bases.
? It can exist in the "enol" as well as "keto"
forms (tautomeric forms).
.
PYRIMIDINE BASES
The pyrimidine bases present in nucleic acids
are cytosine, thymine and uracil.
1. Cytosine (2 deoxy,4 amino pyrimidine) is
present in both DNA and RNA.
.
,
MODIFIED PYRIMIDINE BASES
.
? A few other modified pyrimidine bases like
dihydrouracil and 5-methyl cytosine are also
found rarely in some types of RNA.
.
MODIFIED BASES
5 hydroxy methyl cytosine ? bacteriophages,
viral nucleic acids
5-methyl cytosine ? bacteria and human DNA
Dimethylated adenine & 7- methyl guanine ?
m RNAs
Theophylline ? 1,3 dimethyl xanthine
Theobromine ? 3,7 dimethyl xanthine
Caffeine- 1,3,7 trimethyl xanthine
METHYLATED HETEROCYCLIC PLANT
DERIVATIVES
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NUCLEOSIDES
? Nucleosides are formed when bases are
attached to the pentose sugar, D-ribose or 2-
deoxy-D-ribose.
? 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
.
? All the bases are attached to the corresponding pentose
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
NUCLEOTIDES
.
? These are phosphate esters of nucleosides.
? Base plus pentose sugar plus phosphoric acid is a
nucleotide
? Nucleotides are Polyfunctional Acids
? 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
approximately two or more units above or below
neutrality.
NUCLEOTIDES
? The esterification occurs at the 5th or 3rd hydroxyl group
of the pentose sugar.
? Most of the nucleoside phosphates involved in biological
function are 5'-phosphates.
? Figure : Structure of ATP
NUCLEOTIDES
? Since 5'-nucleotides are more often seen, they
are simply written without any prefix.
? For example, 5'-AMP is abbreviated as AMP;
but 3' variety is always written as 3'-AMP.
? Many co-enzymes are derivatives of adenosine
monophosphate.
? Examples are NAD+, NADP, FAD and Co-
enzyme A.
ATP (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 reaction
? ATP donates phosphate for a variety of phosphotransferase
reactions e.g., hexokinase reaction.
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 dehydrogenase.
ADENOSINE MONO PHOSPHATE (AMP)
? In the glycolytic pathway, the enzyme
phosphofructokinase is inhibited by ATP but
the inhibition is reversed byAMP.
? 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.
.
? cAMP act as second messenger for calcitonin,
corticotrophin, epinephrine, FSH TSH,LH,MSH
etc.
? It enhances glycogenolysis and lipolysis
? Increases acid secretion from gastric mucosa
? Dispersion of melanin pigment
? Aggregation of platelets
ADENOSINE 3'-PHOSPHATE-5'-
PHOSPHOSULFATE (PAPS)
? sulfate donor for sulfated proteoglycans and for
sulfate conjugates of drugs;
S- ADENOSYLMETHIONINE (SAM)?
METHYL DONAR
URIDINE NUCLEOTIDES
? 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.
? When UTP activates a substrate, UDP-substrate is
usually formed and inorganic phosphate is released.
UDP-glucose enters the synthesis of glycogen.
? UTP is used in the metabolism of galactose, where
the activated form UDP-galactose is converted to
UDP-glucose
? UDP-glucuronate is used to conjugate bilirubin to a
more water-soluble bilirubin diglucuronide
UDP ROLE IN GLYCOGEN SYNTHESIS
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CONJUGATION OF BILIRUBIN
CYTIDINE NUCLEOTIDES
? CDP- choline, CDP-glycerol and CDP
ethanolamine are involved in the biosynthesis
of phospholipids
? CMP-acetyl neuraminic acid is an important
precursor of cell-wall polysaccharides in
bacteria.
C GMP
? c-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.
? cGMP serves as a second messenger in
response to nitric oxide (NO) during relaxation
of smooth muscle
INOSINE MONOPHOPHATE
? Hypoxanthine ribonulcleotide, usually
called IMP is a precursor of all purine
nucleotide synthesized de-novo
? Inosinate can also be formed by
deamination of AMP, a reaction which
occurs particularly in muscles as a part of
purine nucleotide cycle.
SYNTHETIC ANALOGUES OF BIOMEDICAL
IMPORTANCE
? Synthetic
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.
.
? Toxic effects reflect either inhibition of
enzymes essential for nucleic acid
synthesis or their incorporation into
nucleic acids with resulting disruption of
base-pairing
APPLICATIONS
6- thio- guanine and 6 mercaptopurine Structural
analogues of inosine and guanine
5-FU and 5-Iodouracil Thymine or thymidine
analogues
used in cancer chemotherapy
Azapurine, Azacytidine, 8 Azaguanine ? cancer
chemothearpy
Allopurinol- inhibitor of xanthinine oxidase, used in
hyperuricemia and gout
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Cytarabine (Arabinose replaces ribose)
Vidarabine ? nucleoside analogue
cancer chemothearpy and viral infection
Azathiopurine catabolized to 6-mercaptopurine
organ transplantation
5 iodo deoxy uridine herpes keratitis
Aminophylline and theophylline- CAMP
levels, Used as bronchodilators
Acyclovir ? guanosine attached to incomplete
ribose herpes simplex
POLYNUCLEOTIDES
? The 5-phosphoryl group of a mononucleotide
can esterify a second -OH group, forming a
phosphodiester.
? The second -OH group is the 3-OH of the
pentose of a second nucleotide.
? 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.
.
? Phosphodiesterases rapidly catalyze the
hydrolysis of phosphodiester bonds
whose spontaneous hydrolysis is an
extremely slow process. Consequently,
DNA persists for considerable periods
and has been detected even in fossils.
WHY UV RAYS ARE MUTAGENIC?
? Nucleotides and nucleic acids absorb light at a
wavelength of 260 nm; this aspect is used to
quantitate them.
? As nucleic acids absorb ultraviolet light,
chemical modifications are produced leading to
mutation and carcinogenesis.
This post was last modified on 30 November 2021