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 NUCLEOTIDE

 It consist of a nitrogenous
base,a pentose & a
phosphate .The nitrogenous
bases found in nucleotide
are aromatic heterocyclic
compound. The bases are
of two types :

 PURINE

 PYRIMIDINE

 PURINES

 purine

 Metabolic pathway for the synthesis of IMP

· . The first purine product of this pathway, IMP (inosinic acid or inosine
monophosphate), serves as a precursor to AMP and GMP.

 Step 1: PRPP synthesis from ribose-5-phosphate and ATP by


ribose-5-phosphate pyrophosphokinase.

 Step 2: 5-Phosphoribosyl-b-1-amine synthesis from a-PRPP,


glutamine, and H2O by glutamine phosphoribosyl pyrophosphate
amidotransferase.

 Step 3: Glycinamide ribonucleotide (GAR) synthesis from glycine,


ATP, and 5-phosphoribosyl-b-amine by glycinamide ribonucleotide
synthetase.

 Step 4: Formylglycinamide ribonucleotide synthesis from N10-


formyl-THF and GAR by GAR transformylase.

 Step 9: 5-Aminoimidazole carboxamide ribonucleotide (AICAR)


formation by the nonhydrolytic removal of fumarate from SAICAR.
The enzyme is adenylosuccinase.

 Step 10: 5-Formylaminoimidazole carboxamide ribonucleotide


(FAICAR) formation from AICAR and N10-formyl-THF by AICAR
transformylase.

 Step 11: Dehydration/ring closure yields the authentic purine


ribonucleotide IMP. The enzyme is IMP synthase.

 Synthesis of AMP & GMP from IMP


 IMP is the immediate precursor for the formation of GMP & AMP

 Aspartate condenses with IMP in the presence of GTP to produce adenyl


succinate which on cleavage forms AMP.

 For the synhtesis of GMP,IMP undergoes NAD+ dependent


dehydrogenation to form XMP.

 Glutamine then transfers amide nitrogen to XMP to produce GMP.

 Degradation of purine nucleotides to uric acid

 The various nucleotides are first converted to nucleosides by the action of


nucleotidase

 The –NH2 group either from AMP or adenosine can be removed to produce
IMP or inosine respectively

 Inosine and Guanosine are respectively converted to hypoxanthine and


guanine (purine bases ) by phosphorylase.Adenosine is not degraded by
this enzyme hence it has to be converted to inosine

 Guanine undergoes deamination by guanase to form xanthine.

 Xanhine oxidase is an important enzyme that converts hypoxanthine to


xanthine,and xanhine to uric acid. This enzyme contains FAD.molybdenum
& irn,& is found in liver &

small intestine.Xanhine oxidase liberates H2O2 to H2O & O2

URIC ACID

It is the final excretory product of purine metabolism in humans.It can serve as


an important antioxidant by itself getting converted to allantoin

 Normal conc. Of uric acid:

3-7 mg/dl (men )

1 mg/dl (women)

 Daily excretion of uric acid : 500-700 mg

 Disorders of Purine metabolism

 HYPERURICEMIA
It refers to an elevation in the serum uric acid

conc.This is sometimes associated with increased uric acid excretion (uricosuria

GOUT

It is a metabolic disease associated with overproduction of uric acid.At


physiological pH,uric acid is found in a more soluble form as sodium urate.In
severe hyperuricemia,crystals of sodium urate get deposited in the soft
tissue,particurly in the joints Such deposits are commonly known as tophi.This
causes inflammation in the joints resulting in a painful gouty arthitis

PSUEDO GOUT

It is caused by the deposition of calcium pyrophosphate crystals in joints

 Type of purine receptor

 There are two main families of purine receptors, adenosine or P1


receptors, and P2 receptors, recognizing primarily ATP, ADP, UTP,
and UDP.

 Adenosine/P1 receptors have been further subdivided, according


to convergent molecular, biochemical, and pharmacological
evidence into four subtypes, A1, A2A, A2B, and A3, all of which
couple to G proteins.

 Based on differences in molecular structure and signal


transduction mechanisms, P2 receptors divide naturally into two
families of ligand-gated ion channels and G protein-coupled
receptors termed P2X and P2Y receptors, respectively; to date
seven mammalian P2X receptors (P2X1–7) and five mammalian
P2Y receptors(P2Y1,2,4,6,11)

 Location

 peripheral tissues having been localized in vas deferens, testis, white


adipose tissue, stomach, spleen, pituitary, adrenal, heart, aorta, liver, eye,
and bladder

 Only very low levels of A1 mRNA are present in lung, kidney, and small
intestine

 Signal transduction

 1)inhibition of adenylate cyclase causing a decrease in the second-


messenger cAMP This in turn modulates the activity of cAMP-dependent
protein kinase, which phosphorylates diverse protein targets.
 A1 coupling to adenylate cyclase has been described in a number of
tissues including brain, adipose tissue, and testes.

 2)activation of phospholipase C (PLC) leading to membrane


phosphoinositide metabolism and increased production of IP3 and
DAG and Ca2+ mobilization.).

 3)IP3stimulates the release of Ca2+ from intracellular stores via


interactions with specific receptors located on the sarcoplasmic
reticulum.

 4)Elevation of cytosolic Ca2+ by IP3 can stimulate a variety of


signaling pathways, including a family of phosphatidyl serine-
dependent serine/threonine-directed kinases collectively called
PKC , phospholipase A2, Ca2+-dependent K+ channels, and nitric
oxide synthase (NOS).

 Depletion of Ca2+ from IP3-sensitive pools may promote Ca2+


influx from extracellular sources.

 Activation of K+ATP channels mediates a reduction in


action potential duration, vasodilatation and an increase in
blood flow, which is consistent with their having a pivotal
role in the coupling of vascular tone to metabolic demand
determined both by intracellular purines (ATP/ADP levels)
and by the extracellular actions of adenosine (released, for
instance, during hypoxia or ischemia).

 Neurons express multiple K+ channels that A1 receptors may couple to


regulate membrane potential and determine action potential frequency
and duration. A1 receptors reduce neuronal excitability and decrease
firing rate by a hyperpolarizing effect mediated mainly by an increase in
K+ conductance

 Agonist

 Certain N6-substituted adenosine derivatives, such as N6-


cyclopentyladenosine (CPA), N6-cyclohexyladenosine (CHA), and R-PIA,
are selective agonists at A1 receptors

 Antagonist

 1,3-dipropyl-8-phenyl(2-amino-4-chlo) xanthine.

 Non xanthine antagonists, including the triazoloquinazolines),


imidazoquinolines

 Biological function
 It is now well established that adenosine is released from
biological tissues during hypoxia and ischemic conditions.

 One of its effects is to reduce neuronal activity and thereby


oxygen consumption; thus it acts as a neuroprotective agent.

 A1 receptors are located pre and postsynaptically on cell bodies,


and on axons, where they mediate inhibition of neurotransmission
by decreasing transmitter release, hyperpolarizing neuronal
membranes, reducing excitability and firing rate, and altering
axonal transmission.

 Adenosine can also exert behavioral effects: adenosine actions at


A1 receptors have been implicated in sedative, anticonvulsant,
anxiolytic, and locomotor depressant effects

 A1 receptors mediate cardiac depression through negative


chronotropic, dromotropic, and inotropic effects

 Slowing of the heart rate occurs via A1 receptors on sinoatrial and


atrioventricular nodes causing bradycardia and heart block,
respectively.

 The inotropic effects include a decrease in atrial contractility and


action potential duration

 This aspect of A1 receptor-mediated effects has found application


in the clinical use of adenosine to treat supraventricular
tachycardia, and in the use of adenosine receptor antagonists in
the treatment of bradyarrhythmias

 In the kidney, activation of A1 receptors mediates diverse effects including


vasoconstriction (principally of the afferent arteriole), a decrease in
glomerular filtration rate, mesangial cell contraction, inhibition of renin
secretion, and inhibition of neurotransmitter release,

 Intravenous and intra-aortic administration of adenosine in rats decrease


water and sodium excretion via A1 receptors, while selective antagonism
of A1 receptors causes diuresis and natriuresis

 Adenosine acts via A1 receptors and inhibition of cAMP to inhibit lipolysis


and increase insulin sensitivity in adipose tissue

 Abnormal A1 receptor function in genetic obesity has been proposed,


showing that lipolysis is less active and A1 receptor signaling more active,
which may be caused by changes in receptor phosphorylation, but also
possibly by adenylate cyclase activity,
 .In contrast, insulin sensitivity is decreased by activation of A1 receptors in
skeletal muscle A1 receptors on pancreatic β cells mediate inhibition of
insulin secretion

 A2A receptor

Location

 immune tissues

 platelets

 CNS

 vascular smooth muscle

 endothelium.

 Signal transduction

 The most commonly recognized signal transduction mechanism for A2A


receptors is activation of adenylate cyclase. This implies coupling with the
G protein Gs, although other G proteins may also be involved

 In striatal nerve terminals, A2A receptors are suggested to mediate dual


signaling via P- and N-type Ca2+ channels linked to Gs/adenylate
cyclase/PKA and cholera toxin-insensitive G protein/PKC, respectively .

 It has been suggested that A2Areceptor-mediated inhibition of superoxide


anion generation in neutrophils may be mediated via cAMP-independent
activation of a serine/threonine protein phosphatase

 Antagonist

 8-(3-chlorostyryl)caffeine (CSC)

 (3,7-dimethyl-1-propargylxanthine)

 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo [2,3-α] [1,3,5]triazin-5-yl


amino]ethyl)phenol)

 A2B receptor

 LOCATION

 caecum, large intestine, and urinary bladder

 lower levels in the brain, spinal cord, lung, vas deferens, and pituitary in
the eye, lung, uterus, and bladder; aorta, stomach, testis, and skeletal
muscle; and the lowest levels in the jejunum, kidney, heart, skin, spleen,
and liver
 Signal transduction

 activation of adenylate cyclase, Gq/G11-mediated coupling to PLC and IP3-


dependent increase in [Ca2+]i (in human mast cells)

 Agonist

 N6-(3-iodobenzyl)-5′-(N-methylcarbamoyl)adenosine (IB-MECA)

 R-PIA

 Biological function

 vasodilatation in both smooth muscle and endothelium

A1 & A2 receptors are blocked by xanthine.

It inhibits cyclic neucleotide PDEs. PDEs catalyse the breakdown of cAMP & cGMP
to 5’-AMP & 5’-GMP respectively.Inhibition of PDEs will lead to accumilation of
cAMP & cGMP, thereby increasing the signal transduction througe this pathway.

Adenosine does not directly contract human isolated bronchial smooth muscle
but when inhaled act as a potent bronchoconstrictor in asthmetic subjects.

 Signal transduction

 stimulates PLC and elevates IP3 levels and intracellular Ca2

 To inhibit adenylate cyclase activity

 Location

 testis, lung, kidneys, placenta, heart, brain, spleen, liver, uterus, bladder,
jejunum, proximal colon, and eye of rat, sheep, and humans

 Agonist

 N6-substituted adenosine-5′-uronamides. N6-benzylNECA

 Antagonist

 (3-(4-methoxyphenyl)-5-amino-7-oxo-thiazolo [3, 2]pyrimidine)

 Biological function

 The A3 receptor on mast cells facilitates the release of allergic mediators


including histamine, suggesting a role in inflammation

 receptors on human eosinophils (and human promyelocytic HL-60 cells


seem to be involved in apoptosis, an active self-destructive process
caused by a genetically programmed cascade of molecular events
involving DNA degradation and death of the cell by nuclear and
cytoplasmic breakup

 P2 receptors are divided into two main classes based on

whether they are ligand-gated ion channels (P2X receptors)

or are coupled to G proteins (P2Y receptors)

 P2X Receptor

 LOCATION

 vas deferens,

 urinary bladder,

 vascular smooth muscle, and to mediate contraction;

 Signal transduction

 P2X receptors mediate the rapid (onset within 10 ms) non-selective


passage of cations (Na+, K+, Ca2+) across the cell membrane
resulting in an increase in intracellular Ca2+ and depolarization

 Cloned P2X receptor

1. P2X1 receptor.

 The P2X1receptor has been cloned from rat vas deferens and human and
mouse urinary bladder

 The recombinant receptor is activated by 2MeSATP ≥ ATP > α,β-meATP ≫


ADP

 Inward currents evoked by these compounds are reversibly blocked by


suramin and PPADS

 The receptor desensitizes very rapidly (in hundreds of milliseconds).

 P2X1 receptor mRNA is expressed in urinary bladder, smooth muscle


layers of small arteries and arterioles, and vas deferens, with lower levels
in lung , spleen ,dorsal root ganglia, trigeminal ganglia, coeliac ganglia,
spinal cord, and rat brain

2.P2X2 receptor

 P2X2 receptor mRNA is distributed in bladder, brain, spinal cord, superior


cervical ganglia, adrenal medulla, intestine, and vas deferens, with highest
levels found in the pituitary gland and vas deferens
 The P2X2receptor first cloned from rat pheochromocytoma PC12 cells
(originally called P2XR1 )

 3. P2X3 receptor.

 The P2X3receptor cloned from rat dorsal root ganglion.

 The P2X3 receptor is activated by agonists with a potency order of


2MeSATP ≫ ATP > α,β-meATP and undergoes rapid desensitization (in less
than 100 ms).

4. P2X4 receptor.

 The P2X4 receptor protein has been cloned from rat hippocampus, DRG
cells rat and human brain as well as rat endocrine tissue

 The recombinant P2X4 receptor is most potently activated by 2MeSATP,

 The P2X4 receptor does not desensitize rapidly, although reversible


rundown of the current occurs during prolonged

 5. P2X5 receptor.

 This P2X receptor was first cloned from rat coeliac ganglia).

 Rapid inward currents are activated by ATP > 2MeSATP > ADP,
whereas α,β-meATP is ineffective as an agonist.

 The receptor does not readily desensitize.

 6. P2X6 receptor.

 This clone was isolated from a rat superior cervical ganglion cDNA library

 1. CNS.

 P2X receptors are widely distributed in the CNS; excitation and activation
of cation channels by ATP and/or α,β-meATP have been described
throughout the brain and spinal cord

 ATP acts as a fast excitatory transmitter in the brain

 2. Sensory nerves.

 Rapid inward currents are mediated by ATP in the dorsal horn of the spinal
cord and there is evidence for P2X receptor-mediated fast synaptic
transmission via ATP in a small subset of dorsal horn neurons

 Glutamate evoked release after activation of P2X receptors on dorsal root


ganglion neurons indicates a role for presynaptic P2X receptors

3. PNS
 receptors in pheochromocytoma cells that mediate NA and dopamine
release

 4. Smooth muscle.

 ATP neurotransmission in the PNS identifies a physiological role for P2X


receptors on smooth muscle, and as mediators of excitatory junction
potentials (EJPs), depolarization, and constriction (Burnstock, 1990;
Burnstock and Ralevic, 1996). The postjunctional response of the vas
deferens, and most blood vessels to sympathetic nerve stimulation, is a
rapid EJP that is blocked by tetrodotoxin, guanethidine,

 P2Y RECEPTOR

 1.P2Y1 RECEPTOR

 LOCATION

 heart, vascular, connective, immune, and neural tissues. The transcript for
chick brain P2Y1 mRNA is distributed in brain,

 Signal transduction

 activates PLCβ isoenzymes via its α subunit Insensitivity or partial


sensitivity to pertussis toxin is characteristic of most endogenous P2Y1-
like receptors coupled to PLC, indicating the involvement of Gq/11
proteins. In contrast, P2Y1-like receptors coupled to inhibition of adenylate
cyclase are typically blocked by pertussis toxin, indicating an involvement
of Gi proteins

 IP3 formation and Ca2+mobilization can stimulate a variety of signaling


pathways including PKC, PLA2, Ca2+-dependent K+ channels, NOS and
subsequent endothelium-derived relaxing factor (EDRF) formation, and
can generate endothelium-derived hyperpolarizing factor (EDHF).

 The main physiological target of DAG is stimulation of PKC, which in turn


may stimulate phosphatidyl choline-specific PLC, PLD, the MAPK pathway,
and Ca2+ influx via voltage-operated Ca2+ channels

 Biological function

 metabolic effects include insulin secretion from pancreatic β-cells,

 renin secretion in renal cortical slices

 glycogenolysis in rat hepatocytes

 vasodilation

 2.P2Y2 RECEPTOR
 LoCATION

 spleen, testes, kidney, liver, lung, heart, and brain

 Signal transduction

 Cloned P2Y2 and endogenous P2Y2-like receptors couple via both Gi/o and
Gq/11 proteins to mediate phospholipid breakdown and phosphoinositides
as well as Ca2+ mobilization via PLCβ

 Secondary to activation of PLC and mobilization of Ca2+, the P2Y2-like


receptor mediates the opening of Ca2+-sensitive Cl− channels in airway
epithelia

 Biological function

 they stimulate the synthesis and release of prostacyclin and NO, leading
to vasodilatation

 Smooth muscle contraction mediated equipotently by UTP and ATP may


indicate P2Y2-like receptors,

 PEPTIDE

 molecules of fewer than 50 amino acid residues are called peptides, larger
molecules being proteins.

 Neural and endocrine mediators range in size from 3 to over 200 residues.
Cytokines, chemokines and growth factors are generally larger than 100
residues.

 Most known peptide mediators come from the nervous system and
endocrine organs. However, some are formed in the plasma, and many
occur at other sites (e.g. vascular endothelium, heart, cells of the immune
system, etc.). The same peptide may occur in several places and serve
different functions

 Types of peptide mediator

The soluble peptide mediators in the body, which are secreted by cells and act
on surface receptors of other cells, can be very broadly divided into four groups:

 neurotransmitters and neuroendocrine mediators:

 hormones from non-neural sources: plasma-derived peptides, notably


angiotensin ,bradykinin and substances such as ( insulin endothelin atrial
natriuretic peptide and leptin

 growth factors: produced by many different cells and tissues and control
cell growth and differentiation
 mediators of the immune system: (cytokines and chemokines )

 Comparision of peptide with conventional transmitters

 The mechanisms for the storage and release and the receptor
mechanisms through which their effects are produced are
essentially the same for peptide and non-peptide transmitters,

 the main difference being that the vesicles are loaded with
peptide precursors in the cell body, the active peptides being
generated within the vesicles as they move to the nerve
terminals.

 Having undergone exocytosis, the vesicles cannot be reloaded in


situ but must be replaced with new pre-loaded vesicles.
Transmitter turnover is, therefore, less rapid than with
conventional mediators.

 recapture of the released mediators does not occur as it does with amine
and amino acid mediators

 peptides do not activate ligand-gated ion channels and, therefore, do not


function as fast neurotransmitters in the manner of non-peptides, such as
acetylcholine, glutamate, glycine or gamma-aminobutyric acid

 they serve mainly as neuromodulators by activating G-protein-coupled


receptors.

 The main difference is constitutional rather than functional and stems


from the fact that peptides, being gene products, represent variations on a
single theme-a linear string of amino acids . Such sequences are much
more susceptible to evolutionary change than are the structures of non-
peptide mediators

 Cellular mechanism for peptide synthesis and release

Proteins synthesised by ribosomes are threaded through the


membrane of the rough endoplasmic reticulum, from where they are
conveyed via transport vesicles to the Golgi apparatus.

 Here they are sorted and packaged into secretory vesicles.

 Processing (cleavage, glycosylation, amidation, sulfation, etc.)


occurs within the transport and secretory vesicles, and the
products are released from the cell by exocytosis.

 Constitutive secretion (e.g. secretion of plasma proteins, clotting


factors, etc. by liver cells) occurs continuously,

 and little material is stored in secretory vesicles.


 Regulated secretion, (e.g. neurosecretion or cytokine secretion) occurs in
response to increased intracellular Ca2+ levels or other intracellular
signals, and material is typically stored in significant amounts in an
accumulation of secretory vesicles

 Synthesis of peptide mediator

 The coding regions of the gene (exons) are transcribed and spliced to give
rise to mRNA, segments of which (blue) are translated to produce
preprohormones.

 Cleavage of the N-terminal signal peptide produces the prohormone, from


which endopeptidases excise peptide fragments.

 These may be active as such or they may undergo further post-


translational processing (amidation etc.).

 PEPTIDE NEUROTRANSMITTERS

1.Vasopressin

2.Oxytocin

3.Neurotensin

4Tachykinins

Substance P

NK-A &NK-B

5.VIP

6.Opiod peptide

B-endorphin

Dynorphin

Endomorphin

Nociceptin

7.Cholecystokinin

8.AG-2

9.Calcitonin gene related peptide

10.Neuropeptide

 VASOPRESSIN
 Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) is
a nonapeptide hormone formed in the hypothalamus and released from
the posterior pituitary. Its primary function in the body is to regulate
extracellular fluid volume by affecting renal handling of water; however, it
also is a potent vasoconstrictor

 Regulation of release of ADH

 Hypovolemia, as occurs during hemorrhage, results in a decrease in atrial


pressure. Specialized stretch receptors within the atrial walls and large
veins (cardiopulmonary baroreceptors) entering the atria decrease their
firing rate when there is a fall in atrial pressure.

 Atrial receptor firing normally inhibits the release of AVP by the posterior
pituitary. With hypovolemia or decreased central venous pressure, the
decreased firing of atrial stretch receptors leads to an increase in AVP
release.

 ADH receptors

 ADH has 2 important sites:

Kidney

Blood vessel

 VP constricts arterial blood vessels by binding to V1 receptors, which are


coupled to the Gq-protein and the phospholipase C/IP3 signal transduction
pathway

 The most important physiological action of AVP is to increase water


reabsorption in the kidneys by increasing water permeability in the
collecting duct, thereby permitting the formation of a more concentrated
urine. This is the antidiuretic effect of AVP and it acts through
vasopressin type 2 (V2) receptors coupled to adenylyl cyclase.

 Specific drug

1 Arginine vasopressin

 Therapeutic effect

 for treating excessive water loss caused by diabetes insipidus and for
treating bleeding caused by esophageal varices. AVP infusion is being
investigated for use in treating septic shock, a condition that can be
caused by a bacterial infection in the blood and the release of bacterial
endotoxins such as lipopolysaccharide

 Side effects & Contraindication


 Side effects include headache, nausea, bronchoconstriction and abdominal
cramps. Its antidiuretic effects can lead to water intoxication and
hyponatremia. Because of AVP's powerful constrictor response, it should
be administered cautiously to patients with coronary artery disease
because it constricts coronary arteries (thereby reducing oxygen delivery)
and increases myocardial oxygen demand by increasing afterload on the
heart.

2.Terlipressin

3.Felypresin

4.Lypressin

 OXYTOCIN

 It is secreted from posterior pitutary,whose primary role is in milk ejection


in a lactating mother

 It also has a facilitory role in initiation of labour & parturition

 Pharmacological action

 Breast

It causes contractions of myoepithelial cells surrounding the mammary alveoli


leading to milk ejection

 Uterus

Estrogen sensitises the uterus to oxytocin action while progesterone decreases

 Misc.

In high doses,it causes vasodilation,a decrease B.P. and reflex tachycardia

 Oxytocin receptor & Antagonist

 Oxytocin receptors are Gq/Gi protein coupled receptors which when


stimulated lead to the generation of IP3 & subsequent mobilisation of
Ca+2 from i.c. stores & depolarisation induced activation of voltage
sensitive Ca+2 channels

 Receptor antagonist,atosiban is used to inhibit premature labour

 NEUROTENSIN

It is found in brain,GIT & in circulation

It causes increased secretion of anterior pitutary hormone,inhibit gastric acid &


pepsin secretion,inhibit gastric motility,causes vasodilation and increase vascular
pereality.
 VIP

 VIP is a 28-amino acid peptide structurally related to secretin. It was


originally isolated from intestinal extracts and shown to be a potent
vasodilator.

 VIP seems to induce smooth muscle relaxation (lower esophageal


sphincter, stomach, gallbladder), stimulate secretion of water into
pancreatic juice and bile, and cause inhibition of gastric acid secretion and
absorption from the intestinal lumen

 PURINE ANALOGUES

 Till today the research is going on for newer analogues of it. although the
founded once such as,

Adenosine

ATP

Infact they are recently classified according to their pharmacological


action.

e.g. 1) Anticancer analogues:

Azathioprine

Fludarabin

Vidarabine

6-Mercapto purine(6-MP)

2) CVS disorder:

Adenosine

3) Immunosuppressive agent:

 As anticancer agent

 6-Mercaptopurine (6-MP):-

 Act as a substrate for enzyme hypoxanthine guanine phosphoribosyl


transferase. (HGPRT)

 HGPRT catalyze the reaction of base analogue with phosphoribosyl


pyrophosphate (PRPP).
 Phosphorylation of 6-MP compete for enzyme that form AMP, incorporated
into cellular DNA & inhibit DNA synthesis.

 Vidarabine:

It is adenosine analogue & it is converted into arabinosyladenine ATP.

This inhibits DNA polymerase by competing with ATP.

 Fludarabine:

Metabolised to triphosphate form and inhibits DNA polymerase.

 Pentostatin:

 Potent inhibitor of adenosine deaminase.

 Deficiency of this enzyme associated with the malfunctioning of T-cells &


B-cells. So also work as immunosupressive.

 Inhibits synthesis of nicotinamide adenine dinucleotide. (NAD)

 As Immunosupressive agent

 Azathioprine:

 Non specific immunosupressive antimetabolite, inhibits lymphocyte purine


metabolism.

 It interfere with purine synthesis which is necessary for cell proliferation.

 It metabolised to mercaptopurine.

 Inhibits Clonal proliferation in the induction phase of immune response &


there by depress cell mediated & humoral immune response.

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