Download MBBS Nucletde Metablsm Lecture PPT

PURINE METABOLISM

? The process of synthesis of complex end

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product(s) in a metabolic pathway from simple

precursors molecule is called as de novo synthesis

(de novo = `anew', i.e. starting `from scratch')

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? The three processes that contribute to purine

nucleotide biosynthesis are, in order of decreasing

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importance.

1.Synthesis from amphibolic intermediates

(synthesis de novo).

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2. Phosphoribosylation of purines.
3. Phosphorylation of purine nucleosides.

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DIGESTION OF NUCLEIC

ACIDS

.

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? The nucleic acids in the diet

are hydrolyzed to a mixture of

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nucleotides by ribonuclease

and

deoxy

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ribonuclease

present in pancreatic and

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intestinal secretions.

? Then nucleotidases liberate the

phosphate from nucleotides.

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? The resulting nucleosides are

hydrolyzed by nucleosidases

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forming free bases and pentose

sugars.
? Dietary purine bases are

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not used for synthesis of tissue

nucleic acids.

? Instead they are degraded to uric acid in the enterocytes.

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? Most of the uric acid enters the blood and is eventually

excreted in the urine.

? Humans synthesize the nucleic acids and their derivatives

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ATP, NAD+, coenzyme A, etc, from amphibolic

intermediates.

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? However, injected purine or pyrimidine analogs,

including potential anticancer drugs, may nevertheless be

incorporated into DNA.

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? The incorporation of injected [3H]thymidine into newly

synthesized DNA thus can be used to measure the rate of

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DNA synthesis


Denovo

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synthesis

Synthesis of purine

base step by step on

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the ribose 5phosphate

Synthesis of

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purine

nucleotides

Addition of ribose 5-

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Salvage

phosphate to the

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pathway

preformed purine

bases or addition of

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phosphate to the

purine nucleosides

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? Denovo purine biosynthesis occurs from basic

precursors and a new purine ring is synthesized

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using various metabolic intermediates as

sources of carbon, nitrogen etc.

? This is then used to produce nucleosides and

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nucleotides
? In de novo purine

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biosynthesis pathway - D-ribose 5

-phosphate is used to synthesize a nucleotide inosine

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monophosphate ( IMP).

? This IMP is then converted into AMP and GMP

which are the end products of this pathway.

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? There is regulation both at the level of synthesis of

IMP and then its conversion into AMP and GMP.

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? Denovo purine biosynthesis is an expensive process

for the cell and uses many metabolic intermediate in

the synthesis of purine ring.

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Sources of different atoms of purine ring

N5N10 ?

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Methenyl
Tetrahydro

N10 ?Formyl

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folate

tetrahydrofolate

Sources of nitrogen and carbon atoms of the purine ring

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Denovo synthesis of purine nucleotides

? Purines are synthesized by most of the tissues
? The major site is--- liver .
? Erythrocytes, polymorphonuclear leukocytes &

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brain cannot produce purines.

? Subcellular site--- cytoplasm

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.
Denovo synthesis of purine nucleotides

SYNTHESIS OF IMP

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STEP 1

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? Ribose

5-phosphate,

produced in the hexose

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monophosphate shunt of
carbohydrate metabolism
is the starting material for
purine

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nucleotide

synthesis.

? It reacts with ATP to

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form

phsophoribosyl

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pyrophosphate (PRPP).

? PRPP

Synthetase

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is

inhibited by PRPP

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STEP 2

Rate limiting step

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? Glutamine transfers it's amide

nitrogen to PRPP to replace
pyrophosphate and produce
5phosphoribosylamine

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? The enzyme PRPP glutamyl

amidotransferase is controlled
by feedback inhibition of

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nucleoltides (IMP, AMP and
GMP,).

? This reaction is the 'committed.

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STEP 3

? Phosphoribosylamine reacts

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with glycine in the presence of
ATP to form glycinamide
ribosyl-5-phosphate

or

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glycinamide ribotide (GAR)


STEP 4

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? N5,N10-formyl-tetrahydrofolate

donates the formyl group and
the

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product

formed

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is

formylglycinamide

ribosyl

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5phosphate.

N5,N10-formyl-tetrahydrofolate

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Formylglycinamide ribosyl 5phosphate


STEP 5

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? Glutamine transfers the

second amido amino group

Formylglycinamide ribosyl-5-phosphate

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to

produce

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formylglycinamidine
ribosyl 5phosphate

Formylglycinamidine ribosyl-5-phosphate

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STEP 6

? The imidazole ring of

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the purine is closed in
an ATP dependent Formylglycinamidine ribosyl-5phosphate
reaction to yield 5-

RING CLOSURE

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aminoimidazole ribosyl
5-phosphate

Aminoimidazole ribosyl-5-phosphate

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STEP 7

? Incorporation of CO2

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(carboxylation) occurs to

yield

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aminoimidazole Aminoimidazole ribosyl-5-phosphate

carboxylate ribosyl 5-

phosphate.

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? This

carboxylation

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reaction does not require

the vitamin biotin and /or

ATP which is the case

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with

most

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of

the

carboxylation reaction.

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Aminoimidazole Carboxylate

ribosyl-5-phosphate
STEP 8

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? Aspartate condenses with

aminoimidazole

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Aminoimidazole Carboxylate

carboxylate ribosyl 5-

ribosyl-5-phosphate

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phosphate.

to

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form

aminoimidazole

4-

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succinyl

carboxamide

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ribosyl 5phosphate



Aminoimidazole -succinyl

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carboxamide ribosyl -5 - phosphate


STEP 9

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? Adenylosuccinase

or

Adenylosuccinate lyase

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cleaves off fumarate and Aminoimidazole -succinyl

carboxamide ribosyl -5 - phosphate

only the amino group of

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aspartate is retained to
yield

aminoimidazole

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carboxamide ribosyl 5-
phosphate.

Aminoimidazole Carboxamide

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ribosyl-5-phosphate


STEP 10

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? N10-formyl-THF donates
a one-carbon moiety to
produce

Aminoimidazole Carboxamide

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formimidoimidazole

4-

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ribosyl-5-phosphate

carboxamide ribosyl 5-
phosphate.

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?With this reaction, all the
carbon and nitrogen atoms
of

purine

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ring

are

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contributed

by

the

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respective sources.

Formimidoimidazole Carboxamide

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ribosyl-5-phosphate


STEP 11

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H2O

Ring closure

IMP cyclohydrolase

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Formimidoimidazole Carboxamide

ribosyl-5-phosphate

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Inosine monophosphate

(IMP)

The final reaction catalysed by cyclohydrolase leads to ring

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closure with an elimination of water molecule from
formimidoimidazole ribosyl-5-P by Inosine monophosphate
(IMP) cyclohydrolase forms IMP.
Synthesis of AMP and GMP from IMP

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? Inosine monophosphate is the immediate precursor for the

formation of AMP & GMP

? Aspartate condences with IMP in the presence of GTP to

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produce Adenylosuccinate which on cleavage forms AMP.

? For the synthesis of GMP, IMP undergoes NAD+

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dependent

dehydrogenation

to

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form

Xanthosine

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monophosphate ( XMP).

? Glutamine then transfers amide nitrogen to XMP to

produce GMP. This requires ATP.

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STEP-13

STEP-12

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STEP-14

Conversion Of IMP to AMP and GMP

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STEP-15
MUST REMEMBER

ANTIFOLATE

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DRUGS

&

GLUTAMINE

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ANALOGS BLOCK PURINE NUCLEOTIDE

BIOSYNTHESIS

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Compounds

that

inhibit

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formation

of

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tetrahydrofolates and therefore block purine

synthesis have been used in cancer chemotherapy.

Inhibitory compounds and the reactions they

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inhibit include

? Azaserine -----------------reaction
? Diazanorleucine ---------reaction

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? 6-mercaptopurine -------reactions and
? mycophenolic acid -------reaction


FORMATION OF DIPHOSPHATE AND

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TRIPHOSPHATE NUCLEOTIDES

? AMP and GMP are phosphorylated using ATP

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as the source of phosphate to first make
nucleoside di phosphate and then nucleoside
triphosphate i.e. ADP, ATP, GDP and GTP
CONVERSION OF RIBONUCLEOTIDES TO

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DEOXY RIBONUCLEOTIDES

? The synthesis of purine & pyrimidine deoxy ribonucleotides

occur from ribonucleotides by a reduction at the C2 of

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ribose moity.

? This reaction is catalyzed by enzyme RIBONUCLEOTIDE

REDUCTASE.

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? The enzyme ribonucleotide reductase itself provides the

hydrogen atoms needed for reduction from its sulfhydryl
groups.

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? The reducing equivalents, in turn, are supplied by

Thioredoxin, a monomeric protein with two cysteine
residues.

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? NADPH-dependent thioredoxin reductase converts the

oxidised thioredoxin to reduced form

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? Deoxy ribonucleotides are formed from reduction of

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ribo-nucleoside diphosphates.

? Monophosphate and triphosphate are not reduced to

corresponding deoxy ribonucleotides

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PURINE SALVAGE PATHWAY

? The free purines ( adenine, guanine & hypoxanthine ) are

formed in the normal turnover of nucleic acids & also

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obtained from the dietary sources.

? The free purines are converted to corresponding

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nucleotides, & this process is known as `salvage pathway'.

? Adenine phosphoribosyl transferase catalyses the

formation of AMP from adenine.

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? Hypoxanthine-guanine

phosphoribosyl

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transferase

(HGPRT) converts guanine & hypoxanthine respectively,

to GMP & IMP.

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? Phosphoribosyl pyrophosphate (PRPP) is the donor of

ribose 5 phosphate in the salvage pathway.

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? The salvage pathway is particularly important in certain

tissues such as erythrocytes & brain where denovo

synthesis of purine nucleotides is not operative.

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1. Pu + PR-PP Pu-RP + PPi

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? A second salvage mechanism involves phosphoryl



transfer from ATP to a purine ribonucleoside (Pu-R):

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Pu-R + ATP PuR-P + ADP
? Phosphorylation of the purine nucleotides, catalyzed

by adenosine kinase converts adenosine and

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deoxyadenosine to AMP and dAMP.

Or
REGULATION OF PURINE NUCLEOTIDE

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BIOSYNTHESIS

? The de novo biosynthesis is regulated in two

ways

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1. Regulation of IMP formation
2. Regulation of AMP and GMP formation from

IMP.

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1. Regulation of IMP formation

? Occurs at first two reaction catalyzed by
i. PRPP synthase
ii. Glutamine phosphoribosyl ? amido-

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transferase.

Though both are regulatory enzymes, the

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second step catalyzed by amidotransferase is
also a committed step for purine synthesis.
Hence it is more important.
i. REGULATION OF PRPP SYNTHASE

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? The overall determinant of the rate of de novo purine

nucleotide biosynthesis is the concentration of PRPP.

? This, in turn, depends on the rate of PRPP synthesis,

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utilization, degradation, and regulation.

? The rate of PRPP synthesis depends on the availability

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of ribose 5-phosphate and on the activity of PRPP
synthase

? Activity of PRPP synthase is allosterically inhibited by

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both the adenosine and guanosine nucleotides i.e
AMP, ADP, GMP and GDP.
ii. REGULATION OF AMIDOTRANSFERASE

? Amidotransferse is feedback inhibited by products i.e.

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AMP, ADP, GMP and GDP.

? AMP and GMP act as competitive inhibitors.
? So, at a high PRPP (substrate ) concentration, AMP and

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GMP will not be able to inhibit the amidotransferase
enzyme.

? Amidotransferse is stimulated by its substrate PRPP.

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(feed forward reaction)

? A very high PRPP concentration will lead to increased

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purines and their catabolism producing hyperuricemia.
Regulation of AMP and GMP formation from IMP

? AMP feedback inhibits its own synthesis at the

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adenylosuccinate synthase level.

? Simultaneously ATP stimulate GMP synthesis at

xanthine transaminidase step.( cross regulation)

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? Similarly GMP inhibits its own synthesis at the IMP

dehydrogenase step.

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? GTP

stimulates

AMP

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synthesis

at

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the

adenylosuccinate synthase step. ( cross regulation)

? This cross regulation ensures that adenine and

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guanine nucleotide synthesis is in equal proportion. If

AMP is decreased, it stimulates its own synthesis and

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inhibits GMP synthesis and vice versa.


REGULATION OF PURINE
NUCLEOTIDE BIOSYNTHESIS

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? Regulation of IMP is

shown by solid lines

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? AMP and GMP synthesis

are shown by dotted lines

E1 = PRPP Synthetase

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E2 = Amido Transferase
E3 = Adenylosuccinate

synthase

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E4 = IMP dehydrogenase

E5

E5 = Xanthine

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transaminidase
DEGREDATION OF PURINE NUCLEOTIDES

1. The end product of purine metabolism in humans is

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uric acid.

2. The nucleotide monophosphates (AMP , IMP &

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GMP) are converted to their respective nucleoside
forms (adenosine,inosine & guanosine ) by the
action of nucleotidase.

3. The amino group, either from AMP or adenosine,

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can be removed to produce IMP or inosine
respectively by deaminase.

4. Inosine & guanosine are, raspectively , converted to

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hypoxanthine & guanine (purine bases) by purine
nucleoside phosphorylase.

.

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5. Adenosine is not



degreded by this enzyme, hence it has

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to be converted to inosine by deaminases.

6. Guanine undergoes deamination by guanase to form

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xanthine.

7. Xanthine oxidase is an important enzyme that converts

hypoxanthine to xanthine, & xanthine to uric acid.

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8. This enzyme contains FAD, Molybdenum & Iron, & is

mainly found in liver & small intestine.

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9. Uric acid ( 2,6,8-trioxopurine ) is the final excretory

product of purine metabolism in humans.

10. Uric acid can serve as an important antioxidant by

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getting itself converted non enzymatically to allantoin.
Guanase
DISORDERS OF PURINE METABOLISM

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1. Hyperuricemia And Gout
2. Lesch-Nyhan syndrome
3. Severe Combined Immuno Deficiency (SCID)
4. Purine Nucleoside Phophorylase Deficiency
URIC ACID

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1. Uric acid (2,6,8-trioxopurine) is the end product of

purine metabolism in humans.

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2. The normal concentration of uric acid in the serum of

adults is in the range of 3-7 mg / dl.

3. In women, it is slightly lower (by about 1mg) than in

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men.

4. The daily excreation of uric acid is about 400-600 mg.

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It is filtered , reabsorbed and secreted by kidney tubules.
5. At the pH of 5.75 and

above, it forms monosodium

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urate salt which is 10 times more soluble than uric
acid.

6. In plasma (pH of 7.4), monosodium urate is

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predominant form present which is relatively more
soluble.

7. Any condition which decreases blood pH (acidosis)

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,therefore, promotes the formation of insoluble uric
acid than the more soluble monosodium urate.
1. HYPERURICEMIA AND GOUT

? Increase in blood uric acid level above the normal

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value of >7 mg% is called hyperuricemia.

? This is sometimes associated with increased uric acid

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excreation ( Uricosuria)

? In severe hyperuricemia, crystals of sodium urate get

deposited in the soft tissues, particularly in the joints.

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? Such deposits are commonly known as TOPHI.
? This causes inflammation in the joints resulting in a

painful arthritis.

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? Sodium urate &/or uric acid may also precipitate in

kidneys & ureters that result in renal damage & stone
formation.

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GOUT

? Hyperuricemia leading to arthritis is called gout.
? Gout is often called a disease of bones and stones due

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to recurrent stones formation and inflammmation of
joints.

? Gouty arthritis is debilitating painful condition

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leading to deformity of joints.

? Typical

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gouty

arthritis

affects

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first

metatarsophalangeal joint.(GREAT TOE)
TYPES OF GOUT

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Two types:
1. Primary ?
due to metabolic defect of uric acid where its

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synthesis as such is increased.

2. Secondary ?
- Due to increased nucleotide turn over

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wherein more uric acid is formed .

- Uric acid metabolism is normal.
- This occurs as a consequence of some

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other primary disease associated with
increased tissue catabolism
CAUSES OF GOUT

? PRIMARY GOUT

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1. PRPP synthetase over activity due to defective enzyme
varient forms of PRPP synthetase-which are not

subjected to feedback regulation-have been detected.

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This leades to increased production of purines.

2. PRPP-glutamyl-amidotransferase - defective enzyme
The lack of feedback control of this enzyme by purine

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nucleotides also leads to their elevated synthesis.

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3.HGPRTase deficiency or Lesch-Nyhan syndrome
? Deficiency of

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HGPRTase causes a decrease in salvage

pathway of hypoxanthine and guanine to reform
nucleotide.

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? This in turn spares PRPP and results in overproduction

of purine nucleotides and their degradation to uric acid.
4. Glu-6-phosphatase dificiency or Von-Gierke's

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disease

? When this enzyme is deficient, glucose-6-phosphate

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cannot be converted to glucose.

? So more glucose-6-phosphate is channeled into the

pentose phosphate shunt pathway, resulting in

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increased availability of ribose-5-phosphate.

? This would lead to increased formation of PRPP

ultimately, purine over production.

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? Von Gierke's disease is also associated with

increased activity of glycolysis. Due to this, lactic
acid accumulates in the body which interferes with

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the uric acid excretion through renal tubules

SECONDARY GOUT

A. Increased Production of Uric Acid

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i. Rapidly growing malignant tissues, e.g.

leukemias, lymphomas, polycythemia.

ii. Cancer patients on radiotherapy or

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chemotherapy (tumor lysis syndrome) due
to increased cellular turnover

iii. Increased tissue damage due to trauma and

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raised rate of catabolism as in starvation

iv Psoriasis ? skin disease
Secondary Hyperuricemia

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B. Reduced Excretion Rate
i. Renal failure
ii. Treatment with thiazide diuretics which

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inhibit tubular secretion of uric acid

iii. Lactic acidosis and keto-acidosis due to

interference with tubular secretion.

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Clinical Findings of Gout

? The typical gouty arthritis affects the first

metatarsophalangeal joint (big toe), but other joints may

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also be affected.

? The joints are extremely painful.
? Synovial fluid will show birefringent urate crystals.

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? In chronic cases, uric acid may get deposited around joints

causing swelling (tophi) composed of sodium urate

? Gouty attacks may be precipitated by high purine diet and

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increased intake of alcohol.

? Often the patients have a few drinks, go to sleep

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symptomless, but are awakened during the early hours of

morning by excruciating joint pains.

? Alcohol leads to accumulation of lactic acid.

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TREATMENT

? Reduce dietary purine intake and restrict alcohol.

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? Increase renal excretion of urate by uricosuric drugs,

which decrease the reabsorption of uric acid from kidney
tubules, e.g. probenecid.

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? Reduce urate production by allopurinol, an analog of

hypoxanthine and competitive inhibitor of xanthine

? Xanthine and hypoxanthine are more soluble and so are

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excreted more easily.

? Xanthine oxidase converts allopurinol to alloxanthine. It

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is a more effective inhibitor of xanthine oxidase.(`suicide
inhibition`).

? Colchicine, an anti-inflammatory agent is very useful to

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arrest the arthritis in gout.
Lesch-Nyhan Syndrome

? Inability of the body to salvage hypoxanthine and

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guanine due to the complete deficiency of HGPRTase
(Hypoxanthine-Guanine phosphoribosyl transferase)

? It is an X-linked inherited disorder of purine

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metabolism, the disease is limited to males only

? Different types of mutations in HGPRTase gene have

been identified in patients with Lesch Nyhan

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syndrome.

? Incidence is 1:10,000 males.

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? HGPRT deficiency results in the accumulation of

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PRPP and decrease in GMP and IMP.

? Increased level of Hypoxanthine and Guanine

in degradation to uric acid

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? Also PRPP accumulates

stimulates production of Purine nucleotides

increases their degradation to uric acid

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? Leads to hyperuricemia---Gout-like symptoms

Nephrolithiasis ( Renal stones)

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Neurological symptoms

? self mutilation
? spasticity,
? aggressiveness,

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? mental retardation
DIAGNOSIS

? Increase urinary urate / creatinine ratio
? Absent / reduced enzyme activity in

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lymphocytes or fibroblast

? Mutation analysis of Hypoxanthine-Guanine

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phosphoribosyl transferase (HGPRT) gene.

Severe combined immunodeficiency (SCID)

? The deficiency of adenosine deaminase (ADA) causes

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severe

combined

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immunodeficiency

(SCID)

involving T-cell and usually B-cell dysfunction.

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? ADA deficiency results in the accumulation of dATP.
? dATP is an inhibitor of ribonucleotide reductase

which causes reduced synthesis of other dNTPs and

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therefore DNA synthesis and cell replication is
inhibited.

? Thus proliferation and differentiation of immune cells

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is compromised.



SCID

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? Lymphocytes usually contain high levels of ADA.
? Therefore, ADA deficiency is mainly manifested as

reduced lymphocytes.

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? This leads to impaired cellular and humoral immunity.
? Hypouricemia is due to defective breakdown of

purine nucleotides.

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ADA estimation in CSF is used for the diagnosis of
tuberculous meningitis.
ADA levels can be estimated in various body fluids like
blood, CSF, pleural fluid, pericardial fluid, ascitic fluid, etc.

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SCID - Treatment

? Antibiotics and periodic injections of

immunoglobulin will be lifesaving.

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? Bone marrow stem cells will increase both T

and B cells in the patients.

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? Enzyme replacement therapy with ADA-

Polyethylene glycol ( the first successful

application of enzyme replacement therapy for

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an inherited disease.

? Gene therapy- recently, ADA gene has been

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successfully transfected into stem cells of

ADA deficient children.

Purine Nucleoside Phophorylase

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Deficiency

? Less severe than ADA deficiency
? Associated with severe deficiency of T- cells

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but apparently normal B- cell function.

? Immune dysfunction appear to result from

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accumulation of dGTP, and dATP, which
inhibit ribonucleotide reductase and thereby
deplete cells of DNA precursors.