SYNTESIS OF PURIN

RIBONUKLEOTIDES
RUHAIDIN
2012-41-166

Salvage Pathways Economize

Intracellular Energy Expenditure

Free purine bases, derived from the

turnover of nucleotides or from the diet,
can be attached to PRPP to form purine
nucleoside monophosphates, in a reaction
analogous to the formation of orotidylate.
Two salvage enzymes with different
specificities recover purine bases. Adenine
phosphoribosyltransferase catalyzes the
formation of adenylate

whereas hypoxanthine-guanine
phosphoribosyltransferase (HGPRT)
catalyzes the formation of
guanylate as well as
inosinate (inosine monophosphate,
IMP), a precursor of guanylate and
adenylate.

The Purine Ring System Is

Assembled on Ribose Phosphate
De novo purine biosynthesis, like
pyrimidine biosynthesis, requires
PRPP, but for purines, PRPP provides
the foundation on which the bases are
constructed step by step. The initial
committed step is the displacement of
pyrophosphate by ammonia, rather
than by a preassembled base, to
produce 5-phosphoribosyl-1-amine,
with the amine in the
configuration

The Purine Ring Is Assembled

by Successive Steps of
Activation by
Phosphorylation Followed by
Displacement

AMP and GMP Are Formed from IMP

The removal of fumarate, the addition of a second formyl

group from N 10- formyltetrahydrofolate, and cyclization
completes the synthesis of inosinate (IMP), a purine
nucleotide.

Inosinate is the precursor of AMP and GMP. AMP is formed by

the addition of aspartate followed by the release of
fumarate. GMP is generated by the addition of water,
dehydrogenation by NAD+, and the replacement of the
carbonyl oxygen atom by -NH2 derived by the hydrolysis of
glutamine

Deoxyribonucleotides Synthesized
by the Reduction of
Ribonucleotides
Through a Radical Mechanism

Figure. Ribonucleotide Reductase R1 Subunit


Figure. Ribonucleotide Reductase R2
Subunit

Figure. Ribonucleotide Reductase Mechanism

The synthesis of purine

nucleotides is controlled by
feedback inhibition at several
sites

Nucleotides are important

constituents not only of RNA and
DNA, but also of a number of key
biomolecules considered many
times in our study of
biochemistry. NAD+ and NADP+,
coenzymes that function in
oxidation-reduction reactions,
are metabolites of ATP. The first
step in the synthesis of
nicotinamide adenine
dinucleotide (NAD+) is the
formation of nicotinate

Flavin adenine dinucleotide (FAD) is

synthesized from riboflavin and two
molecules of ATP. Riboflavin is
phosphorylated by ATP to give riboflavin 5
-phosphate (also called flavin
mononucleotide, FMN). FAD is then formed
from FMN by the transfer of an AMP moiety
from a second molecule of ATP

is the transfer of the AMP moiety of ATP

to the phosphate group of a
phosphorylated intermediate. The
pyrophosphate formed in these
condensations is then hydrolyzed to
orthophosphate. As in many other
biosyntheses, much of the
thermodynamic driving force comes
from the hydrolysis of the released
pyrophosphate.

Disruptions in Nucleotide Metabolism

Can Cause Pathological Conditions

Nucleotides are vital to a host of

biochemical processes. It is not

The nucleotides of a cell undergo

continual turnover. Nucleotides are
hydrolytically degraded to
nucleosides by
nucleotidases. The phosphorolytic
cleavage of nucleosides to free
bases and ribose 1-phosphate (or
deoxyribose 1phosphate) is catalyzed by
nucleoside phosphorylases. Ribose
1-phosphate is isomerized by
phosphoribomutase to ribose 5phosphate, a substrate in the
synthesis of PRPP. Some of the bases
are reused to form nucleotides by

Mutations in genes that encode nucleotide

biosynthetic enzymes can reduce levels of needed
nucleotides and can lead to an accumulation of
intermediates. A nearly total absence of
hypoxanthine-guanine
phosphoribosyltransferase has unexpected and
devastating consequences. The most striking
expression of this inborn error of metabolism,
called the Lesch-Nyhan syndrome, is compulsive
self-destructive behavior. At age 2 or 3, children
with this disease begin to bite their fingers and
lips and will chew them off if unrestrained. These
children also behave aggressively toward others.
Mental deficiency and spasticity are other
characteristics of the Lesch-Nyhan syndrome.
Elevated levels of urate in the serum lead to the
formation of kidney stones early in life, followed
by the symptoms of gout years later. The disease
is inherited as a sex-linked recessive disorder.

Thank you..