Purine Metabolism PDF

Purine
metabolism
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Purine metabolism refers to

the metabolic pathways to
synthesize and break down
purines that are present in
many organisms.
Biosynthesis
Purines are biologically
synthesized as nucleotides and
in particular as ribotides, i.e.
bases attached to ribose
5-phosphate. Both adenine and
guanine are derived from the
nucleotide inosine
monophosphate (IMP), which is
the first compound in the
pathway to have a completely
formed purine ring system.
IMP Edit
The synthesis of IMP.
The color scheme is as follows:
enzymes, coenzymes, substrate
names, metal ions, inorganic molecules
Inosine monophosphate is
synthesized on a pre-existing
ribose-phosphate through a
complex pathway (as shown in
the figure on the right). The
source of the carbon and
nitrogen atoms of the purine
ring, 5 and 4 respectively, come
from multiple sources. The
amino acid glycine contributes
all its carbon (2) and nitrogen
(1) atoms, with additional
nitrogen atoms from glutamine
(2) and aspartic acid (1), and
additional carbon atoms from
formyl groups (2), which are
transferred from the coenzyme
tetrahydrofolate as 10-
formyltetrahydrofolate, and a
carbon atom from bicarbonate
(1). Formyl groups build
carbon-2 and carbon-8 in the
purine ring system, which are
the ones acting as bridges
between two nitrogen atoms.
A key regulatory step is the

production of 5-phospho-α-D-
ribosyl 1-pyrophosphate
(PRPP) by ribose phosphate
pyrophosphokinase, which is
activated by inorganic
phosphate and inactivated by
purine ribonucleotides. It is not
the committed step to purine
synthesis because PRPP is
also used in pyrimidine
synthesis and salvage
pathways.
The first committed step is the

reaction of PRPP, glutamine
and water to 5'-
phosphoribosylamine (PRA),
glutamate, and pyrophosphate -
catalyzed by
amidophosphoribosyltransfera
se, which is activated by PRPP
and inhibited by AMP, GMP and
IMP.
PRPP + L-Glutamine + H2O →

PRA + L-Glutamate + PPi
In the second step react PRA,

glycine and ATP to create GAR,
ADP, and pyrophosphate -
catalyzed by
phosphoribosylamine—glycine
ligase (GAR synthetase). Due to
the chemical lability of PRA,
which has a half-life of 38
seconds at PH 7.5 and 37 °C,
researchers have suggested
that the compound is
channeled from
amidophosphoribosyltransfera
se to GAR synthetase in vivo.[1]
PRA + Glycine + ATP → GAR +
ADP + Pi
The third is catalyzed by

phosphoribosylglycinamide
formyltransferase.
GAR + fTHF → fGAR + THF
The fourth is catalyzed by

phosphoribosylformylglycinami
dine synthase.
fGAR + L-Glutamine + ATP →

fGAM + L-Glutamate + ADP + Pi
The fifth is catalyzed by AIR

synthetase (FGAM cyclase).
fGAM + ATP → AIR + ADP + Pi
+ H2O
The sixth is catalyzed by

phosphoribosylaminoimidazole
carboxylase.
AIR + CO2 → CAIR + 2H+
The seventh is catalyzed by

succinocarboxamide synthase.
CAIR + L-Aspartate + ATP →

SAICAR + ADP + Pi
The eight is catalyzed by

adenylosuccinate lyase.
SAICAR → AICAR + Fumarate
The products AICAR and

fumarate move on to two
different pathways. AICAR
serves as the reactant for the
ninth step, while fumarate is
transported to the citric acid
cycle which can then skip the
carbon dioxide evolution steps
to produce malate. The
conversion of fumarate to
malate is catalyzed by
fumarase. In this way, fumarate
connects purine synthesis to
the citric acid cycle.[2]
The ninth is catalyzed by
carboxamide
formyltransferase.
AICAR + fTHF → FAICAR + THF
The last step is catalyzed by

Inosine monophosphate
synthase.
FAICAR → IMP + H2O
In eukaryotes the second, third,

and fifth step are catalyzed by
trifunctional purine biosynthetic
protein adenosine-3, which is
encoded by the GART gene.
Both ninth and tenth step are

accomplished by a single
protein named Bifunctional
purine biosynthesis protein
PURH, encoded by the ATIC
gene.
GMP Edit
IMP dehydrogenase (IMPDH)

converts IMP into XMP
GMP synthase converts XMP
into GMP
GMP reductase converts
GMP back into IMP
AMP Edit
adenylosuccinate synthase
converts IMP to
adenylosuccinate
adenylosuccinate lyase
converts adenylosuccinate
into AMP
AMP deaminase converts
AMP back into IMP
Degradation
Purines are metabolised by
several enzymes:
Guanine Edit
A nuclease frees the

nucleotide
A nucleotidase creates
guanosine
Purine nucleoside
phosphorylase converts
guanosine to guanine
Guanase converts guanine to
xanthine
Xanthine oxidase (a form of
xanthine oxidoreductase)
catalyzes the oxidation of
xanthine to uric acid
Adenine Edit
A nuclease frees the

nucleotide
A nucleotidase creates
adenosine, then
adenosine deaminase
creates inosine
Alternatively, AMP
deaminase creates
inosinic acid, then a
nucleotidase creates
inosine
Purine nucleoside
phosphorylase acts upon
inosine to create
hypoxanthine
Xanthine oxidase catalyzes
the biotransformation of
hypoxanthine to xanthine
Xanthine oxidase acts upon
xanthine to create uric acid
Regulations of purine
nucleotide biosynthesis
Edit
The formation of 5'-

phosphoribosyalamine from
glutamine and PRPP catalysed
by PRPP amino transferase is
the regulation point for purine
synthesis. The enzyme is an
allosteric enzyme, so it can be
converted from IMP, GMP and
AMP in high concentration
binds the enzyme to exerts
inhibition while PRPP is in large
amount binds to the enzyme
which causes activation. So
IMP, GMP and AMP are
inhibitors while PRPP is an
activator. Between the
formation of 5'-phosphoribosyl,
aminoimidazole and IMP, there
is no known regulation step.
Salvage
Purines from turnover of
cellular nucleic acids (or from
food) can also be salvaged and
reused in new nucleotides.
The enzyme adenine

phosphoribosyltransferase
(APRT) salvages adenine.
The enzyme hypoxanthine-
guanine
phosphoribosyltransferase
(HGPRT) salvages guanine
and hypoxanthine.[3] (Genetic
deficiency of HGPRT causes
Lesch–Nyhan syndrome.)
Disorders
When a defective gene causes
gaps to appear in the metabolic
recycling process for purines
and pyrimidines, these
chemicals are not metabolised
properly, and adults or children
can suffer from any one of
twenty-eight hereditary
disorders, possibly some more
as yet unknown. Symptoms can
include gout, anaemia, epilepsy,
delayed development,
deafness, compulsive self-
biting, kidney failure or stones,
or loss of immunity.
Purine metabolism can have
imbalances that can arise from
harmful nucleotide
triphosphosphates
incorporating into DNA and
RNA which further lead to
genetic disturbances and
mutations, and as a result, give
rise to several types of
diseases. Some of the diseases
are:
1. Severe immunodeficiency
by loss of adenosine
deaminase.
2. Hyperuricemia and
Lesch–Nyhan syndrome
by the loss of
hypoxanthine-guanine
phosphoribosyltransferas
e.
3. Different types of cancer
by an increase in the
activities of enzymes like
IMP dehydrogenase.[4]
Pharmacotherapy
Modulation of purine
metabolism has
pharmacotherapeutic value.
Purine synthesis inhibitors

inhibit the proliferation of cells,
especially leukocytes. These
inhibitors include azathioprine,
an immunosuppressant used in
organ transplantation,
autoimmune disease such as
rheumatoid arthritis or
inflammatory bowel disease
such as Crohn's disease and
ulcerative colitis.
Mycophenolate mofetil is an
immunosuppressant drug used
to prevent rejection in organ
transplantation; it inhibits
purine synthesis by blocking
inositol monophosphate
dehydrogenase. Also
Methotrexate indirectly inhibits
purine synthesis by blocking
the metabolism of folic acid (it
is an inhibitor of the
dihydrofolate reductase).
Allopurinol is a drug that

inhibits the enzyme xanthine
oxidoreductase and, thus,
lowers the level of uric acid in
the body. This may be useful in
the treatment of gout, which is
a disease caused by excess
uric acid, forming crystals in
joints.
See also
Purinergic signaling
Disease-modifying
antirheumatic drug (DMARD)
References
1. Antle VD, Liu D, McKellar
BR, Caperelli CA, Hua M,
Vince R (April 1996).
"Substrate specificity of
glycinamide ribonucleotide
synthetase from chicken
liver". The Journal of
Biological Chemistry. 271
(14): 8192–5.
doi:10.1074/jbc.271.14.81
92 . PMID 8626510 .
2. Garrett RH, Grisham CM
(2016-02-11). Biochemistry
(Sixth ed.). Boston, MA.
pp. 666 & 934.
ISBN 9781305577206.
OCLC 914290655 .
3. Ansari MY, Equbal A, Dikhit
MR, Mansuri R, Rana S, Ali
V, et al. (February 2016).
"Establishment of
correlation between in-
silico and in-vitro test
analysis against
Leishmania HGPRT to
inhibitors". International
Journal of Biological
Macromolecules. 83:
78–96.
doi:10.1016/j.ijbiomac.20
15.11.051 .
PMID 26616453 .
4. Pang B, McFaline JL,
Burgis NE, Dong M,
Taghizadeh K, Sullivan MR,
et al. (February 2012).
"Defects in purine
nucleotide metabolism
lead to substantial
incorporation of xanthine
and hypoxanthine into
DNA and RNA" .
Proceedings of the
National Academy of
Sciences of the United
States of America. 109 (7):
2319–24.
Bibcode:2012PNAS..109.2
319P .
doi:10.1073/pnas.111845
5109 . JSTOR 41477470 .
PMC 3289290 .
PMID 22308425 .
External links
The Medical Biochemistry
Page
Purine metabolism -
Reference pathway
PUMPA: Purine Metabolic
Patients’ Association
Retrieved from
"https://en.wikipedia.org
/w/index.php?title=Purine_metabolis
m&oldid=951764978"
Last edited 11 days ago by OAbot

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Purine

This article includes a list of

Purine metabolism refers to

A key regulatory step is the

The first committed step is the

PRPP + L-Glutamine + H2O →

In the second step react PRA,

The third is catalyzed by

GAR + fTHF → fGAR + THF

The fourth is catalyzed by

fGAR + L-Glutamine + ATP →

The fifth is catalyzed by AIR

The sixth is catalyzed by

AIR + CO2 → CAIR + 2H+

The seventh is catalyzed by

CAIR + L-Aspartate + ATP →

The eight is catalyzed by

The products AICAR and

AICAR + fTHF → FAICAR + THF

The last step is catalyzed by

FAICAR → IMP + H2O

In eukaryotes the second, third,

Both ninth and tenth step are

IMP dehydrogenase (IMPDH)

A nuclease frees the

A nuclease frees the

The formation of 5'-

The enzyme adenine

Purine synthesis inhibitors

Allopurinol is a drug that

Last edited 11 days ago by OAbot

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