Biosynthesis
The synthesis of IMP.
The color scheme is as follows: enzymes, coenzymes,
substrate names, metal
ions, inorganic molecules
Purines are biologically synthesized
as nucleotides
and in particular as ribotides, i.e. bases attached to ribose 5-phosphate. A key regulatory step is the production of 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP) by PRPP synthetase,
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, glutamate, and pyrophosphate
- catalyzed by pyrophosphate amidotransferase, which is activated by PRPP and
inhibited by AMP, GMP and IMP.
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.
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.
GMP
- IMP dehydrogenase converts IMP into XMP
- GMP synthase converts XMP into GMP
- GMP reductase converts GMP back into IMP
AMP
- adenylosuccinate synthase
converts IMP to adenylosuccinate
- adenylosuccinate lyase
converts adenylosuccinate into AMP
- AMP deaminase converts AMP back into IMP
Degradation
Guanine
- 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
- 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 oxidoreductase
catalyzes the biotransformation of hypoxanthine to xanthine
- Xanthine oxidoreductase
acts upon xanthine to create uric acid
Salvage
Purines from turnover of 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. (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.
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.