12.11.3 Catabolism of Purine Nuc1eotides and Uric Acid Synthesis
451
phosphatases. The phosphorolytic cleavage of the
glycosidic bond usually occurs at the level of the
nucleoside. Purine nucleoside phosphorylases are
undoubtedly widely distributed but their comparative biochemistry is largely unknown [217]. In all
vertebrates down to the agnathan Lampetra planeri, these enzymes have the seldom found protein structure of a trimer. The deamination and
oxidation steps can occur at the levels of the nucleotide, nucleoside or free base (Fig. 12.26). For
guanine compounds, deamination occurs either
with the nucleotide, by the action of GMP reductase, or with the free base, catalysed by guanine
deaminase (guanase), which is apparently widely
found but comparatively little investigated [36].
In contrast, for adenine compounds all three possibilities are encountered in the animal kingdom.
Whilst adenine deaminase is restricted to the Kinetoplastida, AMP deaminase and adenosine deaminase are widely found. The oxidation of hypoxanthine to xanthine and further to uric acid is
brought by xanthine dehydrogenases or oxidases.
AMP deaminase serves, on the one hand, to
release ammonia from amino acids in the purine
nucleotide cycle (p.413) and, on the other hand,
it plays an important role in the regulation of the
adenylate pool. The AMP produced in white vertebrate muscle by the combined action of ATPase
and adenylate kinase is immediately metabolized
further to IMP by AMP deaminase. Due to the
relatively low activity of the 5'-nucleotidase, the
IMP is only slowly cleaved to give inosine. AMP
deaminase is not present in the adductor muscles
of the scallop Pecten and other bivalves; hence,
the adenylate pool in these organisms remains
unchanged even after their death. The mantle
muscle of the cephalopods is also rather low in
AMP deaminase activity, but has high activities of
adenosine deaminase and an AMP-specific 5'nucleotidase. In this case, AMP is metabolized to
inosine via adenosine, a pathway that predominates in other aerobic muscles like red skeletal
muscles and heart muscles of the vertebrates [80].
Isoenzymes of AMP deaminase have been
reported from all classes of vertebrates; in
humans and the rat they are encoded by at least
two different genes [158]. The muscle enzymes of
the rat, rabbit, chicken, frog Rana esculenta and
fish Lucioperca lucioperca are all tetramers of
280 kDa and contain two zinc atoms per molecule. They require K+, are activated by ATP and
inhibited by Pi and GTP. In the goldfish, the white
muscles used only for short periods contain a different enzyme to that found in the continuously
active red muscle; the enzyme from the white
muscles is allosterically regulated within broad
limits. The muscles of all vertebrates have high
activities of AMP deaminase; however, in fish the
activities in the gills may be much higher than
those in the muscles [196]. In the dogfish Scyliorrhinus canicula, the erythrocytes contain high
activities of an AMP deaminase that is labile but
otherwise similar to the muscle enzyme; in other
vertebrates the red blood cells contain relatively
low activities of this enzyme [195]. The activity in
the liver of frogs of the genus Rana is tenfold
higher than in the liver of other vertebrates. In
the chicken and the lizard Lacerta agilis, the liver
contains two types of AMP deaminase, one of
which is activated not only by ATP and ADP but
also by GTP; in contrast, GTP is inhibitory to the
liver enzymes of the rat and the frog. It may be
that the existence of an additional, GTPactivated liver enzyme in the birds and reptiles is
associated with their urotelic metabolism [234].
AMP deaminase appears to be completely
absent from many mussels and arthropods; it is
present at relatively low activities in the muscles
of the lobster, in the hepatopancreas of the snail
Helix aspersa and the mussel Meretrix meretrix,
and in the body wall of the polychaete Arenicola
cristata. In contrast, its activity is 18-fold higher in
the gut of the earthworm Lumbricus terrestris
than in the body wall, and in the muscular foot of
the edible snail it is 5- to to-fold higher than in
vertebrate muscle. The Helix enzyme has a very
unusual substrate specificity, in that it is able to
act upon ADP, ATP and NADH as well as AMP
[235]. The AMP deaminases of the crustaceans
Orconectes limosus and Palaemon serratus also
appear to be very different to the vertebrate enzymes in their structural and functional properties
[197].
Adenosine deaminases have been demonstrated in vertebrates of all classes, molluscs, annelids and arthropods, and are probably ubiquitous.
They deaminate deoxyadenosine as well as adenosine. In the muscles of the vertebrates the activity of adenosine « U/g fresh weight) is always
lower than that of the AMP deaminase (10-50
U/g fresh weight); in the crustaceans, gastropods
and bivalves, the two enzymes both have relatively low activities «1 U/g fresh weight). High
activities of adenosine deaminase (12-27 U/g
fresh weight) are found only in the muscles of
various cephalopods which, in contrast, have low
AMP deaminase activities «1 U/g fresh weight)
[80]. Human adenosine deaminase, which is a
polypeptide of 41 kDa with 363 amino acids, has
been sequenced via the cDNA [263]. The only
451
phosphatases. The phosphorolytic cleavage of the
glycosidic bond usually occurs at the level of the
nucleoside. Purine nucleoside phosphorylases are
undoubtedly widely distributed but their comparative biochemistry is largely unknown [217]. In all
vertebrates down to the agnathan Lampetra planeri, these enzymes have the seldom found protein structure of a trimer. The deamination and
oxidation steps can occur at the levels of the nucleotide, nucleoside or free base (Fig. 12.26). For
guanine compounds, deamination occurs either
with the nucleotide, by the action of GMP reductase, or with the free base, catalysed by guanine
deaminase (guanase), which is apparently widely
found but comparatively little investigated [36].
In contrast, for adenine compounds all three possibilities are encountered in the animal kingdom.
Whilst adenine deaminase is restricted to the Kinetoplastida, AMP deaminase and adenosine deaminase are widely found. The oxidation of hypoxanthine to xanthine and further to uric acid is
brought by xanthine dehydrogenases or oxidases.
AMP deaminase serves, on the one hand, to
release ammonia from amino acids in the purine
nucleotide cycle (p.413) and, on the other hand,
it plays an important role in the regulation of the
adenylate pool. The AMP produced in white vertebrate muscle by the combined action of ATPase
and adenylate kinase is immediately metabolized
further to IMP by AMP deaminase. Due to the
relatively low activity of the 5'-nucleotidase, the
IMP is only slowly cleaved to give inosine. AMP
deaminase is not present in the adductor muscles
of the scallop Pecten and other bivalves; hence,
the adenylate pool in these organisms remains
unchanged even after their death. The mantle
muscle of the cephalopods is also rather low in
AMP deaminase activity, but has high activities of
adenosine deaminase and an AMP-specific 5'nucleotidase. In this case, AMP is metabolized to
inosine via adenosine, a pathway that predominates in other aerobic muscles like red skeletal
muscles and heart muscles of the vertebrates [80].
Isoenzymes of AMP deaminase have been
reported from all classes of vertebrates; in
humans and the rat they are encoded by at least
two different genes [158]. The muscle enzymes of
the rat, rabbit, chicken, frog Rana esculenta and
fish Lucioperca lucioperca are all tetramers of
280 kDa and contain two zinc atoms per molecule. They require K+, are activated by ATP and
inhibited by Pi and GTP. In the goldfish, the white
muscles used only for short periods contain a different enzyme to that found in the continuously
active red muscle; the enzyme from the white
muscles is allosterically regulated within broad
limits. The muscles of all vertebrates have high
activities of AMP deaminase; however, in fish the
activities in the gills may be much higher than
those in the muscles [196]. In the dogfish Scyliorrhinus canicula, the erythrocytes contain high
activities of an AMP deaminase that is labile but
otherwise similar to the muscle enzyme; in other
vertebrates the red blood cells contain relatively
low activities of this enzyme [195]. The activity in
the liver of frogs of the genus Rana is tenfold
higher than in the liver of other vertebrates. In
the chicken and the lizard Lacerta agilis, the liver
contains two types of AMP deaminase, one of
which is activated not only by ATP and ADP but
also by GTP; in contrast, GTP is inhibitory to the
liver enzymes of the rat and the frog. It may be
that the existence of an additional, GTPactivated liver enzyme in the birds and reptiles is
associated with their urotelic metabolism [234].
AMP deaminase appears to be completely
absent from many mussels and arthropods; it is
present at relatively low activities in the muscles
of the lobster, in the hepatopancreas of the snail
Helix aspersa and the mussel Meretrix meretrix,
and in the body wall of the polychaete Arenicola
cristata. In contrast, its activity is 18-fold higher in
the gut of the earthworm Lumbricus terrestris
than in the body wall, and in the muscular foot of
the edible snail it is 5- to to-fold higher than in
vertebrate muscle. The Helix enzyme has a very
unusual substrate specificity, in that it is able to
act upon ADP, ATP and NADH as well as AMP
[235]. The AMP deaminases of the crustaceans
Orconectes limosus and Palaemon serratus also
appear to be very different to the vertebrate enzymes in their structural and functional properties
[197].
Adenosine deaminases have been demonstrated in vertebrates of all classes, molluscs, annelids and arthropods, and are probably ubiquitous.
They deaminate deoxyadenosine as well as adenosine. In the muscles of the vertebrates the activity of adenosine « U/g fresh weight) is always
lower than that of the AMP deaminase (10-50
U/g fresh weight); in the crustaceans, gastropods
and bivalves, the two enzymes both have relatively low activities «1 U/g fresh weight). High
activities of adenosine deaminase (12-27 U/g
fresh weight) are found only in the muscles of
various cephalopods which, in contrast, have low
AMP deaminase activities «1 U/g fresh weight)
[80]. Human adenosine deaminase, which is a
polypeptide of 41 kDa with 363 amino acids, has
been sequenced via the cDNA [263]. The only