(Hb B), as found in the NTP-specific haemoglobins of the teleosts. Thus, rhinoceros haemoglobins are modulated by both ATP and DPG [2]. The
organophosphates reduce the intrinsically high O2
affinities of most mammalian and avian haemoglobins to physiologically meaningful values, e.g. the
p50 for human haemoglobin is shifted from 1500 to
3200 Pa. They also effect an increase of the Bohr
effect. Some groups of mammals have haemoglobins with intrinsically low O2 affinities and these
are insensitive to organophosphates. This is true,
above all, for the super-family of the cat species
(Feloidea) with the families Felidae, Viverridae
and Hyaenidae; the super family of the bovine
species (Bovoidea) with the families Cervidae,
Antelocapridae and Bovidae; and the lemurs as
the only primates. The basic amino acid ~NA2His, important for DPG binding, is replaced here
by a neutral residue such as leucine, methionine or
phenylalanine, or, in the case of the ruminants, it
has been completely lost [131, 132]. In some vertebrate haemoglobins, e.g. Hb B of the domestic
cat or the haemoglobins of Crocodilus niloticus
and Alligator mississipiensis, the sensitivity to
organophosphates is reduced by blockage of the achain N-terminus by an acetyl group [1, 131, 132].
Changes in the effect of DPG in mammals
often have to do with adaption to unfavourable
conditions for O2 transport. Llamas and guanacos
are adapted to the lower p02 at high altitudes not
only by having a lower concentration of DPG in
their erythrocytes but also the DPG sensitivity of
their haemoglobin is markedly reduced by the
exchange of ~NA2-His for asparagine. It is more
difficult to understand why the same amino acid
substitution is also found in the haemoglobin of
elephants and the armadillo Dasypus novemcinctus; in the latter case, it might be an adaptation to
a burrowing habit. A reduced organophosphate
sensitivity of its haemoglobin also helps the goose
Anser indicus cope with the low p02 of its habitat.
This species breeds in Central Asian mountains at
altitudes of about 4000 m. The intrinsic O2 affinity of its haemoglobin is little different to that of
the domestic goose Anser anser but it is reduced
much less by IPs [19]. The effect of phosphate
increases with the number of negative charges,
e.g. in the haemoglobin of the ostrich in the order
GTP, ATP < IP4 < IPs < IP6• GTP has a much
stronger effect than ATP in many fish. This is
related to the fact that ATP has the capacity to
form only five H-bridges compared with six
formed with GTP [131, 132]. Nucleoside triphosphates affect not only the T ~ R transition, e.g.
in the haemoglobin of the tench Tinea tinea, but
7.1.3 Heterotropic Interactions
259
also the O2 affinities in the T and R states. This
does not fit the MWC model. Whereas heterotropic interactions affect and stabilize the T state
of haemoglobins in higher vertebrates, nucleoside triphosphates also affect the R state, in particular the binding constant KR [183].
The concentration and composition of the
organophosphates in the erythrocytes vary
greatly with the species and, in addition, can be
regulated during adaptation to large fluctuations
in the internal or external environment. The ATP
content of enucleate mammalian erythrocytes is
consistently lower (less than 1 [lmollml) than that
of the nucleated erythrocytes of other vertebrates
(up to 20 [lmollml). The erythrocytes of some teleosts and amphibian larvae contain about as much
GTP as ATP, and therefore assume a rather special position amongst living cells. DPG is found in
all cells as a cofactor of phosphoglycerate mutase,
but occurs only at high concentrations in the
erythrocytes of amphibians and mammals. Inositol tetracis-, pentacis- and hexacisphosphate (IP4,
IPs and IP6) are found in high concentrations not
only in avian erythrocytes but also in those of several fish and reptile species [8]. ATP normally predominates in fish erythrocytes; more GTP than
ATP is found in Mustelus, Cyp rin us , Carassius,
Anguilla, Lepomis and Esox; DPG predominates
in Entosphenus, IPs in Arapaima and Squalus, and
IP2 in Lepidosiren [8, 169]. In waters low in O2,
the concentration of nucleoside triphosphates is
reduced in most fish and the O2 affinity of the haemoglobin is therefore increased. In some species
(e.g. Pleuronectes, Fundulus, Salmo) it is the ATP
which is regulated and in others (e.g. Cyprinus
and Anquilla) it is the GTP [183].
Amongst the amphibians and reptiles, the
adults of Ambystoma, Rana and Bufo have both
DPG and ATP in their erythrocytes. Embryonal
DPG is found in turtles and crocodiles; adult crocodiles have only ATP and adult turtles also have
IPs. Iguana iguana and various snakes apparently
have IP6 [8]. In the viviparous species Sphenomorphus quoyii and Agkistrodon piscivorus
(Reptilia), Typhlonectes compressicauda (Amphibia: Gymnophiona) and Squalus suckleyi (Elasmobranchii), O2 transport from the mother to the
embryo is facilitated by the presence of organophosphates at a lower concentration in the
embryonal than in the maternal erythrocytes
[183]. The predominant organophosphate of
avian erythrocytes was previously thought to be
IP6, but in 1969 it was identified definitely as IPs.
Other inositol phosphates are present but play a
subsidiary role; the ostrich Struthio camelus is
organophosphates reduce the intrinsically high O2
affinities of most mammalian and avian haemoglobins to physiologically meaningful values, e.g. the
p50 for human haemoglobin is shifted from 1500 to
3200 Pa. They also effect an increase of the Bohr
effect. Some groups of mammals have haemoglobins with intrinsically low O2 affinities and these
are insensitive to organophosphates. This is true,
above all, for the super-family of the cat species
(Feloidea) with the families Felidae, Viverridae
and Hyaenidae; the super family of the bovine
species (Bovoidea) with the families Cervidae,
Antelocapridae and Bovidae; and the lemurs as
the only primates. The basic amino acid ~NA2His, important for DPG binding, is replaced here
by a neutral residue such as leucine, methionine or
phenylalanine, or, in the case of the ruminants, it
has been completely lost [131, 132]. In some vertebrate haemoglobins, e.g. Hb B of the domestic
cat or the haemoglobins of Crocodilus niloticus
and Alligator mississipiensis, the sensitivity to
organophosphates is reduced by blockage of the achain N-terminus by an acetyl group [1, 131, 132].
Changes in the effect of DPG in mammals
often have to do with adaption to unfavourable
conditions for O2 transport. Llamas and guanacos
are adapted to the lower p02 at high altitudes not
only by having a lower concentration of DPG in
their erythrocytes but also the DPG sensitivity of
their haemoglobin is markedly reduced by the
exchange of ~NA2-His for asparagine. It is more
difficult to understand why the same amino acid
substitution is also found in the haemoglobin of
elephants and the armadillo Dasypus novemcinctus; in the latter case, it might be an adaptation to
a burrowing habit. A reduced organophosphate
sensitivity of its haemoglobin also helps the goose
Anser indicus cope with the low p02 of its habitat.
This species breeds in Central Asian mountains at
altitudes of about 4000 m. The intrinsic O2 affinity of its haemoglobin is little different to that of
the domestic goose Anser anser but it is reduced
much less by IPs [19]. The effect of phosphate
increases with the number of negative charges,
e.g. in the haemoglobin of the ostrich in the order
GTP, ATP < IP4 < IPs < IP6• GTP has a much
stronger effect than ATP in many fish. This is
related to the fact that ATP has the capacity to
form only five H-bridges compared with six
formed with GTP [131, 132]. Nucleoside triphosphates affect not only the T ~ R transition, e.g.
in the haemoglobin of the tench Tinea tinea, but
7.1.3 Heterotropic Interactions
259
also the O2 affinities in the T and R states. This
does not fit the MWC model. Whereas heterotropic interactions affect and stabilize the T state
of haemoglobins in higher vertebrates, nucleoside triphosphates also affect the R state, in particular the binding constant KR [183].
The concentration and composition of the
organophosphates in the erythrocytes vary
greatly with the species and, in addition, can be
regulated during adaptation to large fluctuations
in the internal or external environment. The ATP
content of enucleate mammalian erythrocytes is
consistently lower (less than 1 [lmollml) than that
of the nucleated erythrocytes of other vertebrates
(up to 20 [lmollml). The erythrocytes of some teleosts and amphibian larvae contain about as much
GTP as ATP, and therefore assume a rather special position amongst living cells. DPG is found in
all cells as a cofactor of phosphoglycerate mutase,
but occurs only at high concentrations in the
erythrocytes of amphibians and mammals. Inositol tetracis-, pentacis- and hexacisphosphate (IP4,
IPs and IP6) are found in high concentrations not
only in avian erythrocytes but also in those of several fish and reptile species [8]. ATP normally predominates in fish erythrocytes; more GTP than
ATP is found in Mustelus, Cyp rin us , Carassius,
Anguilla, Lepomis and Esox; DPG predominates
in Entosphenus, IPs in Arapaima and Squalus, and
IP2 in Lepidosiren [8, 169]. In waters low in O2,
the concentration of nucleoside triphosphates is
reduced in most fish and the O2 affinity of the haemoglobin is therefore increased. In some species
(e.g. Pleuronectes, Fundulus, Salmo) it is the ATP
which is regulated and in others (e.g. Cyprinus
and Anquilla) it is the GTP [183].
Amongst the amphibians and reptiles, the
adults of Ambystoma, Rana and Bufo have both
DPG and ATP in their erythrocytes. Embryonal
DPG is found in turtles and crocodiles; adult crocodiles have only ATP and adult turtles also have
IPs. Iguana iguana and various snakes apparently
have IP6 [8]. In the viviparous species Sphenomorphus quoyii and Agkistrodon piscivorus
(Reptilia), Typhlonectes compressicauda (Amphibia: Gymnophiona) and Squalus suckleyi (Elasmobranchii), O2 transport from the mother to the
embryo is facilitated by the presence of organophosphates at a lower concentration in the
embryonal than in the maternal erythrocytes
[183]. The predominant organophosphate of
avian erythrocytes was previously thought to be
IP6, but in 1969 it was identified definitely as IPs.
Other inositol phosphates are present but play a
subsidiary role; the ostrich Struthio camelus is