Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 7 The Erythrocyte: Physiology, Metabolism, and Biochemical Disorders
heme acquisition by the β chain. ( Griffith and Kaltashov,
2003 ). Free α globin chains are highly unstable and tend to
aggregate within the cell and generate reactive oxygen species
through chemical reactions catalyzed by their hemebound
iron molecules. Fortunately, free α globin chains are
stabilized by binding to alpha Hb stabilizing protein (AHSP)
until they combine with free β globin chains to form stable
α-β dimers ( Weiss et al. , 2005 ). Two like α-β dimers spontaneously
combine in a readily reversible manner to form
Hb tetramers ( Bunn, 1987 ). Newly synthesized Hb is in the
form of methemoglobin (MetHb) ( Schulman et al. , 1974 ).
3 . Control of Hb Synthesis
Even though three different pathways are required for Hb
synthesis in RBC precursors and reticulocytes, minimal
intermediates (iron, globin chains, or heme) accumulate in
the cytoplasm of these cells. Several positive and negative
feedback mechanisms account for the balanced production
of these Hb components. As already discussed, an increase
in the LIP limits the uptake of additional iron by decreasing
TfR1 synthesis. The availability of iron also limits and,
thereby controls, heme synthesis. Free “ uncommitted ” heme
inhibits iron uptake by erythroid cells and consequently
heme synthesis. In addition, free heme is essential for the
synthesis of globin chains at both the transcriptional and
translational levels ( Koury and Ponka, 2004 ). Consequently,
globin synthesis does not occur in the absence of heme.
4 . Hb Types in Animals
Hb types are different in animal and human embryos than in
fetuses or in adults. Embryonal Hbs are composed of either
one or two pairs of peptide chains not found in adult Hbs
( Kitchen and Brett, 1974 ). In higher primates, embryonal
Hbs are replaced by fetal Hb composed of 2 α chains and 2
γ chains (HbF) in the fetus, followed by Hbs with 2 α chains
and 2 β chains (HbA) or 2 α chains and 2 δ chains (HbA 2 )
after birth. The γ globin gene was deleted during evolution in
artiodactyls (even-toed ungulates). The γ globin gene functions
as an embryonic gene in other nonartiodactyl mammals.
Among nonprimate mammals, a specific fetal globin gene is
expressed only in artiodactyls. In this lineage, a duplicated
β globin gene ( β F ) is expressed in the fetus, rather than a γ
globin gene. The entire β globin gene locus was duplicated
in cattle and HbB sheep and triplicated in goats and HbA
sheep during evolution ( Gumucio et al. , 1996 ). Most fetal
Hb in cattle ( α 2 β F 2 ) is replaced by adult Hb types during the
first 3 weeks after birth ( Lee et al. , 1971 ). Embryonal Hbs
are replaced by adult Hb types during the fetal period in cats,
dogs, horses, and pigs. Consequently, Hb types present in
fetuses are identical to those found in adults in these species
( Bunn and Kitchen, 1973 ; Kitchen and Brett, 1974 ).
In addition to expressing fetal Hb ( α 2 β F 2 ) in the fetus,
most goats and some sheep express a juvenile Hb ( α 2 β C 2 )
FIGURE 7-2 Changes in proportion of β globin types in Hb from five
newborn goats during the first 120 days of life. Fetal Hb contains β F . HbC
contains β C . HbD differs from HbA by a single amino acid substitution in
position 21 of their β chains, β D and β A , respectively. Modification of a
figure by Huisman et al. , 1969 .
called HbC during the neonatal period that is subsequently
replaced with adult Hb types. Sheep that produce adult
HbA ( α 2 β A 2 ) express variable amounts (generally less than
10%) of HbC during the neonatal period, but sheep that
produce adult HbB ( α 2 β B 2 ) do not express HbC in the neonatal
period ( Huisman et al. , 1969 ; Yu et al. , 2005 ). Fetal
Hb in the newborn goat is replaced almost entirely by HbC
during the first 40 days of life ( Fig. 7-2 ), and then HbC is
gradually replaced by adult Hbs ( Huisman et al. , 1969 ).
The switch from production of fetal Hb to the production
of adult Hb appears to result from an inherent programming
of hematopoietic stem cells ( Wood et al. , 1985 ).
In contrast, HbC synthesis appears to be mediated by
Epo, which is low at birth and increases after birth as the
hematocrit decreases (see Section V.C) ( Barker et al. , 1980 ;
Huisman et al. , 1969 ). Adult sheep RBCs contain little or
no HbC, but adult goat RBCs may have as much as 10%
HbC ( Huisman et al. , 1969 ). Sheep and goats that synthesize
HbC during the neonatal period will also increase HbC
synthesis in anemic adults and in nonanemic adults treated
with Epo ( Vestri et al. , 1983 ; Yu et al. , 2005 ). Most goats
and sheep with HbA have 12 genes in the β-globin locus,
including the β C gene. Cattle and sheep with HbB have 8
genes in the β -globin locus and lack the β C gene ( Garner
and Lingrel, 1988 ). HbC was not reported to occur in three
breeds of Omani goats after birth even though they were
reported to be either homozygous for HbA or heterozygous
for HbA and HbB ( Johnson et al. , 2002 ). The composition
of the β -globin locus was not investigated in these animals.
The α -globin genes have been duplicated in humans and
other mammals. Triplication of α -globin genes is relatively
common in sheep and quadruplication of genes also occurs.
There is an expression gradient of α -globin protein and α -
globin mRNA levels produced by duplicated and triplicated