Homo Sapiens Fetal
Deoxyhemoglobin
Ubongabasi Asuquo '23 and Serena Liu '23
Contents:
I. Introduction
Homo sapiens fetal hemoglobin (HbF) is an oxygen carrier
protein in the human fetus. It constitutes approximately 60 to
80 percent of total hemoglobin in the full-term newborn. It
transports oxygen from the mother's bloodstream to the fetal
circulation. From early pregnancy through the first six months
of postnatal life, erythroid precursor cells produce HbF cells.
HbF contains
and
as
opposed to human adult hemoglobin (HbA), which consist of two
alpha subunits and two beta subunits. Compared to HbA, HbF has a
higher affinity of oxygen in vivo as a result of
negatively charged phosphates, giving HbF the ability to bind to
oxygen from maternal circulation. Here, we elaborate on the
structure of human fetal deoxyhemoglobin. Deoxyhemoglobin is the
form of hemoglobin that is not combined with oxygen. The four
subunits are free, and because of that it is in the tense (T)
state of hemoglobin. It is more soluble in this form, and it has
a decreased binding affinity to 2,3-bisphosphoglycerate (2,3-DPG), an
allosteric regulator, relative to deoxyHbA.
II. General Structure
HbF is an α2γ2 tetramer with a more compact overall
structure. It can exist in both
.
The two α chains are termed αA and
αF chains respectively. They are identical in amino
acid composition, with both containing
of alanine,
leucine, and valine
and none containing isoleucine. They also contain the same the
tryptic peptide patterns and other subunit hydrizations. Out of
fourteen possible tryptic peptides, twelve soluble peptides
present in the αF chains showed similar amino acid
compositions to equivalent peptides present in the αA
chain.
The γ subunits contain 146 residues each and
are considered to be homologous to the β adult hemoglobin chains.
Despite its close similarity, γ differs from β at 39 positions.
The gamma subunit is responsible for the 70 fold enhanced strength
of its tetramer-dimer dissociation constant. This is caused by the
18-amino-acid
in the
A helix, particularly
. In addition, the γ
subunit generally contains four isoleucine residues per
polypeptide chain and its N-terminal sequence is often acetylated
ending in
.
Unfortunately, the biological role of this acetylation is unknown
at this time. In terms of protein charge, the positive charge of
the gamma chain is relatively greater in the
lys-104,
ser-139, and ser-143.
Some residues on side chains participate in hydrogen bonding;
others are responsible for subunit contacts, internal and external
surfaces and surface cervice. γ chains can also participate in
disulfide bond formation as a result of
on the chains.
III. Adult vs. Fetal Hemoglobin
The three main functional differences between adult and
fetal hemoglobin include: the increased oxygen affinity of HbF,
the higher solubility of HbF in its deoxygenated form, and its
higher tetramer-dimer dissociation constant. The higher
solubility of deoxyHbF is a result of replacement of Glu by
on the γ chains.
This replacement lengthens the distance between the carboxyl
group and the imidazole and thus weakens the electrostatic
attraction between them. The primary sequence differences are
mainly characterized in the
,
,
,
,
, and the
of the
polypeptide chain (Table 1). These amino acid sequences hence
contribute to the above mentioned functional differences.
Table 1. Sequence
differences between beta chain and gamma chain (Frier and
Perutz, 1977).
IV. Subunit Assembly & Interactions
The ways through which the assembly of the α and γ
subunits occur have been explored and are characterized to
be slower when compared to the assembly of adult
hemoglobin. This assembly is generally believed to occur
by a multi-step mechanism, through which gamma chains assemble
with alpha chains first with the help of
: helix
A, helix E,
and helix H, and then
stable γ2-chain dimers will be formed.
In addition, the dimers when formed are relatively
stable unlike the dimers formed with beta chains,
particularly α1γ1 versus α1β1. In addition, alpha chains
exist in a monomer/dimer equilibrium and favor formation of
monomers, whereas gamma chains are stablized in a
monomer/tetramer equilibrium and favor the formation of
tetramers. In general, when compared to beta adult
hemoglobin chain, ala-51,
thr-112, ile-116,
glu-125, and asp-43
help at the
to
assemble the tetramer.
These interactions mentioned about are
responsible for the increased stability of fetal hemoglobin.
They are also
responsible for the observed differences in the assembly of
αγ versus αβ assembly in vitro and promotes the dissociation
of gamma tetramers to dimers and monomers.
on the gamma chain at the tetramer-dimer
allosteric interaction contributes to the increased oxygen
affinity of HbF by tightening the tetramer-dimer interface.
When HbF binds oxygen, there is a rearrangement of subunits
at the tetramer-dimer interface. This leads to the position
of the R/T equilibrium changing, tightening the interface
thus increasing the affinity for oxygen binding and
gradually changing the protein configuration from a deoxy- to
oxy- state. On the opposite end, this subtitution also lowers
the response of HbF to the binding of
2,3-bisphosphoglycerate (2,3-DPG), which is an allosteric
regulator synthesized in tissues with low ATP and high acid
production.
In addition, two water molecules are also found at the α1γ1
interface of fetal deoxyhemoglobin. They form two
, one between
alpha thr-38 and gamma
asp-99, and another
between alpha thr-41 and
gamma asp-99. The third
water molecule which would usually be present in adult
hemoglobin is not found in the α1γ1 contact of deoxyHbF.
Instead, it is bonded to the carbonyl oxygen of Thr-41 and
to N of Arg-40.
V. Heme Group
Fetal hemoglobin contains
with each chain containing one respectively. Each heme
includes a Fe2+
bound in
the center of a porphyrin, a large heterocyclic organic
ring. The ferrous ion has two axial binding sites. The
first site is occupied by an N of the closest histidine.
The second site makes reversible binding to an oxygen atom
possible through ion-induced dipole forces. The heme groups can bind and unbind oxygen, allowing oxygen to be transported (Figure 1).
Figure 1.
Difference between oxy- and deoxy-heme. (A)
Oxyhemoglobin has dioxygen (depicted as red)
bound to the iron core of each heme group.
The Fe2+ is centered in the
porphyrin plane. (B) Deoxyhemoglobin is
pictured (no oxygen is bound). The Fe2+
ion lies 0.4 Å outside of the porphyrin
plane (Hemoglobin: Oxygen transport in
mammals [Internet]. 2020).
VI. References
Adachi, K., Y. Zhao,
T. Yamaguchi, and S. Surrey. 2000.
Assembly of γ- with α-Globin Chains to
Form Human Fetal Hemoglobin in Vitro and
in Vivo. Journal of Biological
Chemistry 275:1242412429. Elsevier.
Frier, J. A., and
M. F. Perutz. 1977. Structure of human
foetal deoxyhaemoglobin. J Mol Biol
112:97-112.
Hemoglobin: Oxygen
transport in mammals [Internet]. 2020
[cited Dec 16 2021]. Available from:
https://chem.libretexts.org/@go/page/188720
Kaufman, D. P., J.
Khattar, and S. L. Lappin. 2021.
Physiology, Fetal Hemoglobin. StatPearls.
StatPearls Publishing, Treasure Island
(FL).
Schroeder, W. A.,
J. R. Shelton, J. B. Shelton, and J.
Cormick. 1962. Further sequences in the
γ chain of human fetal hemoglobin. National
Academy of Sciences .PNAS
48:284-287.
Schroeder, W. A.,
J. R. Shelton, J. B. Shelton, and J.
Cormick. 1963. The amino acid sequence
of the α chain of human fetal
hemoglobin. Biochemistry 2:1353-1357.
Schroeder, W. A.,
J. R. Shelton, J. B. Shelton, J.
Cormick, and R. T. Jones. 1963b. The
Amino Acid Sequence of the γ Chain of
Human Fetal Hemoglobin. Biochemistry
2:992-1008. American Chemical Society.
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