Gene Ther Mol Biol Vol 9, 181-182,
2005
Elongation of a globin
chains, does excessive amino acids and helices relate to clinical
manifestation?
Viroj Wiwanitkit
Department of Laboratory Medicine, Faculty of Medicine,
Chulalongkorn University, Bangkok Thailand 10330
__________________________________________________________________________________
*Correspondence: Viroj Wiwanitkit, M.D., Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 10330; Tel: 662 256 4136; Fax: 662 218 3640; e-mail: Viroj.W@Chula.ac.th
Key words: Hb disorder, a, globin, elongation, helix,
amino acid
Summary
Haemoglobin
variants in which a disorder results in chain elongation are unusual. For a globin chain, the elongation of
haemoglobin is believed to relate to the clinical manifestations such as those
in hemoglobin H diseases. Although the primary structures of Hb disorders with elongated a globin chains are well-known the secondary structure of
them is not well documented. The study on the tertiary structures of the
elongated part in those Hb can help explain more in the pathogenesis of the
disorders is needed. Here, the author performs a bioinformatic analysis for
nanohematology to study the secondary structures of three well described Hb
disorders, Hb Pak Num Po, Hb Pakse and Hb Constant Spring with elongated a globin chains. According to the
analysis, the trend of increase aberration relating with increased excessive
amino acids and excessive helical residues are noted. However, generalization
to other Hb disorders, than these 3 disorders, needs further experimental
studies..
Haemoglobin variants in which a disorder results in
chain elongation are unusual (Bunn et al, 1975; Wiwanitkit, 2004). The first
two well-known disorders are haemoglobin Tak (Wiwanitkit, 2004) and haemoglobin
Cranston (Bunn et al, 1975). However, there are other haemoglobinopathies with chain
elongation. For a globin chain, the
elongation of haemoglobin is believed to relate to the clinical manifestations
such as those in hemoglobin H diseases.
Although the primary structures of Hb disorders with elongated a globin chains are well-known the secondary structure of them is not well documented. The study on the tertiary structures of the elongated part in those Hb can help explain
more in the pathogenesis of the disorders is
needed. Here, the author
performs a bioinformatic analysis for nanohematology to study the secondary structures of three well described Hb disorders with elongated a globin chains. Answering this question, a computer-based
study for protein structure modeling is performed.
II. Material and Methods
The author used the bioinformatics
techniques to perform structure modelings. The four studied Hb disorders with
abnormal elongation of a globin chains include Hb
Pakse [codon 142 (TAA-->TAT or Term-->Tyr)](Sanchaisuriya et al, 2002),
Hb Constant spring [codon 142 (TAA-->CAA or Term-->Gln)] (Steinberg and
Adams, 1983; Harteveld et al, 2001) and Hb Pak Num Po [codon 131/132 +T]
(Viprakasit et al, 2004a). The primary amino acid sequence of the elongated part in those Hb disorders is used for further
structural modeling. Concerning secondary
structure modeling, the author performs protein secondary structure predictions
from its primary sequence using NNPREDICT server (Kneller et al, 1990). Briefly, this server is the copyright of the
University of California (www.cmpharm.ucsf.edu). The best case prediction is
79% for the class of all-aproteins (Kneller et al, 1990).
III. Results
Using NNPREDICT
server, the calculation for secondary structure of the elongated part of each
disorder was performed. A table showing the number of excessive amino acids and
helices is presented (Table 1).
Here, the author performed a structural analysis for
the elongated part of common Hb disorders with elongation of a globin chains. Concerning the secondary structure
analysis, the alterations of folds in structure of globin in each structure can
be identified.
As shown in Table 1, the
hemoglobin with more
Table 1.
Underlying pathogenesis, the number of excessive amino acids and helices in
studied Hb disorders with elongated a globin chains.
|
Hb
disorders |
Number of
excessive amino acids |
Number of
excessive helical residue* |
Underlying
pathogenesis |
|
Hb Pak Num Po Hb Pakse Hb Constant Spring |
34 31 31 |
14 14 11 |
thymidine insertion after codon 131 codon 142 TAA-->TAT codon 142 TAA-->CAA |
*Data from
secondary structures prediction
excessive
amino acids has more relation to severe clinical manifestation. In this case,
the Hb Pak Num Po contains the most excessive amino acids. Indeed, this Hb
disorder,resulting frameshift, gives rise to a highly unstable a globin chain (Viprakasit et al, 2004b). This unusual a globin variant clearly causes a thalassemia and have additional effects on red cell
physiology (Viprakasit et al, 2004b). Transfusion-dependent Hb H disease is
noted (Viprakasit et al, 2004b).
There are two Hb disorders with fewer excessive amino
acids, Hb Constant Spring and Hb Pakse. Indeed, these two disorders usually
present with transfusion-independent Hb H diseases. Hb Pakse differs from Hb CS
by having lysine at 142 instead of glutamine. It also seems to lead to an
unstable a globin mRNA and slighter higher Hb H levels
(Viprakasit et al, 2002; Turbpaiboon et al, 2004). According to this study, Hb
Pakse has more additional helices comparing to Hb CS. This might imply that the
disorders with same number of excessive amino acid, one with more excessive
helical residues trends to have more severe clinical manifestation. Indeed,
the structural aberration relating to the helical residue of the globin chain
seems to show some possible correlation to hemolysis. Coleman et al studied the molecular basis of transfusion-dependent hemolytic anemia
in Hb Medicine Lake and noted that the potentially distorted B helix might
provoke further molecular instability including the presentation of mild
hemolytic anaemia (Coleman et al, 1995). However, further studies are needed to
verify this hypothesis.
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