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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3106-3112
RED CELLS
Distinct behavior of mutant triosephosphate isomerase in
hemolysate and in isolated form: molecular basis of enzyme
deficiency
Ferenc Orosz,
Judit Oláh,
Marco Alvarez,
György M. Keser ,
Beáta Szabó,
Gábor Wágner,
Zoltán Kovári,
Margit Horányi,
Klára Baróti,
Joseph A. Martial,
Susan Hollán, and
Judit Ovádi
From the Institute of Enzymology, Biological
Research Center, Hungarian Academy of Sciences; Computer Assisted Drug
Discovery, Chemical Works of Gedeon Richter; National Institute of
Haematology and Immunology and National Institute of Blood Transfusion;
all of Budapest, Hungary; Laboratory of Molecular Biology
and Genetics; and University of Liege, Institute of Chemistry,
Belgium.
In a Hungarian family with severe decrease in triosephosphate
isomerase (TPI) activity, 2 germ line-identical but phenotypically differing compound heterozygote brothers inherited 2 independent (Phe240Leu and Glu145stop codon) mutations. The kinetic, thermodynamic, and associative properties of the recombinant human wild-type and
Phe240Leu mutant enzymes were compared with those of TPIs in normal and
deficient erythrocyte hemolysates. The specific activity of the
recombinant mutant enzyme relative to the wild type was much higher
(30%) than expected from the activity (3%) measured in hemolysates.
Enhanced attachment of mutant TPI to erythrocyte inside-out vesicles
and to microtubules of brain cells was found when the binding was
measured with TPIs in hemolysate. In contrast, there was no difference
between the binding of the recombinant wild-type and Phe240Leu
mutant enzymes. These findings suggest that the missense mutation by
itself is not enough to explain the low catalytic activity and
"stickiness" of mutant TPI observed in hemolysate. The activity of
the mutant TPI is further reduced by its attachment to inside-out
vesicles or microtubules. Comparative studies of the hemolysate from a
British patient with Glu104Asp homozygosity and with the platelet
lysates from the Hungarian family suggest that the
microcompartmentation of TPI is not unique for the hemolysates from the
Hungarian TPI-deficient brothers. The possible role of cellular
components, other than the mutant enzymes, in the distinct
behavior of TPI in isolated form versus in hemolysates from the
compound heterozygotes and the simple heterozygote family members is discussed.
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