Triosephosphate isomerase (TPI) deficiency is a unique glycolytic enzymopathy coupled with neurodegeneration. Two Hungarian compound heterozygote brothers inherited the same TPI mutations (F240L and E145Stop), but only the younger one suffers from neurodegeneration. In the present study, we determined the kinetic parameters of key glycolytic enzymes including the mutant TPI for rational modelling of erythrocyte glycolysis. We found that a low TPI activity in the mutant cells (lower than predicted from the protein level and specific activity of the purified recombinant enzyme) is coupled with an increase in the activities of glycolytic kinases. The modelling rendered it possible to establish the steady-state flux of the glycolysis and metabolite concentrations, which was not possible experimentally due to the inactivation of the mutant TPI and other enzymes during the pre-steady state. Our results showed that the flux was 2.5-fold higher and the concentration of DHAP (dihydroxyacetone phosphate) and fructose 1,6-bisphosphate increased 40- and 5-fold respectively in the erythrocytes of the patient compared with the control. Although the rapid equilibration of triosephosphates is not achieved, the energy state of the cells is not ‘sick’ due to the activation of key regulatory enzymes. In lymphocytes of the two brothers, the TPI activity was also lower (20%) than that of controls; however, the remaining activity was high enough to maintain the rapid equilibration of triosephosphates; consequently, no accumulation of DHAP occurs, as judged by our experimental and computational data. Interestingly, we found significant differences in the mRNA levels of the brothers for TPI and some other, apparently unrelated, proteins. One of them is the prolyl oligopeptidase, the activity decrease of which has been reported in well-characterized neurodegenerative diseases. We found that the peptidase activity of the affected brother was reduced by 30% compared with that of his neurologically intact brother.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
December 2005
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
December 06 2005
Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels
Judit Oláh;
Judit Oláh
*Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1518, P.O. Box 7, Budapest, Hungary
Search for other works by this author on:
Ferenc Orosz;
Ferenc Orosz
*Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1518, P.O. Box 7, Budapest, Hungary
Search for other works by this author on:
László G. Puskás;
László G. Puskás
†Laboratory of Functional Genomics, Biological Research Center, Hungarian Academy of Sciences, H-6701, P.O. Box 521, Szeged, Hungary
Search for other works by this author on:
László Hackler, Jr;
László Hackler, Jr
†Laboratory of Functional Genomics, Biological Research Center, Hungarian Academy of Sciences, H-6701, P.O. Box 521, Szeged, Hungary
Search for other works by this author on:
Margit Horányi;
Margit Horányi
‡National Institute of Blood Transfusion, Budapest, Hungary
Search for other works by this author on:
László Polgár;
László Polgár
*Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1518, P.O. Box 7, Budapest, Hungary
Search for other works by this author on:
Susan Hollán;
Susan Hollán
‡National Institute of Blood Transfusion, Budapest, Hungary
Search for other works by this author on:
Judit Ovádi
Judit Ovádi
1
*Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1518, P.O. Box 7, Budapest, Hungary
1To whom correspondence should be addressed (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
June 22 2005
Revision Received:
August 05 2005
Accepted:
August 09 2005
Accepted Manuscript online:
August 09 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 392 (3): 675–683.
Article history
Received:
June 22 2005
Revision Received:
August 05 2005
Accepted:
August 09 2005
Accepted Manuscript online:
August 09 2005
Citation
Judit Oláh, Ferenc Orosz, László G. Puskás, László Hackler, Margit Horányi, László Polgár, Susan Hollán, Judit Ovádi; Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels. Biochem J 15 December 2005; 392 (3): 675–683. doi: https://doi.org/10.1042/BJ20050993
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |