Differential effects on enzyme stability and kinetic parameters of mutants related to human triosephosphate isomerase deficiency.


Abstract

Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D.

Submission Details

ID: uiAUwBD64

Submitter: Shu-Ching Ou

Submission Date: Jan. 17, 2019, 3:27 p.m.

Version: 1

Publication Details
Cabrera N;Torres-Larios A;García-Torres I;Enríquez-Flores S;Perez-Montfort R,Biochim Biophys Acta Gen Subj (2018) Differential effects on enzyme stability and kinetic parameters of mutants related to human triosephosphate isomerase deficiency. PMID:29571745
Additional Information

C41->C43, A62->A64, G72->G74, E104->E106, G122->G124, V154->V156, I170->I172, V231->V233, F240->F242

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
4P61 2014-08-27 1.34 CHICKEN TRIOSEPHOSPHATE ISOMERASE WITH LOOP6 MUTATIONS, V167P AND W168E.
1R2R 2003-12-23 1.5 CRYSTAL STRUCTURE OF RABBIT MUSCLE TRIOSEPHOSPHATE ISOMERASE
4UNL 2015-02-04 1.5 Crystal structure of a single mutant (N71D) of triosephosphate isomerase from human
4OWG 2014-03-05 1.55 Crystal structure of rabbit muscle triosephosphate isomerase-PEP complex
4POC 2015-01-14 1.6 Structure of Triosephosphate Isomerase Wild Type human enzyme.
4ZVJ 2016-03-09 1.7 Structure of human triose phosphate isomerase K13M
2JK2 2008-07-01 1.7 STRUCTURAL BASIS OF HUMAN TRIOSEPHOSPHATE ISOMERASE DEFICIENCY. CRYSTAL STRUCTURE OF THE WILD TYPE ENZYME.
1SW0 2004-08-24 1.71 Triosephosphate isomerase from Gallus gallus, loop 6 hinge mutant K174L, T175W
1TPH 1994-04-30 1.8 1.8 ANGSTROMS CRYSTAL STRUCTURE OF WILD TYPE CHICKEN TRIOSEPHOSPHATE ISOMERASE-PHOSPHOGLYCOLOHYDROXAMATE COMPLEX
2VOM 2008-06-17 1.85 Structural basis of human triosephosphate isomerase deficiency. Mutation E104D and correlation to solvent perturbation.
4BR1 2013-06-12 1.9 Protease-induced heterodimer of human triosephosphate isomerase.
1TPB 1995-02-14 1.9 OFFSET OF A CATALYTIC LESION BY A BOUND WATER SOLUBLE
1TPU 1995-04-20 1.9 S96P CHANGE IS A SECOND-SITE SUPPRESSOR FOR H95N SLUGGISH MUTANT TRIOSEPHOSPHATE ISOMERASE
1TPC 1995-02-14 1.9 OFFSET OF A CATALYTIC LESION BY A BOUND WATER SOLUBLE
1TPV 1995-04-20 1.9 S96P CHANGE IS A SECOND-SITE SUPPRESSOR FOR H95N SLUGGISH MUTANT TRIOSEPHOSPHATE ISOMERASE
1TPW 1995-04-20 1.9 TRIOSEPHOSPHATE ISOMERASE DRINKS WATER TO KEEP HEALTHY
1KLU 2002-08-02 1.93 Crystal structure of HLA-DR1/TPI(23-37) complexed with staphylococcal enterotoxin C3 variant 3B2 (SEC3-3B2)
4POD 2015-01-14 1.99 Structure of Triosephosphate Isomerase I170V mutant human enzyme.
4UNK 2015-02-04 2.0 Crystal structure of human triosephosphate isomerase (mutant N15D)
1SW3 2004-08-24 2.03 Triosephosphate isomerase from Gallus gallus, loop 6 mutant T175V
6D43 2018-05-16 2.04 CHARACTERIZATION OF HUMAN TRIOSEPHOSPHATE ISOMERASE S-NITROSYLATION
1SPQ 2004-08-24 2.16 Understanding protein lids: Structural analysis of active hinge mutants in triosephosphate isomerase
1WYI 2005-04-12 2.2 human triosephosphate isomerase of new crystal form
6NLH 2019-06-19 2.2 Structure of human triose phosphate isomerase R189A
1SW7 2004-08-24 2.22 Triosephosphate isomerase from Gallus gallus, loop 6 mutant K174N, T175S, A176S
1R2T 2003-12-23 2.25 CRYSTAL STRUCTURE OF RABBIT MUSCLE TRIOSEPHOSPHATE ISOMERASE
6C2G 2018-03-21 2.3 Human triosephosphate isomerase mutant V231M
1KLG 2002-08-02 2.4 Crystal structure of HLA-DR1/TPI(23-37, Thr28-->Ile mutant) complexed with staphylococcal enterotoxin C3 variant 3B2 (SEC3-3B2)
1TIM 1976-10-15 2.5 STRUCTURE OF TRIOSE PHOSPHATE ISOMERASE FROM CHICKEN MUSCLE
8TIM 1999-02-16 2.5 TRIOSE PHOSPHATE ISOMERASE
4E41 2012-08-29 2.6 Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor G4
1SU5 2004-08-24 2.7 Understanding protein lids: Structural analysis of active hinge mutants in triosephosphate isomerase
2IAN 2007-04-03 2.8 Structural basis for recognition of mutant self by a tumor-specific, MHC class II-restricted TCR
1HTI 1995-01-26 2.8 CRYSTAL STRUCTURE OF RECOMBINANT HUMAN TRIOSEPHOSPHATE ISOMERASE AT 2.8 ANGSTROMS RESOLUTION. TRIOSEPHOSPHATE ISOMERASE RELATED HUMAN GENETIC DISORDERS AND COMPARISON WITH THE TRYPANOSOMAL ENZYME
2IAM 2007-04-03 2.8 Structural basis for recognition of mutant self by a tumor-specific, MHC class II-restricted TCR
1SQ7 2004-08-24 2.85 Understanding protein lids: Structural analysis of active hinge mutants in triosephosphate isomerase
1R2S 2003-12-23 2.85 CRYSTAL STRUCTURE OF RABBIT MUSCLE TRIOSEPHOSPHATE ISOMERASE
1SSG 2004-08-24 2.9 Understanding protein lids: Structural analysis of active hinge mutants in triosephosphate isomerase
1SSD 2004-08-24 2.9 Understanding protein lids: Structural analysis of active hinge mutants in triosephosphate isomerase

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
200.0 A,B Triosephosphate isomerase P60174 TPIS_HUMAN
200.0 A,B Triosephosphate isomerase P60175 TPIS_PANTR
198.4 A,B Triosephosphate isomerase Q60HC9 TPIS_MACFA
198.4 A,B Triosephosphate isomerase P15426 TPIS_MACMU
198.4 A,B Triosephosphate isomerase Q2QD07 TPIS_GORGO
199.2 A,B Triosephosphate isomerase Q5R928 TPIS_PONAB
196.8 A,B Triosephosphate isomerase P00939 TPIS_RABIT
196.8 A,B Triosephosphate isomerase P54714 TPIS_CANLF
195.2 A,B Triosephosphate isomerase Q5E956 TPIS_BOVIN
192.0 A,B Triosephosphate isomerase P17751 TPIS_MOUSE
188.8 A,B Triosephosphate isomerase P48500 TPIS_RAT
187.0 A,B Triosephosphate isomerase Q29371 TPIS_PIG
180.4 A,B Triosephosphate isomerase P00940 TPIS_CHICK