Reviewed, UniProtKB/Swiss-Prot P60174 (TPIS_HUMAN)

Names and origin

Protein names

Recommended name:
    Triosephosphate isomerase
      Short name=TIM
    EC=5.3.1.1
Alternative name(s):
    Triose-phosphate isomerase

Gene names

Name:	TPI1
Synonyms:	TPI

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	249 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	D-glyceraldehyde 3-phosphate = glycerone phosphate.
Pathway	Carbohydrate biosynthesis; gluconeogenesis. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate from glycerone phosphate: step 1/1.
Subunit structure	Homodimer. Ref.20 Ref.22
Involvement in disease	Defects in TPI1 are the cause of triosephosphate isomerase deficiency (TPI deficiency) [MIM:190450]. TPI deficiency is an autosomal recessive disorder. It is the most severe clinical disorder of glycolysis. It is associated with neonatal jaundice, chronic hemolytic anemia, progressive neuromuscular dysfunction, cardiomyopathy and increased susceptibility to infection.
Sequence similarities	Belongs to the triosephosphate isomerase family.

Ontologies

Keywords
Biological process	Fatty acid biosynthesis Gluconeogenesis Glycolysis Lipid synthesis Pentose shunt
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Molecular function	Isomerase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	fatty acid biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW gluconeogenesis Inferred from electronic annotation. Source: UniProtKB-KW glycolysis Inferred from electronic annotation. Source: UniProtKB-KW pentose-phosphate shunt Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.1 Inferred from Experiment. Source: Reactome
Molecular function	triose-phosphate isomerase activity Ref.1 Ref.2 Ref.23 Traceable author statement. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P60174-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P60174-2)

The sequence of this isoform differs from the canonical sequence as follows:
     180-249: QQAQEVHEKL...EFVDIINAKQ → PHPNCIFLYC...EGRRETILSL

Note: No experimental confirmation available. Alternative splicing seems doubtful, since exon-intron junctions are not the consensus ones.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.8 Ref.9

Chain

2 – 249

248

Triosephosphate isomerase

PRO_0000090113

Sites

Active site

96

1

Electrophile

Active site

166

1

Proton acceptor

Binding site

12

1

Substrate

Binding site

14

1

Substrate

Amino acid modifications

Modified residue

21

1

Phosphoserine Ref.12 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18

Modified residue

188

1

N6-acetyllysine Ref.13

Natural variations

Alternative sequence

180 – 249

70

QQAQE…INAKQ → PHPNCIFLYCLYLHPVMVGT RPIPSPLTIMVGTKRHQGGF SLAERWKAWWDLLLGSLGPS EGRRETILSL in isoform 2.

VSP_011958

Natural variant

42

1

C → Y in TPI deficiency.

VAR_007534

Natural variant

73

1

G → A in TPI deficiency.

VAR_007535

Natural variant

105

1

E → D in TPI deficiency; the enzyme becomes thermolabile.

VAR_007536

Natural variant

123

1

G → R in Manchester; thermolabile.

VAR_007537

Natural variant

155

1

V → M in TPI deficiency.

VAR_007538

Natural variant

171

1

I → V in TPI deficiency.

VAR_007539

Natural variant

232

1

V → M in TPI deficiency.

VAR_007540

Natural variant

241

1

F → L in TPI deficiency; Hungary; thermolabile.

VAR_007541

Experimental info

Sequence conflict

20 – 21

2

QS → KN AA sequence Ref.1

Sequence conflict

27

1

G → S AA sequence Ref.1

Sequence conflict

30 – 31

2

NA → QG AA sequence Ref.1

Sequence conflict

43 – 44

2

AP → IG AA sequence Ref.1

Sequence conflict

58

1

P → Q AA sequence Ref.1

Sequence conflict

155

1

V → A in AAH17917. Ref.7

Sequence conflict

167

1

P → N AA sequence Ref.1

Sequence conflict

244

1

I → L AA sequence Ref.1

Secondary structure

1

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249

Helix Strand Turn

Details...

Beta strand

7 – 12

6

Helix

19 – 30

12

Beta strand

38 – 43

6

Helix

46 – 48

3

Helix

49 – 55

7

Beta strand

60 – 65

6

Beta strand

69 – 74

6

Helix

81 – 86

6

Beta strand

91 – 95

5

Helix

97 – 100

4

Helix

107 – 119

13

Beta strand

124 – 128

5

Helix

132 – 137

6

Helix

140 – 153

14

Beta strand

161 – 165

5

Helix

168 – 170

3

Beta strand

171 – 174

4

Helix

179 – 196

18

Helix

199 – 204

6

Beta strand

207 – 209

3

Turn

215 – 217

3

Helix

218 – 223

6

Beta strand

229 – 233

5

Helix

234 – 237

4

Helix

240 – 245

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 73844175635F858E	FASTA	249	26,669
	10 20 30 40 50 60 MAPSRKFFVG GNWKMNGRKQ SLGELIGTLN AAKVPADTEV VCAPPTAYID FARQKLDPKI 70 80 90 100 110 120 AVAAQNCYKV TNGAFTGEIS PGMIKDCGAT WVVLGHSERR HVFGESDELI GQKVAHALAE 130 140 150 160 170 180 GLGVIACIGE KLDEREAGIT EKVVFEQTKV IADNVKDWSK VVLAYEPVWA IGTGKTATPQ 190 200 210 220 230 240 QAQEVHEKLR GWLKSNVSDA VAQSTRIIYG GSVTGATCKE LASQPDVDGF LVGGASLKPE FVDIINAKQ
	Isoform 2. Checksum: AC986AEA381D3536	FASTA	249	27,126
	10 20 30 40 50 60 MAPSRKFFVG GNWKMNGRKQ SLGELIGTLN AAKVPADTEV VCAPPTAYID FARQKLDPKI 70 80 90 100 110 120 AVAAQNCYKV TNGAFTGEIS PGMIKDCGAT WVVLGHSERR HVFGESDELI GQKVAHALAE 130 140 150 160 170 180 GLGVIACIGE KLDEREAGIT EKVVFEQTKV IADNVKDWSK VVLAYEPVWA IGTGKTATPP 190 200 210 220 230 240 HPNCIFLYCL YLHPVMVGTR PIPSPLTIMV GTKRHQGGFS LAERWKAWWD LLLGSLGPSE GRRETILSL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Primary structure of human triosephosphate isomerase." Lu H.S., Yuan P.M., Gracy R.W. J. Biol. Chem. 259:11958-11968(1984) [PubMed: 6434534] [Abstract] Cited for: PROTEIN SEQUENCE (ISOFORM 1).
[2]	"Human triosephosphate isomerase cDNA and protein structure. Studies of triosephosphate isomerase deficiency in man." Maquat L.E., Chilcote R., Ryan P.M. J. Biol. Chem. 260:3748-3753(1985) [PubMed: 2579079] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"Characterization of the functional gene and several processed pseudogenes in the human triosephosphate isomerase gene family." Brown J.R., Daar I.O., Krug J.R., Maquat L.E. Mol. Cell. Biol. 5:1694-1706(1985) [PubMed: 4022011] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	Belgrader P., Boyer T., Daar I., Cheng J., Nesic D., Maquat L.E. Submitted (DEC-1992) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE (ISOFORM 1). Tissue: Liver.
[5]	"A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13." Ansari-Lari M.A., Muzny D.M., Lu J., Lu F., Lilley C.E., Spanos S., Malley T., Gibbs R.A. Genome Res. 6:314-326(1996) [PubMed: 8723724] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Large-scale sequencing in human chromosome 12p13: experimental and computational gene structure determination." Ansari-Lari M.A., Shen Y., Muzny D.M., Lee W., Gibbs R.A. Genome Res. 7:268-280(1997) [PubMed: 9074930] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Brain, Kidney, Placenta, Prostate, Skeletal muscle, Skin and Uterus.
[8]	"Two-dimensional electrophoretic analysis of human breast carcinoma proteins: mapping of proteins that bind to the SH3 domain of mixed lineage kinase MLK2." Rasmussen R.K., Ji H., Eddes J.S., Moritz R.L., Reid G.E., Simpson R.J., Dorow D.S. Electrophoresis 18:588-598(1997) [PubMed: 9150946] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-20. Tissue: Mammary carcinoma.
[9]	"A two-dimensional gel database of human colon carcinoma proteins." Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J. Electrophoresis 18:605-613(1997) [PubMed: 9150948] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-20. Tissue: Colon carcinoma.
[10]	"Transcriptional regulatory sequences of the housekeeping gene for human triosephosphate isomerase." Boyer T.G., Krug J.R., Maquat L.E. J. Biol. Chem. 264:5177-5187(1989) [PubMed: 2925688] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-5.
[11]	Lubec G., Vishwanath V., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 6-14; 19-53; 60-131; 143-156; 161-175 AND 195-219, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[12]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY. Tissue: Epithelium.
[13]	"Substrate and functional diversity of lysine acetylation revealed by a proteomics survey." Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T., Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y. Mol. Cell 23:607-618(2006) [PubMed: 16916647] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-188, MASS SPECTROMETRY. Tissue: Epithelium.
[14]	"Phosphoproteomic analysis of the human pituitary." Beranova-Giorgianni S., Zhao Y., Desiderio D.M., Giorgianni F. Pituitary 9:109-120(2006) [PubMed: 16807684] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY. Tissue: Pituitary.
[15]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY. Tissue: Epithelium.
[16]	"Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction." Tang L.-Y., Deng N., Wang L.-S., Dai J., Wang Z.-L., Jiang X.-S., Li S.-J., Li L., Sheng Q.-H., Wu D.-Q., Li L., Zeng R. Mol. Cell. Proteomics 6:1952-1967(2007) [PubMed: 17693683] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY.
[17]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY.
[18]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, MASS SPECTROMETRY.
[19]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[20]	"Crystal structure of recombinant human triosephosphate isomerase at 2.8-A resolution. Triosephosphate isomerase-related human genetic disorders and comparison with the trypanosomal enzyme." Mande S.C., Mainfroid V., Kalk K.H., Goraj K., Martial J.A., Hol W.G.J. Protein Sci. 3:810-821(1994) [PubMed: 8061610] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH SUBSTRATE ANALOG, HOMODIMERIZATION.
[21]	"Structure of a high-resolution crystal form of human triosephosphate isomerase: improvement of crystals using the gel-tube method." Kinoshita T., Maruki R., Warizaya M., Nakajima H., Nishimura S. Acta Crystallogr. F 61:346-349(2005) [PubMed: 16511037] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
[22]	"Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface." Rodriguez-Almazan C., Arreola R., Rodriguez-Larrea D., Aguirre-Lopez B., de Gomez-Puyou M.T., Perez-Montfort R., Costas M., Gomez-Puyou A., Torres-Larios A. J. Biol. Chem. 283:23254-23263(2008) [PubMed: 18562316] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF MUTANT ASP-105, SUBUNIT, CHARACTERIZATION OF VARIANT ASP-105.
[23]	"Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme." Daar I.O., Artymiuk P.J., Phillips D.C., Maquat L.E. Proc. Natl. Acad. Sci. U.S.A. 83:7903-7907(1986) [PubMed: 2876430] [Abstract] Cited for: VARIANT TPI DEFICIENCY ASP-105.
[24]	"Relation between genetic defect, altered protein structure, and enzyme function in triose-phosphate isomerase (TPI) deficiency." Neubauer B.A., Pekrun A., Eber S.W., Lakomek M., Schroeter W. Eur. J. Pediatr. Suppl. 151:232-232(1992) Cited for: VARIANTS TPI DEFICIENCY ASP-105 AND MET-232.
[25]	"Human triosephosphate isomerase: substitution of Arg for Gly at position 122 in a thermolabile electromorph variant, TPI-Manchester." Perry B.A., Mohrenweiser H.W. Hum. Genet. 88:634-638(1992) [PubMed: 1339398] [Abstract] Cited for: VARIANT MANCHESTER ARG-123.
[26]	"Human triosephosphate isomerase deficiency resulting from mutation of Phe-240." Chang M.-L., Artymiuk P.J., Wu X., Hollan S., Lammi A., Maquat L.E. Am. J. Hum. Genet. 52:1260-1269(1993) [PubMed: 8503454] [Abstract] Cited for: VARIANT TPI DEFICIENCY HUNGARY LEU-241.
[27]	"Molecular analysis of a series of alleles in humans with reduced activity at the triosephosphate isomerase locus." Watanabe M., Zingg B.C., Mohrenweiser H.W. Am. J. Hum. Genet. 58:308-316(1996) [PubMed: 8571957] [Abstract] Cited for: VARIANTS TPI DEFICIENCY ALA-73; ASP-105 AND MET-155.
[28]	"Evidence for founder effect of the Glu104Asp substitution and identification of new mutations in triosephosphate isomerase deficiency." Arya R., Lalloz M.R.A., Bellingham A.J., Layton D.M. Hum. Mutat. 10:290-294(1997) [PubMed: 9338582] [Abstract] Cited for: VARIANTS TPI DEFICIENCY TYR-42; ASP-105 AND VAL-171.
+	Additional computationally mapped references.

Web resources

Wikipedia

Triosephosphate isomerase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

M10036 mRNA. Translation: AAB59511.1.
X69723 Genomic DNA. Translation: CAA49379.1.
U47924 Genomic DNA. Translation: AAB51316.1.
BC007086 mRNA. Translation: AAH07086.1.
BC007812 mRNA. Translation: AAH07812.1.
BC009329 mRNA. Translation: AAH09329.1.
BC011611 mRNA. Translation: AAH11611.1.
BC015100 mRNA. Translation: AAH15100.1.
BC017165 mRNA. Translation: AAH17165.1.
BC017917 mRNA. Translation: AAH17917.1.
BC070129 mRNA. Translation: AAH70129.1.
J04603 Genomic DNA. Translation: AAN86636.1.

IPI

IPI00451401.
IPI00465028.

PIR

ISHUT. S29743.

RefSeq

NP_000356.1.

UniGene

Hs.524219

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HTI	X-ray	2.80	A/B	2-249	[»]
1WYI	X-ray	2.20	A/B	2-249	[»]
2IAM	X-ray	2.80	P	23-37	[»]
2IAN	X-ray	2.80	C/H/M/R	23-37	[»]
2JK2	X-ray	1.70	A/B	2-249	[»]
2VOM	X-ray	1.85	A/B/C/D	2-249	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P60174. 4 interactions.

PTM databases

PhosphoSite

P60174.

2-D gel databases

SWISS-2DPAGE

P60174.

Aarhus/Ghent-2DPAGE

1111. IEF.
2112. IEF.

DOSAC-COBS-2DPAGE

P60174.

HSC-2DPAGE

P60174.

PMMA-2DPAGE

P60174.

REPRODUCTION-2DPAGE

IPI00797687.
P60174.

Siena-2DPAGE

P60174.

Proteomic databases

PRIDE

P60174.

Genome annotation databases

Ensembl

ENSG00000111669. Homo sapiens. [Contig view]

GeneID

7167.

KEGG

hsa:7167.

Organism-specific databases

GeneCards

GC01P076926.
GC12P006846.

H-InvDB

HIX0010385.
HIX0029631.

HGNC

HGNC:12009. TPI1.

HPA

CAB004675.

MIM

190450. gene+phenotype.

Orphanet

868. Triose phosphate-isomerase deficiency.

PharmGKB

PA36689.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P60174.

OMA

P60174. PNCIFLY.

Enzyme and pathway databases

BRENDA

5.3.1.1. 247.

Reactome

REACT_474. Metabolism of carbohydrates.

Gene expression databases

Bgee

P60174.

CleanEx

HS_TPI1.

GermOnline

ENSG00000111669. Homo sapiens.

Family and domain databases

InterPro

IPR013785. Aldolase_TIM.
IPR000652. Triosephosphate_isomerase.
[Graphical view]

Gene3D

G3DSA:3.20.20.70. Aldolase_TIM. 1 hit.

PANTHER

PTHR21139. Triophos_ismrse. 1 hit.

Pfam

PF00121. TIM. 1 hit.
[Graphical view]

ProDom

PD001005. Triophos_ismrse. 1 hit.
[Graphical view] [Entries sharing at least one domain]

TIGRFAMs

TIGR00419. tim. 1 hit.

PROSITE

PS00171. TIM_1. 1 hit.
PS51440. TIM_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

28066.

SOURCE

Search...

Entry information

Entry name

TPIS_HUMAN

Accession

Primary (citable) accession number: P60174
Secondary accession number(s): P00938 , Q6IS07, Q8WWD0, Q96AG5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	June 16, 2009
This is version 71 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)