View source for TPI1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Triosephosphate isomerase''' is an [[enzyme]] that in humans is encoded by the ''TPI1'' [[gene]].
This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of [[glyceraldehyde 3-phosphate]] (G3P) and [[dihydroxyacetone phosphate]] (DHAP) in [[glycolysis]] and [[gluconeogenesis]]. Mutations in this gene are associated with triosephosphate isomerase deficiency. [[Pseudogene]]s have been identified on chromosomes 1, 4, 6 and 7. [[Alternative splicing]] results in multiple transcript variants.<ref name="entrez">{{cite web | title = Entrez Gene: TPI1 triosephosphate isomerase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7167}}</ref>
== Structure ==
Triose Phosphate Isomerase is a member of the alpha and beta (α/β) class of proteins; it is a homodimer, and each subunit contains 247 amino acids. Each TPI1 monomer contains the full set of catalytic residues, but the enzyme is only active in the oligomeric form.<ref>{{cite journal | vauthors = Rodríguez-Almazán C, Arreola R, Rodríguez-Larrea D, Aguirre-López B, de Gómez-Puyou MT, Pérez-Montfort R, Costas M, Gómez-Puyou A, Torres-Larios A | title = Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface | journal = The Journal of Biological Chemistry | volume = 283 | issue = 34 | pages = 23254–63 | date = Aug 2008 | pmid = 18562316 | doi = 10.1074/jbc.M802145200 | doi-access = free }}</ref> Therefore, the enzyme must be in a dimer in order to achieve full function of the enzyme, even though it is not believed that the two active sites participate in cooperativity with each other.<ref>{{cite journal | vauthors = Schnackerz KD, Gracy RW | title = Probing the catalytic sites of triosephosphate isomerase by 31P-NMR with reversibly and irreversibly binding substrate analogues | journal = European Journal of Biochemistry | volume = 199 | issue = 1 | pages = 231–8 | date = Jul 1991 | pmid = 2065677 | doi=10.1111/j.1432-1033.1991.tb16114.x| doi-access = free }}</ref> Each subunit contains 8 exterior alpha helices surrounding 8 interior beta strands, which form a conserved structural domain called a closed alpha/beta barrel (αβ) or more specifically a [[TIM barrel]].  Characteristic of most all TIM barrel domains is the presence of the enzyme's active site in the lower loop regions created by the eight loops that connect the C-termini of the beta strands with the N-termini of the alpha helices. TIM barrel proteins also share a structurally conserved [[phosphate]] binding motif, with the phosphate group found in the substrate or [[Cofactor (biochemistry)|cofactor]]s.<ref name=entrez />
In each chain, nonpolar amino acids pointing inward from the beta strands contribute to the hydrophobic core of the structure. The alpha helices are amphipathic: their outer (water-contacting) surfaces are polar, while their inner surfaces are largely hydrophobic.
== Function ==
TPI catalyzes the transfer of a hydrogen atom from carbon 1 to carbon 2, an intramolecular oxidation-reduction reaction. This isomerization of a ketose to an aldose proceeds through an ''cis''-enediol(ate) intermediate. This isomerization proceeds without any cofactors and the enzyme confers a 10<sup>9</sup> rate enhancement relative to the nonenzymatic reaction involving a chemical base (acetate ion).<ref>{{cite journal | vauthors = Davenport RC, Bash PA, Seaton BA, Karplus M, Petsko GA, Ringe D | title = Structure of the triosephosphate isomerase-phosphoglycolohydroxamate complex: an analogue of the intermediate on the reaction pathway | journal = Biochemistry | volume = 30 | issue = 24 | pages = 5821–6 | date = Jun 1991 | pmid = 2043623 | doi=10.1021/bi00238a002}}</ref> In addition to its role in glycolysis, TPI is also involved in several additional metabolic biological processes including gluconeogenesis, the pentose phosphate shunt, and fatty acid biosynthesis.
== Clinical significance ==
Triosephosphate isomerase deficiency is a disorder characterized by a shortage of red blood cells (anemia), movement problems, increased susceptibility to infection, and muscle weakness that can affect breathing and heart function. The anemia in this condition begins in infancy. Since the anemia results from the premature breakdown of red blood cells (hemolysis), it is known as hemolytic anemia. A shortage of red blood cells to carry oxygen throughout the body leads to extreme tiredness (fatigue), pale skin (pallor), and shortness of breath. When the red cells are broken down, iron and a molecule called bilirubin are released; individuals with triosephosphate isomerase deficiency have an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice, which is a yellowing of the skin and the whites of the eyes. Movement problems typically become apparent by age 2 in people with triosephosphate isomerase deficiency. The movement problems are caused by impairment of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. This impairment leads to muscle weakness and wasting (atrophy) and causes the movement problems typical of triosephosphate isomerase deficiency, including involuntary muscle tensing (dystonia), tremors, and weak muscle tone (hypotonia). Affected individuals may also develop seizures. Weakness of other muscles, such as the heart (a condition known as cardiomyopathy) and the muscle that separates the abdomen from the chest cavity (the diaphragm) can also occur in triosephosphate isomerase deficiency. Diaphragm weakness can cause breathing problems and ultimately leads to respiratory failure. Individuals with triosephosphate isomerase deficiency are at increased risk of developing infections because they have poorly functioning white blood cells. These immune system cells normally recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The most common infections in people with triosephosphate isomerase deficiency are bacterial infections of the respiratory tract. People with triosephosphate isomerase deficiency often do not survive past childhood due to respiratory failure. In a few rare cases, affected individuals without severe nerve damage or muscle weakness have lived into adulthood.<ref name=entrez /> The deficiency is most commonly caused by mutations in TPI1, although mutations in other isoforms have been identified. A common marker for TPI deficiency is the increased accumulation of DHAP in erythrocyte extracts; this is because the defective enzyme no longer has the ability to catalyze the isomerization to GAP. The point mutation does not affect the catalysis rate, but rather, affects the assembly of the enzyme into a homodimer.<ref>{{cite journal | vauthors = Ralser M, Heeren G, Breitenbach M, Lehrach H, Krobitsch S | title = Triose phosphate isomerase deficiency is caused by altered dimerization--not catalytic inactivity--of the mutant enzymes | journal = PLOS ONE | volume = 1 | pages = e30 | date = 20 December 2006 | issue = 1 | pmid = 17183658 | doi = 10.1371/journal.pone.0000030 | pmc=1762313| bibcode = 2006PLoSO...1...30R | doi-access = free }}</ref><ref>{{cite journal | vauthors = Schneider AS | title = Triosephosphate isomerase deficiency: historical perspectives and molecular aspects | journal = Baillière's Best Practice & Research. Clinical Haematology | volume = 13 | issue = 1 | pages = 119–40 | date = Mar 2000 | pmid = 10916682 | doi=10.1053/beha.2000.0061}}</ref>
Recent discoveries in [[Alzheimer's disease]] research have indicated that [[amyloid beta]] peptide-induced nitro-oxidative damage promotes the nitrotyrosination of TPI in human neuroblastoma cells.<ref>{{cite journal | vauthors = Guix FX, Ill-Raga G, Bravo R, Nakaya T, de Fabritiis G, Coma M, Miscione GP, Villà-Freixa J, Suzuki T, Fernàndez-Busquets X, Valverde MA, de Strooper B, Muñoz FJ | title = Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation | journal = Brain | volume = 132 | issue = Pt 5 | pages = 1335–45 | date = May 2009 | pmid = 19251756 | doi = 10.1093/brain/awp023 | doi-access = free | hdl = 10230/60551 | hdl-access = free }}</ref> Nitrosylated TPI was found to be present in brain slides from double transgenic mice over-expressing human amyloid precursor protein as well as in Alzheimer's disease patients. Specifically, the nitrotyrosination occurs on Tyr164 and Tyr208 within the protein, which are near the center of catalysis; this modification correlates with reduced isomerization activity.
==Interactive pathway map==
{{GlycolysisGluconeogenesis_WP534|highlight=TPI1}}
== See also ==
* [[Triosephosphate isomerase]]
== References ==
{{reflist|33em}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Ationu A, Humphries A | title = The feasibility of replacement therapy for inherited disorder of glycolysis: triosephosphate isomerase deficiency (review) | journal = International Journal of Molecular Medicine | volume = 2 | issue = 6 | pages = 701–4 | date = Dec 1998 | pmid = 9850739 | doi = 10.3892/ijmm.2.6.701 }}
* {{cite journal | vauthors = Oláh J, Orosz F, Keserü GM, Kovári Z, Kovács J, Hollán S, Ovádi J | title = Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 30–8 | date = Apr 2002 | pmid = 12023819 | doi = 10.1042/BST0300030 }}
* {{cite journal | vauthors = Rethoré MO, Kaplan JC, Junien C, Lejeune J | title = 12pter to 12p12.2: possible assignment of human triose phosphate isomerase | journal = Human Genetics | volume = 36 | issue = 2 | pages = 235–7 | date = Apr 1977 | pmid = 858628 | doi = 10.1007/BF00273263 | s2cid = 25241150 }}
* {{cite journal | vauthors = Perry BA, Mohrenweiser HW | title = Human triosephosphate isomerase: substitution of Arg for Gly at position 122 in a thermolabile electromorph variant, TPI-Manchester | journal = Human Genetics | volume = 88 | issue = 6 | pages = 634–8 | date = Mar 1992 | pmid = 1339398 | doi = 10.1007/BF02265287 | s2cid = 35721080 | url = https://zenodo.org/record/1232532 }}
* {{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–20 | date = May 1992 | pmid = 1602151 | doi = 10.1016/S0163-4453(05)80037-4 }}
* {{cite journal | vauthors = Boyer TG, Maquat LE | title = Minimal sequence and factor requirements for the initiation of transcription from an atypical, TATATAA box-containing housekeeping promoter | journal = The Journal of Biological Chemistry | volume = 265 | issue = 33 | pages = 20524–32 | date = Nov 1990 | doi = 10.1016/S0021-9258(17)30534-3 | pmid = 2243103 | doi-access = free }}
* {{cite journal | vauthors = Maquat LE, Chilcote R, Ryan PM | title = Human triosephosphate isomerase cDNA and protein structure. Studies of triosephosphate isomerase deficiency in man | journal = The Journal of Biological Chemistry | volume = 260 | issue = 6 | pages = 3748–53 | date = Mar 1985 | doi = 10.1016/S0021-9258(19)83687-6 | pmid = 2579079 | doi-access = free }}
* {{cite journal | vauthors = Daar IO, Artymiuk PJ, Phillips DC, Maquat LE | title = Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 20 | pages = 7903–7 | date = Oct 1986 | pmid = 2876430 | pmc = 386831 | doi = 10.1073/pnas.83.20.7903 | bibcode = 1986PNAS...83.7903D | doi-access = free }}
* {{cite journal | vauthors = Boyer TG, Krug JR, Maquat LE | title = Transcriptional regulatory sequences of the housekeeping gene for human triosephosphate isomerase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 9 | pages = 5177–87 | date = Mar 1989 | doi = 10.1016/S0021-9258(18)83716-4 | pmid = 2925688 | doi-access = free }}
* {{cite journal | vauthors = Brown JR, Daar IO, Krug JR, Maquat LE | title = Characterization of the functional gene and several processed pseudogenes in the human triosephosphate isomerase gene family | journal = Molecular and Cellular Biology | volume = 5 | issue = 7 | pages = 1694–706 | date = Jul 1985 | pmid = 4022011 | pmc = 367288 | doi =  10.1128/mcb.5.7.1694}}
* {{cite journal | vauthors = Lu HS, Yuan PM, Gracy RW | title = Primary structure of human triosephosphate isomerase | journal = The Journal of Biological Chemistry | volume = 259 | issue = 19 | pages = 11958–68 | date = Oct 1984 | doi = 10.1016/S0021-9258(20)71304-9 | pmid = 6434534 | doi-access = free }}
* {{cite journal | vauthors = Mande SC, Mainfroid V, Kalk KH, Goraj K, Martial JA, Hol WG | title = Crystal structure of recombinant human triosephosphate isomerase at 2.8 A resolution. Triosephosphate isomerase-related human genetic disorders and comparison with the trypanosomal enzyme | journal = Protein Science | volume = 3 | issue = 5 | pages = 810–21 | date = May 1994 | pmid = 8061610 | pmc = 2142725 | doi = 10.1002/pro.5560030510 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Chang ML, Artymiuk PJ, Wu X, Hollán S, Lammi A, Maquat LE | title = Human triosephosphate isomerase deficiency resulting from mutation of Phe-240 | journal = American Journal of Human Genetics | volume = 52 | issue = 6 | pages = 1260–9 | date = Jun 1993 | pmid = 8503454 | pmc = 1682273 }}
* {{cite journal | vauthors = Watanabe M, Zingg BC, Mohrenweiser HW | title = Molecular analysis of a series of alleles in humans with reduced activity at the triosephosphate isomerase locus | journal = American Journal of Human Genetics | volume = 58 | issue = 2 | pages = 308–16 | date = Feb 1996 | pmid = 8571957 | pmc = 1914533 }}
* {{cite journal | vauthors = Mainfroid V, Terpstra P, Beauregard M, Frère JM, Mande SC, Hol WG, Martial JA, Goraj K | title = Three hTIM mutants that provide new insights on why TIM is a dimer | journal = Journal of Molecular Biology | volume = 257 | issue = 2 | pages = 441–56 | date = Mar 1996 | pmid = 8609635 | doi = 10.1006/jmbi.1996.0174 | s2cid = 18248594 | url = https://www.rug.nl/research/portal/en/publications/three-htim-mutants-that-provide-new-insights-on-why-tim-is-a-dimer(1a3d492e-b53c-4673-95ba-6f998bb85af5).html }}
* {{cite journal | vauthors = Ansari-Lari MA, Muzny DM, Lu J, Lu F, Lilley CE, Spanos S, Malley T, Gibbs RA | title = A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13 | journal = Genome Research | volume = 6 | issue = 4 | pages = 314–26 | date = Apr 1996 | pmid = 8723724 | doi = 10.1101/gr.6.4.314 | doi-access = free }}
* {{cite journal | vauthors = Ansari-Lari MA, Shen Y, Muzny DM, Lee W, Gibbs RA | title = Large-scale sequencing in human chromosome 12p13: experimental and computational gene structure determination | journal = Genome Research | volume = 7 | issue = 3 | pages = 268–80 | date = Mar 1997 | pmid = 9074930 | doi = 10.1101/gr.7.3.268 | doi-access = free }}
* {{cite journal | vauthors = Rasmussen RK, Ji H, Eddes JS, Moritz RL, Reid GE, Simpson RJ, Dorow DS | title = Two-dimensional electrophoretic analysis of human breast carcinoma proteins: mapping of proteins that bind to the SH3 domain of mixed lineage kinase MLK2 | journal = Electrophoresis | volume = 18 | issue = 3–4 | pages = 588–98 | year = 1997 | pmid = 9150946 | doi = 10.1002/elps.1150180342 | s2cid = 37336552 }}
* {{cite journal | vauthors = Ji H, Reid GE, Moritz RL, Eddes JS, Burgess AW, Simpson RJ | title = A two-dimensional gel database of human colon carcinoma proteins | journal = Electrophoresis | volume = 18 | issue = 3–4 | pages = 605–13 | year = 1997 | pmid = 9150948 | doi = 10.1002/elps.1150180344 | s2cid = 25454450 }}
{{refend}}
== External links ==
* {{PDBe-KB2|P60174|Triosephosphate isomerase}}
{{PDB Gallery|geneid=7167}}
[[Category:Genes mutated in mice]]