| Structural highlights
2j0f is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 1uou |
| Activity: | Thymidine phosphorylase, with EC number 2.4.2.4 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[TYPH_HUMAN] Mitochondrial neurogastrointestinal encephalomyopathy. The disease is caused by mutations affecting the gene represented in this entry.[1] [2]
Function
[TYPH_HUMAN] May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro.[3] Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.[4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design.,El Omari K, Bronckaers A, Liekens S, Perez-Perez MJ, Balzarini J, Stammers DK Biochem J. 2006 Oct 15;399(2):199-204. PMID:16803458[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999 Jan 29;283(5402):689-92. PMID:9924029
- ↑ Gamez J, Ferreiro C, Accarino ML, Guarner L, Tadesse S, Marti RA, Andreu AL, Raguer N, Cervera C, Hirano M. Phenotypic variability in a Spanish family with MNGIE. Neurology. 2002 Aug 13;59(3):455-7. PMID:12177387
- ↑ Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun. 1992 May 15;184(3):1311-6. PMID:1590793
- ↑ Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun. 1992 May 15;184(3):1311-6. PMID:1590793
- ↑ El Omari K, Bronckaers A, Liekens S, Perez-Perez MJ, Balzarini J, Stammers DK. Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design. Biochem J. 2006 Oct 15;399(2):199-204. PMID:16803458 doi:10.1042/BJ20060513
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