4z3k

From Proteopedia

(Difference between revisions)

Revision as of 06:27, 26 July 2016

Human sepiapterin reductase in complex with the cofactor NADP+ and the trypthophan metabolite xanthurenic acid

Structural highlights

4z3k is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	4xwy
Activity:	Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming), with EC number 1.1.1.153
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[SPRE_HUMAN] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:612716]. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures.^[1] ^[2] ^[3]

Function

[SPRE_HUMAN] Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.

Publication Abstract from PubMed

Tryptophan metabolites in the kynurenine pathway are up-regulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.

Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid.,Haruki H, Hovius R, Pedersen MG, Johnsson K J Biol Chem. 2016 Jan 8;291(2):652-7. doi: 10.1074/jbc.C115.680488. Epub 2015 Nov, 12. PMID:26565027^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet. 2001 Aug;69(2):269-77. Epub 2001 Jul 6. PMID:11443547 doi:10.1086/321970
↑ Abeling NG, Duran M, Bakker HD, Stroomer L, Thony B, Blau N, Booij J, Poll-The BT. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol Genet Metab. 2006 Sep-Oct;89(1-2):116-20. Epub 2006 May 2. PMID:16650784 doi:10.1016/j.ymgme.2006.03.010
↑ Friedman J, Hyland K, Blau N, MacCollin M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology. 2006 Dec 12;67(11):2032-5. PMID:17159114 doi:10.1212/01.wnl.0000247274.21261.b4
↑ Haruki H, Hovius R, Pedersen MG, Johnsson K. Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid. J Biol Chem. 2016 Jan 8;291(2):652-7. doi: 10.1074/jbc.C115.680488. Epub 2015 Nov, 12. PMID:26565027 doi:http://dx.doi.org/10.1074/jbc.C115.680488

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4z3k"

@@ Line 1: / Line 1: @@
 ==Human sepiapterin reductase in complex with the cofactor NADP+ and the trypthophan metabolite xanthurenic acid==
 <StructureSection load='4z3k' size='340' side='right' caption='[[4z3k]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xwy|4xwy]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sepiapterin_reductase_(L-erythro-7,8-dihydrobiopterin_forming) Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.153 1.1.1.153] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4z3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z3k OCA], [http://pdbe.org/4z3k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z3k RCSB], [http://www.ebi.ac.uk/pdbsum/4z3k PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4z3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z3k OCA], [http://pdbe.org/4z3k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z3k RCSB], [http://www.ebi.ac.uk/pdbsum/4z3k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4z3k ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN]] Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Tryptophan metabolites in the kynurenine pathway are up-regulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.
+Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid.,Haruki H, Hovius R, Pedersen MG, Johnsson K J Biol Chem. 2016 Jan 8;291(2):652-7. doi: 10.1074/jbc.C115.680488. Epub 2015 Nov, 12. PMID:26565027<ref>PMID:26565027</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4z3k" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4z3k

From Proteopedia

Revision as of 06:27, 26 July 2016

Human sepiapterin reductase in complex with the cofactor NADP+ and the trypthophan metabolite xanthurenic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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