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| | ==Crystal structure of human sepiapterin reductase in complex with sulfathiazole== | | ==Crystal structure of human sepiapterin reductase in complex with sulfathiazole== |
| - | <StructureSection load='4j7u' size='340' side='right' caption='[[4j7u]], [[Resolution|resolution]] 2.44Å' scene=''> | + | <StructureSection load='4j7u' size='340' side='right'caption='[[4j7u]], [[Resolution|resolution]] 2.44Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4j7u]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. The August 2015 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Tetrahydrobiopterin Biosynthesis'' by David Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2015_8 10.2210/rcsb_pdb/mom_2015_8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J7U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J7U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4j7u]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The August 2015 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Tetrahydrobiopterin Biosynthesis'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2015_8 10.2210/rcsb_pdb/mom_2015_8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J7U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J7U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YTZ:4-AMINO-N-(1,3-THIAZOL-2-YL)BENZENESULFONAMIDE'>YTZ</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YTZ:4-AMINO-N-(1,3-THIAZOL-2-YL)BENZENESULFONAMIDE'>YTZ</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hwk|4hwk]], [[4j7x|4j7x]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4j7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j7u OCA], [https://pdbe.org/4j7u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j7u RCSB], [https://www.ebi.ac.uk/pdbsum/4j7u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j7u ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SPR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| - | <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=4j7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j7u OCA], [http://pdbe.org/4j7u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j7u RCSB], [http://www.ebi.ac.uk/pdbsum/4j7u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j7u ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN]] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:[http://omim.org/entry/612716 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.<ref>PMID:11443547</ref> <ref>PMID:16650784</ref> <ref>PMID:17159114</ref> | + | [https://www.uniprot.org/uniprot/SPRE_HUMAN SPRE_HUMAN] Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:[https://omim.org/entry/612716 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.<ref>PMID:11443547</ref> <ref>PMID:16650784</ref> <ref>PMID:17159114</ref> |
| | == Function == | | == 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. | + | [https://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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: RCSB PDB Molecule of the Month]] | | [[Category: RCSB PDB Molecule of the Month]] |
| | [[Category: Tetrahydrobiopterin Biosynthesis]] | | [[Category: Tetrahydrobiopterin Biosynthesis]] |
| - | [[Category: Johnsson, K]] | + | [[Category: Groenlund Pedersen M]] |
| - | [[Category: Pedersen, M Groenlund]] | + | [[Category: Johnsson K]] |
| - | [[Category: Pojer, F]] | + | [[Category: Pojer F]] |
| - | [[Category: Oxidoreductase-antibiotic complex]]
| + | |
| - | [[Category: Reductase]]
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| Structural highlights
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
The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.
Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs.,Haruki H, Pedersen MG, Gorska KI, Pojer F, Johnsson K Science. 2013 May 24;340(6135):987-91. doi: 10.1126/science.1232972. PMID:23704574[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, Pedersen MG, Gorska KI, Pojer F, Johnsson K. Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs. Science. 2013 May 24;340(6135):987-91. doi: 10.1126/science.1232972. PMID:23704574 doi:10.1126/science.1232972
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