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Literature summary for 1.1.1.153 extracted from
- Effect of sulfasalazine on human neuroblastoma: Analysis of sepiapterin reductase (SPR) as a new therapeutic target (2015), BMC Cancer, 15, 477.
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | high sepiapterin reductase expression is significantly correlated to unfavorable neuroblastoma characteristics like high age at diagnosis, MYCN amplification, and high INSS stage. Sulfasalazine inhibits the growth of neuroblastoma cells in vitro, presumably due to the inhibition of sepiapterin reductase. The combination of sulfasalazine with alpha-difluoromethylornitine produces synergistic antiproliferative effects in vitro | Homo sapiens |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| modeling and docking of sulfasalazine into sepiapteron reductase | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| alpha-difluoromethylornithine | DFMO, IC50 value of 4.07 mM for SK-N-Be(2)c and 5.79 mM for LAN-5 cells | Homo sapiens |  |
| alpha-difluoromethylornitine | the combination of sulfasalazine with alpha-difluoromethylornitine produces synergistic antiproliferative effects on neuroblastoma cells in vitro | Homo sapiens | |
| additional information | synergism of sulfasalazine and alpha-difluoromethylornithine (DFMO) combination treatment in neuroblastoma cells | Homo sapiens | |
| sulfasalazine | i.e. 5-((4-(2-pyridylsulfamoyl) phenyl)azo) salicylic acid or 2-hydroxy-5-[(E)-2-{4-[(pyridin-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzoic acid or SSZ, an FDA-approved salicylate-based anti-inflammatory and immuno-modulatory drug, inhibits sepiapterin reductase. Computational docking of inhibitor sulfasalazine into sepiapterin reductase. The receptor pocket comprises residues Gly11, Ser13, Arg14, Phe16 (region 1), Ala38, Arg39 (region 2), Asn97, Ala98, Gly99, Ser100 (region 3), Tyr167 (region 4), and Leu198, Thr200, Met202 (region 5). Sulfasalazine exhibits an IC50 value of 0.133 mM for SK-N-Be(2)c and 0.337 mM for LAN-5 cells; inhibits the growth of neuroblastoma cells in vitro, presumably due to the inhibition of sepiapterin reductase as predicted by computational docking of sulfasalazine into sepiapterin reductase. The combination of sulfasalazine with alpha-difluoromethylornitine produces synergistic antiproliferative effects in vitro | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| additional information | Homo sapiens | physical interaction between key polyamines biosynthesis enzyme ornithine decarboxylase (ODC) and sepiapterin reductase (SPR) | ? | - |
? | |
| sepiapterin + NADPH + H+ | Homo sapiens | - |
tetrahydrobiopterin + NADP+ | no stereochemic specification in the publication | ? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P35270 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| LAN-5 cell | - |
Homo sapiens | - |
| neuroblastoma cell | SPR mRNA expression is highest in all neuroblastoma clinical groups with poor outcome | Homo sapiens | - |
| SK-N-BE(2)C cell | - |
Homo sapiens | - |
| SK-N-SH cell | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| additional information | physical interaction between key polyamines biosynthesis enzyme ornithine decarboxylase (ODC) and sepiapterin reductase (SPR) | Homo sapiens | ? | - |
? | |
| sepiapterin + NADPH + H+ | - |
Homo sapiens | tetrahydrobiopterin + NADP+ | no stereochemic specification in the publication | ? | |
| sepiapterin + NADPH + H+ | - |
Homo sapiens | tetrahydrobiopterin + NADP+ | no stereochemic specification of the substrate in the publication | ? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| dimer | the SPR monomer is an alpha and beta (a/b) class protein with a 3-layer (aba) sandwich architecture and Rossmann fold topology, and it contains an NADP-binding Rossmann-like domain | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| sepiapterin reductase | - |
Homo sapiens |
| SPR | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| NADPH | - |
Homo sapiens | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | RNAi-mediated SPR expression knockdown in the MYCN2 NB cell line | additional information |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | RNAi-mediated knockdown of SPR expression significantly reduces native ornithine decarboxylase enzyme activity and impedes neuroblastoma cell proliferation | Homo sapiens |
| additional information | computational docking of inhibitor sulfasalazine into sepiapterin reductase using crystal structure of human SPR in complex with NADP+ in a hexameric assembly, PDB ID 1Z6Z | Homo sapiens |
| physiological function | high SPR expression is significantly correlated to unfavorable neuroblastoma characteristics like high age at diagnosis, MYCN oncogene amplification, and high INSS disease stage. Sulfasalazine inhibits the growth of neuroblatoma cells in vitro, presumably due to the inhibition of sepiapterin reductase | Homo sapiens |
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