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
Genome-wide-association studies in chronic low back pain patients identified sepiapterin reductase as a high interest target for developing new analgesics. Here we used (19)F NMR fragment screening for the discovery of novel, ligand-efficient SPR inhibitors. We report the crystal structures of six chemically diverse inhibitors complexed with SPR, identifying relevant interactions and binding modes in the sepiapterin pocket. Exploration of our initial fragment screening hit led to double-digit nanomolar inhibitors of SPR with excellent ligand efficiency.
Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors.,Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P J Med Chem. 2019 Jun 25. doi: 10.1021/acs.jmedchem.9b00218. PMID:31244106[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
- ↑ Alen J, Schade M, Wagener M, Christian F, Nordhoff S, Merla B, Dunkern TR, Bahrenberg G, Ratcliffe P. Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors. J Med Chem. 2019 Jun 25. doi: 10.1021/acs.jmedchem.9b00218. PMID:31244106 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00218
