4xwy
Crystal structure of human sepiapterin reductase in complex with an N-acetylserotinin analogue
Structural highlights
DiseaseSPRE_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] FunctionSPRE_HUMAN Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin. Publication Abstract from PubMedHuman genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo. VIDEO ABSTRACT. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway.,Latremoliere A, Latini A, Andrews N, Cronin SJ, Fujita M, Gorska K, Hovius R, Romero C, Chuaiphichai S, Painter M, Miracca G, Babaniyi O, Remor AP, Duong K, Riva P, Barrett LB, Ferreiros N, Naylor A, Penninger JM, Tegeder I, Zhong J, Blagg J, Channon KM, Johnsson K, Costigan M, Woolf CJ Neuron. 2015 Jun 17;86(6):1393-406. doi: 10.1016/j.neuron.2015.05.033. PMID:26087165[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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