Sepiapterin reductase deficiency is caused by mutations in the spr gene. Disease description a form of doparesponsive dystonia. Sepiapterin reductase and alr2 aldose reductase from. Stateoftheart algorithm used for plasmid design gene synthesis. Sepiapterin reductase, 1261 aa, human, histagged, recombinant, li sepiapterin reductase spr belongs to the shortchain dehydrogenasereductase sdr family and also reduces various exogenous carbonyl compounds including phenylpropanedione. New paradigm for pathway interaction by proteinprotein binding of sentinel pathway enzymes ornithine decarboxylase odc and sepiapterin reductase spr discovered. Doparesponsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Crystal structure of human sepiapterin reductase in complex with an nacetylserotinin analogue. Sepiapterin reductase spr is an enzyme that catalyzes the final step of bh 4 biosynthesis. Most spr gene mutations result in an enzyme with little or no function. California twins noah and alexis beery have gene variants that cause them to have lifethreatening low levels of three neurotransmitters.
Other movement problems can include muscle stiffness spasticity, tremors, problems with coordination and balance ataxia, and involuntary jerking movements chorea. A comparative structural analysis of sepiapterin reductase from drosophila by homology modeling a comparative structural analysis of sepiapterin reductase from drosophila by homology modeling kim, kiyoung. Studies on spr from several insects and other organisms have been reported. Jun 01, 2015 abstract sepiapterin reductase sr catalyzes the final steps of bh 4 biosynthesis.
These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. This gene provides instructions for making the sepiapterin reductase enzyme, which is involved in the productions of a molecule called tetrahydrobiopterin also known as bh4. Homology modeling of srs for protein structure and function prediction showed that the two srs have different surface electrostatic distributions and different shapes of the substrate sepiapterin. Other common features include axial hypotonia, oculogyric crises, and delays in motor and cognitive development. In order to truly appreciate and successfully model this years protein modeling event structures, a thorough understanding of protein structure. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. Sepiapterin reductase promotes hepatocellular carcinoma. Sepiapterin reductase deficiency srd is a rare genetic disorder that is characterized by abnormally low levels of certain neurotransmitters. There was no detectable sr activity in the nonstimulated fibroblasts and mutation analysis revealed a homozygous arg to gly exchange at codon 150 r150g. Tetrahydrobiopterin bh4 is an essential cofactor for aromatic acid hydroxylases and nitric oxide synthase. Bh 4 is an essential cofactor for nitric oxide synthase and aromatic amino acid hydrolases, including tyrosine. The enzyme, which is found in higher animals and some fungi and bacteria, produces the erythro form of tetrahydrobiopterin. Repurposing of tranilast for potential neuropathic pain. Increasing pieces of evidence suggest that bh4 is upregulated in chronic pain.
Does any member of your family have sepiapterin reductase deficiency or may be more predisposed to developing the condition. Spr sepiapterin reductase homo sapiens human spr gene. Since the original description, 14 cases of sepiapterin reductase deficiency have been described or collected in the database 1,2,47. Apr 19, 2016 sepiapterin reductase deficiency is a neurometabolic disorder characterized by a pattern of involuntary sustained muscle contractions known as dystonia. Spr sepiapterin reductase homo sapiens human gene ncbi. Treatment of sepiapterin reductase deficiency may involve levodopa ldopa. Sulfa drugs inhibit sepiapterin reduction and chemical redox cycling by sepiapterin reductase shaojun yang, yihua jan, vladimir mishin, jason r. Use and redistribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material hmdb and the original publication see the hmdb citing page. Sepiapterin reductase is expressed with a 20 amino acid his tag at nterminus and purified by proprietary chromatographic techniques. A comparative structural analysis of sepiapterin reductase from.
As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate. Threedimensional structure predictions of drosophila srs and zebrafish sr were generated by the i. Sulfa drugs inhibit sepiapterin reduction and chemical. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in bh 4 biosynthesis and metabolism has been increasing, only a handful of cases of spr deficiency have been reported, and the. Coli purified by multistep, protein specific process to ensure crystallization grade. Rcsb pdb protein feature view sepiapterin reductase. The present study reports the identification of another sr gene in the drosophila genome and the structural characteristics and differences of the two drosophila srs, using homology modeling analysis. The disease is caused by mutations affecting the gene represented in this entry. Sepiapterin reductase spr recombinant protein mybiosource. Sepiapterin reductase plays an enzymatic role in the biosynthesis of tetrahydrobiopterin, which is reported in limited studies to regulate the progression of several tumors. Swissmodel is a fully automated protein structure homologymodelling server.
Help pages, faqs, uniprotkb manual, documents, news archive and biocuration projects. Sepiapterin reductase is specifically responsible for the last step in the production of tetrahydrobiopterin. Spr sepiapterin reductase human recombinant protein. Home page for protein modeling event at the center for biomolecular modeling amazing resource. Sepiapterin reductase spr protein profile protein summary this gene encodes an aldoketo reductase that catalyzes the nadphdependent reduction of pteridine derivatives and is important in the biosynthesis of tetrahydrobiopterin bh4. A murine model for human sepiapterinreductase deficiency. The beery twins story proteins, dna and genomes this years proteins. Sepiapterin reductase spr catalyzes the final steps of bh4 biosynthesis. Coli purified by multistep, proteinspecific process to ensure crystallization grade. The new mutation in sepiapterin reductase sr is likely to impair transcription processing and cause deficiencies in sepiapterin reductase, thus decreasing levels of bh 4 and dopa.
Other movement problems can include muscle stiffness spasticity, tremors, problems with coordination and balance ataxia, and involuntary jerking movements chor. A homozygous frameshift mutation of sepiapterin reductase gene causing parkinsonism with onset in childhood. When the mutation occurs in the first 23 nucleotides of the intron, all protein expression is suppressed because splicing is severely impaired. Cbm science olympiad center for biomolecular modeling. Previously, a gene encoding sr has been cloned and. Role of sepiapterin reductase gene at the park3 locus in parkinsons disease. Sepiapterin reductase spr catalyzes both the reversible reduction of. It was first described in silkworms where it was shown to be a separate enzyme from dihydrofolate reductase matsubara et al. Previously, a gene encoding sr has been cloned and characterized from a drosophila cdna library in vitro.
Sepiapterin reductase custom model molecular modeling. Contents 1 function 2 reaction 3 clinical significance 4. Sepiapterin reductase expression is increased in parkinson. Hmdb is offered to the public as a freely available resource. Unstimulated cells were lysed by freezing and thawing, and centrifuged for 5 minutes at 15000 x g. Jun 22, 2015 in this video, alban latremoliere, michael costigan, and clifford woolf describe how they genetically manipulated the tetrahydrobiopterin synthesis pathway in mice to formally validate its role in. The purpose of the jmol exploration component of this years event is to allow students to demonstrate their skill in using jmol to manipulate and explore a pdb file, and navigate the rcsb protein data bank. Sepiapterin reductase spr catalyzes the reduction of sepiapterin to dihydrobiopterin bh2, the precursor for tetrahydrobiopterin bh4, a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism.
Spr also mediates chemical redox cycling, catalyzing oneelectron reduction of redoxactive chemicals, including quinones and bipyridinium herbicides e. Sepiapterin reductase deficiency results when two copies of the spr gene are mutated in each cell. The concentration of our recombinant proteins is measured using the absorbance at 280nm. Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement. The enzymatic activities of gtp cyclohydrolase, sepiapterin. Apr 20, 2020 sepiapterin reductase plays an enzymatic role in the biosynthesis of tetrahydrobiopterin, which is reported in limited studies to regulate the progression of several tumors. Translation is the biological process through which proteins are. The purpose of this server is to make protein modelling accessible to all life. Spr sepiapterin reductase bos taurus bovine spr gene. Expression and enzyme activity detection of a sepiapterin. Sepiapterin reductase deficiency genetic and rare diseases.
After years of extremely limited mobility, severe breathing problems, costly emergency department visits, imaging tests, and visits to specialists, genome sequencing identified mutations in a gene called spr that encodes the enzyme sepiapterin reductase. Role of sepiapterin reductase gene at the park3 locus in. Human sprsepiapterin reductase recombinant protein bosterbio. More than a dozen mutations in the spr gene have been found to cause sepiapterin reductase deficiency, a condition characterized by progressive problems with movement. Mapping the mutations to a physical model of sepiapterin reductase. Sepiapterin reductase how is sepiapterin reductase abbreviated. Catalyzes the final one or two reductions in tetra hydrobiopterin biosynthesis to form 5,6,7,8tetrahydrobiopterin. In this video, alban latremoliere, michael costigan, and clifford woolf describe how they genetically manipulated the tetrahydrobiopterin synthesis. Catalyzes the final one or two reductions in tetrahydrobiopterin biosynthesis to form 5,6,7,8tetrahydrobiopterin. The pdb archive contains information about experimentallydetermined structures of proteins, nucleic acids, and complex assemblies. Human sprsepiapterin reductase recombinant protein.
Sepiapterin reductase how is sepiapterin reductase. Systems used to automatically annotate proteins with high accuracy. Coli is a single,nonglycosylated polypeptide chain containing 2830. Protein modeling c page 5 science olympiad student center. Tetrahydrobiopterin bh4 is a cofactor in the production of various signaling molecules including nitric oxide, dopamine, adrenaline, and noradrenaline. Repurposing of tranilast for potential neuropathic. The phenotypic spectrum of sepiapterin reductase deficiency srd, which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated.
Here you can see if sepiapterin reductase deficiency can be hereditary. This section will explore these amazing macromolecules in more detail using suggested physical model kits, online resources and additional websites. Molecular modeling predicts both monomer and dimer interaction between odc and spr, in silico. Mutations in this gene result in doparesponsive dystonia due to sepiaterin reductase deficiency. Whole genome sequencing in 2010 identified a mutation in the gene that encodes the sepiapterin reductase enzyme, leading to a molecular diagnosis and successful treatment. Spr gene mutations disrupt the production of sepiapterin reductase.
These mutations include changes that replace amino acids. A nonfunctional sepiapterin reductase leads to a lack of tetrahydrobiopterin and a decrease in the production of dopamine and serotonin in the brain. Sepiapterin c9h11n5o3 cid 5398579 structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities. The rcsb pdb also provides a variety of tools and resources. Please introduce links to this page from related articles. Bh4 levels are critical for processes associated with cardiovascular function, inflammation, mood, pain, and neurotransmission. Jul 01, 2015 the phenotypic spectrum of sepiapterin reductase deficiency srd, which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated. Sepiapterin reductase deficiency genetics home reference.
Sepiapterin reductase deficiency genetics home reference nih. Sepiapterin reductase deficiency is a condition characterized by movement problems, most often a pattern of involuntary, sustained muscle contractions known as dystonia. Neurotransmitter biosynthesis and the role of sepiapterin. Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Sulfa drugs inhibit sepiapterin reduction and chemical redox. Subscriber profile repository various companies spr. Targeting sepiapterin reductase to treat neuropathic pain. Biosystems blast basic local alignment search tool. This year, instead of modeling a protein during the onsite competition, teams will answer questions as part of a jmol exploration. Clinical features in the majority of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises.
1628 1627 1344 133 1392 1601 464 103 1487 751 342 1007 376 1310 1090 312 1200 1586 1143 970 1548 724 381 790 1581 58 365 56 387 502 1027 52 1370 721 992 1440