Disease relevance of Spr

• The enzyme encoded by the cDNA insert was shown to have sepiapterin reductase activity after expression in E. coli [1].
• The partial amino acid sequence of rat sepiapterin reductase was determined using peptides generated by cleavage of the S-carboxyamidomethylated protein with Achromobacter protease I, cyanogen bromide, chymotrypsin or BNPS-skatole [2].
• By immunohistochemistry, the SPR antiserum was found to bind to neurons in the dorsal horn of the rat spinal cord and to ganglion cells in the myenteric plexus of the rat ileum near substance P-immunoreactive nerve fibers [3].
• The rat substance P (SP) receptor (SPR) was expressed in insect Sf9 cells by infection with recombinant baculovirus [4].
• Gamma-camera scintigraphic studies were carried out with control rats to visualize the SPR+ salivary glands in rats bearing the SPR+ transplantable pancreatic tumor CA20948 and in rats with SPR+ adjuvant arthritic joints, which was induced after injection of a homogenate of Mycobacterium tuberculosis [5].

High impact information on Spr

• Within the dendrites the SPR undergoes a striking translocation from the plasma membrane to endosomes, and these dendrites also undergo a morphological reorganization, changing from a structure of rather uniform diameter to one characterized by large, swollen varicosities connected by thin fibers [6].
• We have investigated this phenomenon in rat striatum, using substance P (SP)-induced internalization of the SP receptor (SPR) as our model system [6].
• These data demonstrate that in the central nervous system in vivo, SP induces a rapid and widespread SPR internalization in the cell bodies and dendrites and a structural reorganization of the dendrites [6].
• Electron microscopic analysis in cortex, striatum, and spinal cord revealed that approximately 70% of the surface membrane of immunoreactive neurons is SPR laden [7].
• Although some SP terminals contacted SPR-immunoreactive membrane, no more than 15% of the SPR-laden membrane apposed synaptic terminals [7].

Chemical compound and disease context of Spr

• Distribution of SPR-like immunoreactivity in the medullary visceral zone of the rat and changes following acute myocardial ischemia induced by intravenous injection of vasopressin [8].

Biological context of Spr

• The complete amino acid sequence of the mature form of rat sepiapterin reductase [2].
• Each of these serine residues in SPR was found in the consensus sequence (Arg-X-X-Ser/Thr) of the phosphorylation site [9].
• Suggestive linkage (lod score 1.9) was found for total cholesterol on chromosome 4 at the Spr locus [10].
• Cosegregation of microsatellites on chromosomes 4 (Spr, Npy, D4mit6, Il-6) and 13 (Atp1a2, D13Mit1, D13Uwm1) with blood pressure was evaluated using one-way analysis of variance [11].
• In contrast, the catalytic activity of sepiapterin reductase remains constant throughout the cell-cycle [12].

Anatomical context of Spr

• Light microscopy revealed an excellent correlation between the patterns of SPR immunoreactivity and of 125I-labeled SPR-binding sites in the central nervous system [7].
• These results suggest that in contrast to more "classical" central and peripheral nervous system synapses, wherein the receptor immediately apposes the site of neurotransmitter storage and release, much of the surface of SPR-expressing neurons can be targeted by SP that diffuses a considerable distance from its site of release [7].
• The SPR antiserum recognized a broad protein band on Western blots of membranes prepared from cells expressing SPR but not from cells transfected with vector alone [3].
• Binding of 125I-SPR393-407 to the antiserum was also displaced in a parallel manner by membrane proteins from tissues expressing high levels of the SPR (brain and submaxillary gland) [3].
• These antibodies can be used to localize the SPR in tissues and cells and to examine the function of the receptor in cell lines [3].

Associations of Spr with chemical compounds

• In the present study we used an antiserum raised against a synthetic peptide corresponding to the carboxyl-terminal tail of the substance P (SP) receptor (SPR) to further explore the relationship between a neuropeptide and its receptor [7].
• Second, a chimeric SPR construct of a hydrophilic Flag peptide (DYKDDDDK) genetically engineered in sequence with the extracellular N-terminus of rat SPR was generated by polymerase chain reaction [3].
• The results suggest that when sepiapterin reductase activity is limiting, a large proportion of BH4 synthesis proceeds through the 6-lactoyl intermediate [13].
• Further studies with sepiapterin, methotrexate, and N-acetylserotonin (an inhibitor of the BH4 synthetic enzyme, sepiapterin reductase) indicated that the BH4 is synthesized in RASMC predominantly from GTP; however, a lesser amount may derive from pterin salvage [14].
• Measurements were made of the rate of conversion of 6PPH4, generated from dihydroneopterin triphosphate with purified 6PPH4 synthase, to BH4 in the presence of mixtures of pure sepiapterin reductase and the 6PPH4 (2'-oxo)reductase purified from rat brains [13].

Other interactions of Spr

• In contrast, the effect of QTL on serum total cholesterol on chromosome 4 (Npy-Spr) was maximal at 32 weeks of age [15].
• At G0 the steady state mRNA levels specific for GTP cyclohydrolase I and sepiapterin reductase, respectively, are below the limits of detection [12].
• The activities of sepiapterin reductase and dihydrofolate reductase, putative enzymes in the biosynthetic pathway from GTP to BH4, were not increased by reserpine [16].
• 6-Pyruvoyl tetrahydropterin (2'-oxo) reductase, which has now been shown to be a member of the aldose reductase family, catalyzes the formation of only the 2'-hydroxy-1'-oxo intermediate which still requires sepiapterin reductase for final conversion to tetrahydrobiopterin [17].
• NGF, EGF or IFN-gamma did not affect the activity of sepiapterin reductase, the final enzyme in BH4 biosynthesis [18].

Analytical, diagnostic and therapeutic context of Spr

• CONCLUSION: [Indium-111-DTPA-Arg1]SP can be used successfully to visualize SPR+ processes in vivo by gamma camera scintigraphy [5].
• Two-dimensional gel electrophoresis of rat striatum and liver demonstrated that the isoelectric point of sepiapterin reductase from both tissues was 6.16 and that the higher molecular weight immunoreactive material in liver had an isoelectric point of 7.06 [19].
• Thus, in the present study, the distribution pattern of trigeminohypothalamic and spinohypothalamic tract neurons showing SPR-like immunoreactivity (SPR-LI) was examined in the rat by a retrograde tract-tracing method combined with immunofluorescence histochemistry for SPR [20].
• Moreover, electrical stimulation sufficient to excite C fibers evoked SPR internalization in 22% of SPR+ lamina III neurons after nerve transection and in 32-36% of SPR+ neurons in lamina III and IV after inflammation [21].
• To examine possible differences in the catalytic sites of SPR for exogenous carbonyl compounds and the native pteridine substrates, we investigated by site-directed mutagenesis the role of the highly conserved Ser-Tyr-Lys triad (Ser and YXXXK motif) in SPR, which was shown to be the catalytic site of SDR-family enzymes [22].

References