Disease relevance of Spr

• With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia [1].
• In the present study, we have demonstrated that the embryonic fibroblastic cells from a feral-origin strain (SPR) expressed 74 kDa Mx2 protein, which prevented the accumulation of viral transcripts and proteins of hantaviruses when the Mx2 gene was constitutively expressed in transfected Vero cells [2].

High impact information on Spr

• Sepiapterin reductase catalyses the last steps in the biosynthesis of tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases and nitric oxide synthases [3].
• We have determined the crystal structure of mouse sepiapterin reductase by multiple isomorphous replacement at a resolution of 1.25 A in its ternary complex with oxaloacetate and NADP [3].
• The Spr(-/-) mice exhibit phenylketonuria, dwarfism, and impaired body movement [4].
• Here, we report that mice deficient in the Spr gene (Spr(-/-)) display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH(4) and for the normal functions of BH(4)-dependent enzymes [4].
• Recently, mutations in the Pax-3 gene have been described in the radiation-induced Spr and Sp2H alleles [5].

Biological context of Spr

• The promoter region of the Spr gene is embedded within a CpG island [6].
• Transient transfection of a series of 5' deletion derivatives of the Spr promoter showed the sequence between -83 and -51 to be essential for promoter activity [6].
• The authentic Spr gene is present as a single copy in the mouse genome and is composed of three exons containing the entire coding region [6].
• None of the inhibitors that were tested, including N-chloroacetyl-dopamine and N-acetylserotonin, which are specific for sepiapterin reductase, can block MEL cells in G1-phase or induce the cells to commit to terminal differentiation [7].
• The amino acid sequence of mouse sepiapterin reductase revealed the identity of 88% with rat and 74% with human sequence [8].

Anatomical context of Spr

• In contrast, the activities of 6-pyruvoyltetrahydropterin synthase and of sepiapterin reductase of erythrocytes are only reduced to about one half of the reticulocyte level [9].
• These findings suggest that carboxy-PTIO accumulates BH4 under basal and LPS-treated conditions in vascular endothelial cells due to both inhibition of the decomposition of BH4 to pterin and activation of the salvage pathway of BH4 synthesis via sepiapterin reductase [10].

Associations of Spr with chemical compounds

• Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined [11].
• Inhibition of BH4 biosynthesis in rapidly dividing MEL cells with N-acetylserotonin, a potent inhibitor of sepiapterin reductase, the terminal enzyme in the BH4 biosynthetic pathway, results in inhibition of DNA synthesis and mitogenesis without induction of hemoglobin synthesis [12].
• Furthermore, inhibitors of sepiapterin reductase are found to reduce or to abolish hemoglobin synthesis in differentiating MEL cells induced by hexamethylene bisacetamide [7].
• Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin [13].
• However, the mRNA expression level of 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, both of which are involved successively after GTP cyclohydrolase I in tetrahydrobiopterin biosynthesis, were not affected by the lipopolysaccharide administration [14].

Other interactions of Spr

• The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase [1].

Analytical, diagnostic and therapeutic context of Spr

• We carried out the cloning of a mouse cDNA encoding a sepiapterin reductase which is involved in the final step of tetrahydrobiopterin biosynthesis as a first step toward gene-targeting technique in mice [8].

References