9.B.88 The Putative Selenoprotein P Hydrogen Selenide Uptake Protein (SelP) Family
The distribution of selenium in mammals has been shown to be mediated primarily by selenoprotein P, homologous to vascular endothelial growth factor, VEGF-C4 (in residues 215-375). Even in the absence of selenoprotein P, selenium is distributed from the liver into all organs and tissues when supplemented in the diet. The form of selenium that is actively taken up by mammalian cells at trace concentrations is probably the reduced form of selenide, HSe-.
A reduced form of selenium, presumably selenide, was actively transported into keratinocytes and displayed saturation kinetics with an apparent Km of 279 nM (Ganyc and Self, 2007). ATPase inhibitors blocked the uptake of selenide, as did the competing anions molybdate and chromate, but not sulfate. Thus, the form of selenium that is distributed in tissues is hydrogen selenide, despite its sensitivity to oxygen and reactivity to thiols. SelP has a histidine-rich domain that is similar to those in many proteins, from mammals to bacteria. The protein has 2-4 putative TMSs and a possible repeat sequence of about 150 residues.
Selenoprotein P (SelP or SePP) is central for selenium transport and distribution (Renko et al., 2008). Targeted inactivation of the Sepp gene in mice leads to reduced selenium content in plasma, kidney, testis and brain. Accordingly, activities of selenoenzymes are reduced in Sepp(-/-) organs. Male Sepp(-/-) mice are infertile. Unlike selenium deficiency, Sepp deficiency leads to neurological impairment with ataxia and seizures. Hepatocyte-specific inactivation of selenoprotein biosynthesis reduces plasma and kidney selenium levels similarly to Sepp(-/-) mice, but does not result in neurological impairment, suggesting a physiological role of locally expressed SePP in the brain. Secreted human SePP expressed in mice was immunologically detectable in serum from SEPP1-transgenic mice. Selenium content and selenoenzyme activities in serum, kidney, testis and brain of Sepp(-/-;SEPP1) (SEPP1-transgenic Sepp(-/-)) mice were increased compared with Sepp(-/-) controls. When a selenium-adequate diet (0.16-0.2 mg/kg of body weight) was fed to the mice, liver-specific expression of SEPP1 rescued the neurological defects of Sepp(-/-) mice and rendered Sepp(-/-) males fertile. When fed on a low-selenium diet (0.06 mg/kg of body weight), Sepp(-/-;SEPP1) mice survived 4 weeks longer than Sepp(-/-) mice, but ultimately developed the neurodegenerative phenotype. These results indicate that plasma SePP derived from hepatocytes is the main transport form of selenium supporting the kidney, testis and brain. Nevertheless, local Sepp expression is required to maintain selenium content in selenium-privileged tissues such as the brain and testis during dietary selenium restriction (Renko et al., 2008). SelP has a signal sequence for secretion followed by two hydrophobic regions that could be transmembrane. It is found in most animals and possibly in other eukaryotes. It may be homologous to parts of vascular endothelial growth factor (VEGF) C preprotein of mammals (P49767 for the human protein).