RESUMEN
The trace element selenium is found in polypeptides as selenocysteine, the 21(st) amino acid that is co-translationally inserted into proteins at a UGA codon. In proteins, selenocysteine usually plays a role as an efficient redox catalyst. Trypanosomatids previously examined harbor a full set of genes encoding the machinery needed for selenocysteine biosynthesis and incorporation into three selenoproteins: SelK, SelT and, the parasite-specific, Seltryp. We investigated the selenoproteome of kinetoplastid species in recently sequenced genomes and assessed the in vivo relevance of selenoproteins for African trypanosomes. Database mining revealed that SelK, SelT and Seltryp genes are present in most kinetoplastids, including the free-living species Bodo saltans, and Seltryp was lost in the subgenus Viannia from the New World Leishmania. Homology and sinteny with bacterial sulfur dioxygenases and sulfur transferases suggest a putative role for Seltryp in sulfur metabolism. A Trypanosoma brucei selenocysteine synthase (SepSecS) null-mutant, in which selenoprotein synthesis is abolished, displayed similar sensitivity to oxidative stress induced by a short-term exposure to high concentrations of methylglyoxal or H2O2 to that of the parental wild-type cell line. Importantly, the infectivity of the SepSecS knockout cell line was not impaired when tested in a mouse infection model and compensatory effects via up-regulation of proteins involved in thiol-redox metabolism were not observed. Collectively, our data show that selenoproteins are not required for survival of African trypanosomes in a mammalian host and exclude a role for selenoproteins in parasite antioxidant defense and/or virulence. On this basis, selenoproteins can be disregarded as drug target candidates.
Asunto(s)
Kinetoplastida/metabolismo , Proteínas Protozoarias/genética , Selenocisteína/metabolismo , Selenoproteínas/genética , Transferasas/genética , Trypanosoma brucei brucei/metabolismo , Animales , Minería de Datos , Bases de Datos Genéticas , Eliminación de Gen , Regulación de la Expresión Génica , Interacciones Huésped-Parásitos , Peróxido de Hidrógeno/farmacología , Kinetoplastida/clasificación , Kinetoplastida/efectos de los fármacos , Kinetoplastida/crecimiento & desarrollo , Ratones , Filogenia , Proteoma/genética , Proteoma/metabolismo , Proteínas Protozoarias/metabolismo , Piruvaldehído/farmacología , Selenoproteínas/deficiencia , Transferasas/deficiencia , Trypanosoma brucei brucei/clasificación , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/crecimiento & desarrollo , Tripanosomiasis Africana/parasitología , Tripanosomiasis Africana/patologíaRESUMEN
Galactose is a major nutrient in normal newborn infants and serves as a substrate for energy production and fuel storage and a regulator of carbohydrate assimilation. Inborn errors of galactose metabolism have contributed to our understanding of the potential toxicity of this carbohydrate. In addition to the classic acute manifestations of neonatal galactosemia, long-term follow-up of surviving patients have revealed unusual neurodevelopmental and reproductive problems. Many investigators have suggested that the newborn infant can utilize galactose better than adults and that neonatal galactose assimilation exceeds that of glucose. Galactose may be an excellent substitute for glucose among hyperinsulinemic infants of diabetic mothers or premature infants with glucose intolerance. However, until further investigations are performed to define the role of galactose in newborn nutrition and to determine its potential toxicity, galactose should not be used as the primary carbohydrate in sick newborn infants.
Asunto(s)
Galactosa/metabolismo , Galactosemias/genética , Recién Nacido , Permeabilidad de la Membrana Celular , Metabolismo Energético , Femenino , Estudios de Seguimiento , Galactoquinasa/deficiencia , Galactosa/fisiología , Galactosemias/metabolismo , Galactosemias/terapia , Galactosafosfatos/metabolismo , Variación Genética , Humanos , Lactante , Absorción Intestinal , Hígado/metabolismo , Embarazo , Diagnóstico Prenatal , Transferasas/deficiencia , UDPglucosa 4-Epimerasa/deficiencia , UTP-Hexosa-1-Fosfato Uridililtransferasa/deficienciaRESUMEN
Four patients with hypermethioninemia were ascertained in neonatal mass metabolic screening programs. Hypermethioninemia has persisted in all cases. There were no other abnormalities in sulfur-amino acid concentrations, and routine serum chemical determinations, including the results of "liver function" tests, were normal. Hepatic methionine adenosyltransferase activity was found to be low, ranging from 7.8 to 17.5% (mean 11.4%) of the normal adult control value. Electron microscopy of liver showed increased smooth endoplasmic reticulum, decreased rough endoplasmic reticulum, and increased lysosomes; short breaks in the outer membranes of mitochondria were present to a variable extent. Despite the persistent hypermethioninemia, which argues for continued deficiency of hepatic MAT, all four children appear well. This ostensible well being may be a result of the normal activity of extrahepatic MATs, as shown for erythrocytes and for cultured fibroblasts and lymphoid cells.