EC:2.3.1.108 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.108 (TAT)
2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A generalized deficiency of the mitochondrial enzyme, ornithine aminotransferase (OAT) is the inborn error in gyrate atrophy, an autosomal recessive degenerative disease of the choroid and retina of the eye that leads to blindness. Southern analysis, using the OAT cDNA probe, of the OAT gene in a gyrate atrophy patient whose level of OAT protein is markedly decreased indicated the functional gene to be grossly intact. Northern analysis of his OAT mRNA demonstrated only half the normal level of OAT message, suggesting expression of only one of the two alleles of the OAT gene. A functional assay of the expressed OAT mRNA by in vitro translation and immunoprecipitation with anti-human OAT antibody indicated synthesis of an OAT protein from the message. The expressed message was cloned and sequenced and was shown to contain a single base change from C to T, resulting in an amino acid codon change from CAT (histidine) to TAT (tyrosine) at position 319 in the translated OAT protein. The mutant and normal OAT precursors were synthesized using transcriptional expression clones of OAT and in vitro translation of the expressed mRNA and tested in an in vitro mitochondrial transport/processing system. The results indicate that the mutant OAT precursor from the gyrate atrophy patient can be transported to the mitochondria but is minimally processed there, which would lead to degradation of the labile precursor and loss of OAT activity as phenotypically observed.
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PMID:Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. 279 65

Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR.
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PMID:High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1. 2643 26

Retinitis pigmentosa (RP) is a group of inherited retinal degenerative conditions and a leading cause of irreversible blindness. 25%-30% of RP cases are caused by inherited autosomal dominant (ad) mutations in the rhodopsin (Rho) protein of the retina, which impose a barrier for developing therapeutic treatments for this genetically heterogeneous disorder, as simple gene replacement is not sufficient to overcome dominant disease alleles. Previously, we have explored using the genomic short-form of Rho (sgRho) for gene augmentation therapy of RP in a Rho knockout mouse model. We have shown improved gene expression and fewer epigenetic modifications compared with the use of a Rho cDNA expression construct. In the current study, we altered our strategy by delivering a codon-optimized genomic form of Rho (co-sgRho) (for gene replacement) in combination with an RNAi-based inactivation of endogenous Rho alleles (gene suppression of both mutant Rho alleles, but mismatched with the co-sgRho) into a homozygous Rho^P23H/P23H knock-in (KI) RP mouse model, which has a severe phenotype of adRP. In addition, we have conjugated a cell penetrating TAT peptide sequence to our previously established CK30PEG10 diblock co-polymer. The DNAs were compacted with CK30PEG10-TAT diblock co-polymer to form DNA nanoparticles (NPs). These NPs were injected into the sub-retinal space of the KI mouse eyes. As a proof of concept, we demonstrated the efficiency of this strategy in the partial improvement of visual function in the Rho^P23H/P23H KI mouse model.
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PMID:Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model. 2923 24