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α-AMINOADIPATE SEMIALDEHYDE DEHYDROGENASE:
In man an α-Aminoadipate semialdehyde dehydrogenase has not been identified. In S. cerevisiae, which synthesize rather than degrade lysine, the conversion of α-aminoadipate to α-aminoadipate semialdehyde requires two distinct genes. LYS2 encodes the α-aminoadipate reductase activity, while LYS5 encodes a phosphopantetheinyl transferase activity that is required to activate Lys2p. A human cDNA homologous to the yeast LYS5 gene has been reported (Praphanphoj et al,2001). The cDNA contains an open reading frame of 930 bp predicted to encode 309 amino acids, and the human protein is 26% identical and 44% similar to its yeast counterpart. In northern blot analysis the cDNA hybridizes to a single transcript of approximately 3 kb in all tissues except testis, where there is an additional transcript of 1.5 kb. Expression is highest in brain followed by heart and skeletal muscle, and to a lesser extent in liver. Fluorescence in situ hybridization analysis mapped the gene to chromosome 11q22. Complementation studies in S. cerevisiae using a lys5 knockout strain demonstrated that the human homolog encodes α-aminoadipate dehydrogenase phosphopantetheinyl transferase activity. It is unclear whether an orthologous step exists in man and the human equivalent of LYS2 has not been reported.
The conversion of α-aminoadipate to α-ketoadipate requires α-aminoadipate aminotransferase. A human gene encoding α-aminoadipate aminotransferase (AADAT) activity has been reported (Goh et al,2002). It has a 2329 bp cDNA, a 1278 bp open-reading frame and is predicted to encode 425 amino acids with a mitochondrial cleavage signal and a pyridoxal-phosphate binding site. AADAT is 73% and 72% identical to the mouse and rat orthologues, respectively. The genomic structure spans 30kb and consists of 13 exons. FISH studies localized the gene to 4q32.2. Two transcripts (~2.9 kb and ~4.7 kb) were identified, with expression highest in liver. Bacterial expression studies confirmed that the gene encodes for AADAT activity. Deficiency of AADAT is expected to produce α-aminoadipic aciduria, with possible accumulation of other lysine and tryptophan catabolites. α-Aminoadipic acid is a specific gliotoxic agent both in vivo and in vitro (Olney et al,1980). This suggests that individuals with AAAT deficiency may present with neurological impairment, though the precise phenotype is hard to predict. The majority of reported cases of α-aminoadipic aciduria are associated with α-ketoadipic aciduria (Chapter 124). These cases are likely to represent defects in α-ketoadipic dehydrogenase, the subsequent enzyme to AADAT in lysine and tryptophan catabolism. To date there are only two reported cases of isolated α-aminoadipic aciduria. One case involved a mentally retarded girl with dysmorphism and persistent fetal hemoglobinemia (Manders et al,1981). A normal degradation of DL-aminoadipate in fibroblasts of this patient makes a primary defect in AADAT ...