Disease relevance of ALDH18A1

• Here, we describe a newly recognized inborn error due to the deficiency of P5CS in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts [1].
• Recently, we reported a newly recognised inborn error due to deficiency of P5CS in two sibs, one presenting at birth with hypotonia, dysmorphic signs, pes planus and clonic seizures [2].
• The phenotypic features for deficiency of P5CS include joint hyperlaxity, skin hyperelasticity, cataract and mental retardation with hyperammonemia and low plasma levels of proline, citrulline and ornithine [3].
• Under dehydration conditions, when expression of the gene for P5CS is strongly induced, expression of the gene for ProDH is inhibited [4].

High impact information on ALDH18A1

• delta(1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine [1].
• Both are homozygous for the missense mutation, R84Q, which alters a conserved residue in the P5CS gamma-glutamyl kinase domain [1].
• Previously, we showed that mammalian P5CS undergoes alternative splicing to generate two isoforms differing only by a 2 amino acid insert at the N-terminus of the gamma-glutamyl kinase active site [1].
• R84Q is not present in 194 control chromosomes and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells [1].
• We conclude that transcriptional regulation of these genes for P5CS is probably not important for the osmotic or pollen-specific regulation of Pro synthesis in tomato [5].

Biological context of ALDH18A1

• We cloned a human P5CS cDNA by database cloning strategy and sequenced 2,907 bp from this cDNA which has a closed open reading frame (ORF) of 2,385 bp coding for a polypeptide of 795 amino acid residues [3].
• The clones share 65% identity in nucleotide sequences, 74% homology in deduced amino acid sequences, and both show a high similarity to Vigna aconitifolia and Arabidopsis thaliana P5CS cDNA clones [6].

Anatomical context of ALDH18A1

• This is the first documented report of an inborn error of P5CS and suggests that this disorder should be considered in the differential diagnosis in patients with neurodegeneration and/or cataracts and connective tissue disease [1].

Associations of ALDH18A1 with chemical compounds

• Furthermore, we show the results of ornithine loading tests and indirect enzyme studies corroborating the biological significance of the defect in P5CS in vivo [2].
• Delta1-pyrroline-5-carboxylate synthase (P5CS) catalyses the reduction of glutamate to Delta1-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine [2].
• delta 1-pyrroline-5-carboxylate synthetase (P5CS) catalyzes the ATP and the NAD(P)H-dependent conversion of L-glutamate to glutamic gamma-semialdehyde (GSA) which is the metabolic precursor for proline biosynthesis [3].

Analytical, diagnostic and therapeutic context of ALDH18A1

• Assignment of the human gene encoding the delta 1-pyrroline-5-carboxylate synthetase (P5CS) to 10q24.3 by in situ hybridization [7].
• Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis [3].
• Southern blot analysis confirmed the presence of two different P5CS genes [6].
• By contrast, under rehydration conditions, when the expression of the gene for ProDH is strongly induced, the expression of the gene for P5CS is inhibited [4].
• All structures have been solved from high-resolution laboratory or synchrotron powder diffraction data with the direct-space parallel-tempering program FOX and refined with the Rietveld module of GSAS [8].

References