?-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child

Manders, A. J.; Oostrom, C.G. van; Trijbels, J. M. F.; Rutten, F. J.; Kleijer, W. J.

doi:10.1007/bf00441711

Cited by 9 publications

(6 citation statements)

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“…Therefore the hyperactive behaviour observed in katII -/- mice [47] raised an interesting question as to whether the aminoadipate level is increased in the knockout mouse brain and consequently contributes to the pathological mechanisms of the abnormal behaviour. High levels of aminoadipate in serum and/or urine have also been observed in many cases with neurological and other disorders [77-87]. …”

Section: Discussionmentioning

confidence: 99%

Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II

et al. 2008

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SynopsisKAT (kynurenine aminotransferase) II is a primary enzyme in the brain for catalysing the transamination of kynurenine to KYNA (kynurenic acid). KYNA is the only known endogenous antagonist of the N-methyl-D-aspartate receptor. The enzyme also catalyses the transamination of aminoadipate to α-oxoadipate; therefore it was initially named AADAT (aminoadipate aminotransferase). As an endotoxin, aminoadipate influences various elements of glutamatergic neurotransmission and kills primary astrocytes in the brain. A number of studies dealing with the biochemical and functional characteristics of this enzyme exist in the literature, but a systematic assessment of KAT II addressing its substrate profile and kinetic properties has not been performed. The present study examines the biochemical and structural characterization of a human KAT II/ AADAT. Substrate screening of human KAT II revealed that the enzyme has a very broad substrate specificity, is capable of catalysing the transamination of 16 out of 24 tested amino acids and could utilize all 16 tested α-oxo acids as amino-group acceptors. Kinetic analysis of human KAT II demonstrated its catalytic efficiency for individual amino-group donors and acceptors, providing information as to its preferred substrate affinity. Structural analysis of the human KAT II complex with α-oxoglutaric acid revealed a conformational change of an N-terminal fraction, residues 15-33, that is able to adapt to different substrate sizes, which provides a structural basis for its broad substrate specificity.Keywords aminoadipic acid; crystal structure; kynurenic acid (KYNA); kynurenine; kynurenine aminotransferase (KAT); neurodegenerative disease INTRODUCTIONAminotransferase, capable of catalysing the transamination of kynurenine to KYNA (kynurenic acid), has commonly been termed KAT (kynurenine aminotransferase). KYNA is the only known endogenous antagonist of the NMDA (N-methyl-D-aspartate) subtype of 1 To whom correspondence should be addressed (emailqianhan@vt.edu).The structural co-ordinates reported will appear in the Protein Data Bank under accession code 3DC1. In humans, rats and mice, four enzymes, KAT I, II, III and IV, are considered to be involved in KYNA synthesis in the central nervous system [16][17][18][19][20][21]. Of these, KAT I and KAT II have been extensively studied and the crystal structures of hKAT I (human kynurenine aminotransferase I) and hKAT II (human kynurenine aminotransferase II) are now available [16,17,19,[22][23][24][25]. It has been reported that KAT I has a broad substrate specificity and displays maximum activity at relatively basic conditions. This poses critical questions regarding the contribution of KAT I to brain KYNA production [16,17]. On the other hand, KAT II is identical to AADAT (aminoadipate aminotransferase) and catalyses the transamination of kynurenine and aminoadipate and is localized in the soluble cytoplasm [16]. The enzyme has been cloned from both rats and humans and its presence in the brain has been confirmed by Northern and...

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Section: Discussionmentioning

confidence: 99%

Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II

et al. 2008

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“…Combined alpha-aminoadipic and alpha-ketoadipic aciduria as described in most cases, is consistent with a defect at the level of the KAA dehydrogenase complex, but some individuals with exclusive alpha-aminoadipic aciduria have been reported. In two children (Gray et al 1979;Manders et al 1981), the exclusive excretion of AAA coincided with a normal degradation of AAA in fibroblasts of the patient suggesting the existence of a second defect in AAA catabolism. In other cases no good explanation for the failure to detect KAA was found (Casey et al 1978) or KAA was not determined (Lormans and Lowenthal 1974).…”

Section: Introductionmentioning

confidence: 93%

“…Urine AAA and KAA as well as plasma AAA were elevated. Patient 7 was a girl with severe mental retardation, frequent petit-mal seizures which responded poorly to clonazepam, and dysmorphic features (Manders et al 1981). AAA was increased in plasma and urine, but neither KAA nor HAA was detected.…”

Section: Case Reportsmentioning

confidence: 99%

“…Following these initial findings, alpha-aminoadipic aciduria often with alpha-ketoadipic aciduria has been diagnosed mainly in individuals with mental retardation. Other reported symptoms are moderate metabolic acidosis , seizures (Casey et al 1978;Manders et al 1981;Duran et al 1984), obesity (Casey et al 1978), immunodeficiency (Gray et al 1979), dysmorphic features (Manders et al 1981), hypotonia with delayed motor development Vianey-Liaud et al 1985), mild speech retardation (Takechi et al 1993), episodic vomiting (Sewell et al 1999), apnea due to gastroesophageal reflux and tremor (Sewell et al 1999). At the same time, a causal relationship between the biochemical abnormality and the clinical findings has been questioned ever since the identification of the first patient.…”

Section: Introductionmentioning

confidence: 99%

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Genetic basis of alpha‐aminoadipic and alpha‐ketoadipic aciduria

Hagen

Brinke

Wanders

et al. 2015

J of Inher Metab Disea

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Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations, one of which was reported before, were observed in the majority of cases. The clinical presentation of this group of patients was inhomogeneous. Our results confirm that alpha-aminoadipic and alpha-ketoadipic aciduria is caused by mutations in DHTKD1, and further establish that DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex.

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“…ct-Aminoadipic aciduria (c~-AAAuria, McKusick 204750) was first described by Lormans and Lowenthal (1974). Since then several patients have been reported (Fischer et al 1974;Przyrembel et al 1975;Wendel et al 1975;Wilson et al 1975Wilson et al , 1976Casey et al 1978;Gray et al 1979;Fischer and Brown 1980;Manders et al 1981;Duran et al 1984;Vianey-Liaud et al 1985). In addition patients were found to have c~-ketoadipic aciduria (~-KAAuria, McKusick 245130) Wendel et al 1975;Wilson et al 1975Wilson et al , 1976Fischer and Brown 1980;Duran et al 1984;Vianey-Liaud et al 1985), probably due to a 2-ketoadipic acid dehydrogenase deficiency.…”

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confidence: 99%

Identification ofN‐acetyl‐α‐aminoadipic acid in the urine of a patient with α‐aminoadipic and α‐ketoadipic aciduria

Takechi¹,

Okada²,

Wakiguchi³

et al. 1992

J of Inher Metab Disea

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A 3.5-year-old Japanese boy with a mild speech disturbance excreted a large amount of alpha-aminoadipic acid into the urine. The amino acid analysis using an amino acid analyser confirmed the presence of alpha-aminoadipic acid in both urine and plasma. We detected alpha-aminoadipic acid in the hydrolysate of the effluent and washwater fraction through cation exchange resin. This suggested the presence of acetylated derivatives and we identified N-acetyl-alpha-aminoadipic acid using liquid chromatography-atmospheric pressure ionization mass spectrometry (LC-API-MS). The concentrations of alpha-aminoadipic acid and N-acetyl-alpha-aminoadipic acid in the urine of a patient with alpha-aminoadipic aciduria were 376.9 nmol/mg creatinine and 18.1 nmol/mg creatinine, respectively. We also detected alpha-ketoadipic acid in the urine of this patient using LC-API-MS.

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?-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child

Cited by 9 publications

References 9 publications

Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II

Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II

Genetic basis of alpha‐aminoadipic and alpha‐ketoadipic aciduria

Identification ofN‐acetyl‐α‐aminoadipic acid in the urine of a patient with α‐aminoadipic and α‐ketoadipic aciduria

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