The in vivo decrease of .BETA.-alanine-2-oxoglutarate aminotransferase activity caused by 6-azauracil and 5-fluorouracil.

Kubo, Keiko; Funatsuka, Akimi; Tamaki, Nanaya

doi:10.3177/jnsv.28.575

Cited by 8 publications

(3 citation statements)

References 11 publications

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“…The affinity of β‐alanine for the mature liver β‐AlaAT I polypeptide is stronger than that for the mature brain β‐AlaAT I (Table 1). β‐Alanine concentration is about 0.1 and 0.01–0.04 m m in liver [28] and brain [29,30], respectively. The level of GABA in whole brain is about 4 m m , but no GABA (< 0.01 m m ) was detected in liver [28].…”

Section: Discussionmentioning

confidence: 99%

“…β‐Alanine concentration is about 0.1 and 0.01–0.04 m m in liver [28] and brain [29,30], respectively. The level of GABA in whole brain is about 4 m m , but no GABA (< 0.01 m m ) was detected in liver [28]. The β‐alanine‐synthesizing enzymes dihydropyrimidine dehydrogenase, dihydropyrimidinase and β‐ureidopropionase are found mainly in liver, followed by kidney in rats [31–34].…”

Section: Discussionmentioning

confidence: 99%

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The mature size of rat 4‐aminobutyrate aminotransferase is different in liver and brain

Kontani¹,

Sakata²,

Matsuda³

et al. 1999

European Journal of Biochemistry

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The amino acid sequence predicted from a rat liver cDNA library indicated that the precursor of b-AlaAT I (4-aminobutyrate aminotransferase, b-alanine±oxoglutarate aminotransferase) consists of a mature enzyme of 466 amino acid residues and a 34-amino acid terminal segment, with amino acids attributed to the leader peptide. However, the mass of b-AlaAT I from rat brain was larger than that from rat liver and kidney, as assessed by Western-blot analysis, mass spectroscopy and N-terminal sequencing. The mature form of b-AlaAT I from the brain had an ISQAAAK-peptide on the N-terminus of the liver mature b-AlaAT I. Brain b-AlaAT I was cleaved to liver b-AlaAT I when incubated with fresh mitochondrial extract from rat liver. These results imply that mature rat liver b-AlaAT I is proteolytically cleaved in two steps. The first cleavage of the motif XRX(5)XS is performed by a mitochondrial processing peptidase, yielding an intermediate-sized protein which is the mature brain b-AlaAT I. The second cleavage, which generates the mature liver b-AlaAT I, is also carried out by a mitochondrial endopeptidase. The second peptidase is active in liver but lacking in brain.Keywords: 4-aminobutyrate aminotransferase; GABA; mitochondrial processing peptidase; b-alanine aminotransferase; b-alanine. [4,5]. Malonate semialdehyde is converted into acetyl-CoA by methylmalonate semialdehyde dehydrogenase in the mitochondrial fraction [6,7].It is well established that 4-aminobutyrate (GABA) is a major inhibitory transmitter in many invertebrate systems and in the vertebrate central nervous system [8±10]. b-AlaAT I (GABA aminotransferase) together with succinate semialdehyde dehydrogenase and glutamate decarboxylase are the main components of the GABA shunt. b-AlaAT I in the brain is localized in the mitochondrial matrix [11] or in the inner mitochondrial membrane [12]. We proposed that the immunological and kinetic properties of b-AlaAT I from rat liver are similar to those of GABA aminotransferase from rat brain [13]. However, the N-terminal amino acid of rat liver b-AlaAT I is Val [13], while that of rat brain GABA aminotransferase has been identified as Ile by the dansyl method [14] and as Ser from the deduced amino acid sequence of the cDNA [15]. On the other hand, the N-terminal amino acid of liver and brain b-AlaAT I from pigs and humans is Ser [16,17]. This paper describes the N-terminal amino acid sequence and the molecular mass of mature b-AlaAT I in the liver and brain of rats. The N-terminal amino acid sequence of b-AlaAT I from rats is also compared with those from pigs [16] and humans [17].

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mature size of rat 4‐aminobutyrate aminotransferase is different in liver and brain

Kontani¹,

Sakata²,

Matsuda³

et al. 1999

European Journal of Biochemistry

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“…The affinity of β‐alanine for β‐AlaAT I is significantly higher than that for GABA AT in rats [10]. The β‐alanine concentration is about 0.1 mM in the liver [27] and 0.01–0.04 mM in the brain [28,29], Therefore, liver‐type mature‐β‐AlaAT I may be more favorable for β‐alanine catabolism than brain‐type mature‐GABA AT at least.…”

Section: Discussionmentioning

confidence: 95%

Purification and expression of a processing protease on β‐alanine‐oxoglutarate aminotransferase from rat liver mitochondria

et al. 2004

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GABA[arrow beta]AlaAT convertase is an endopeptidase that processes brain-type 4-aminobutyrate aminotransferase (GABA AT; EC 2.6.1.19) to liver-type b-alanine-oxoglutarate aminotransferase (b-AlaAT I) in rats. Its molecular mass was 180 kDa as determined by gel filtration. A subunit molecular mass of 97 652 Da was measured using MALDI-TOF MS. The N-terminal sequence of the purified GABA[arrow beta]AlaAT convertase was SRVEVSKVLILGSGGLSIGQAGEFDYSGS-QAV-and was identical to residues 418-449 of carbamoylphosphate synthetase I (CPS I; EC 1.2.1.27) purified from rat liver. The subunit molecular mass and the N-terminal amino acid sequence suggested that GABA[arrow beta]AlaAT convertase was the 418-1305 peptide of CPS I. An expression vector containing the coding region of the 418-1305 peptide of rat CPS I was transfected into NIH3T3 cells and the extract of the cells showed GABA[arrow beta]AlaAT convertase activity.

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Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

et al. 1990

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The limiting toxicity of low dose continuous infusion 5-fluorouracil (200-300 mg/m2/day) is often palmar-plantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42%-82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m2/day until toxicity or progressive disease forced discontinuation. The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42-92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6-61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups. Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

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The in vivo decrease of .BETA.-alanine-2-oxoglutarate aminotransferase activity caused by 6-azauracil and 5-fluorouracil.

Cited by 8 publications

References 11 publications

The mature size of rat 4‐aminobutyrate aminotransferase is different in liver and brain

The mature size of rat 4‐aminobutyrate aminotransferase is different in liver and brain

Purification and expression of a processing protease on β‐alanine‐oxoglutarate aminotransferase from rat liver mitochondria

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

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