Flux of the l-Serine Metabolism in Rabbit, Human, and Dog Livers

Xue, Hai-Hui; Sakaguchi, Takanori; Fujie, Manabu; Ogawa, Hirofumi; Ichiyama, Arata

doi:10.1074/jbc.274.23.16028

Cited by 50 publications

(13 citation statements)

References 22 publications

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“…SDS converts serine to pyruvate and ammonia (14). AGXT is also involved in the metabolism of pyruvate and serine (15). GOT1 is involved in the malate-aspartate shuttle and thereby in the production of oxaloacetate, which serve as substrates for gluconeogenesis via a PEPCK-mediated reaction (16).…”

Section: Resultsmentioning

confidence: 99%

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Watanabe

Seino²,

Miyahira³

et al. 2011

Diabetes

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Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon–green fluorescent protein (gfp) knock-in mice (Gcggfp/gfp: GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.

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Section: Resultsmentioning

confidence: 99%

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Watanabe

Seino²,

Miyahira³

et al. 2011

Diabetes

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“…Previous studies have shown that AGT also has serine:pyruvate aminotransferase activity, which although much lower than its alanine:glyoxylate aminotransferase activity might be important for its gluconeogenic role (28). In the present study, the serine:pyruvate aminotransferase activity of purified recombinant AGT-His, AGT (23,29).…”

Section: Expression and Purification Of His-tagged Agt-many Of The Agmentioning

confidence: 88%

Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations

Lumb

Danpure

2000

Journal of Biological Chemistry

130

135

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The autosomal recessive disorder primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver-specific pyridoxal-phosphate-dependent enzyme alanine:glyoxylate aminotransferase (AGT). Numerous mutations and polymorphisms in the gene encoding AGT have been identified, but in only a few cases has the causal relationship between genotype and phenotype actually been demonstrated. In this study, we have determined the effects of the most common naturally occurring amino acid substitutions (both normal polymorphisms and disease-causing mutations) on the properties, especially specific catalytic activity, of purified recombinant AGT. The results presented in this paper show the following: 1) normal human His-tagged AGT can be expressed at high levels in Escherichia coli and purified in a correctly folded, dimerized and catalytically active state; 2) presence of the common P11L polymorphism decreases the specific activity of purified recombinant AGT by a factor of three; 3) AGTs containing four of the most common PH1-specific mutations (G41R, F152I, G170R, and I244T) are all soluble and catalytically active in the absence of the P11L polymorphism, but in its presence all lead to protein destabilization and aggregation into inclusion bodies; 4) naturally occurring and artificial amino acid substitutions that lead to peroxisome-to-mitochondrion AGT mistargeting in mammalian cells also lead to destabilization and aggregation in E. coli; and 5) the PH1-specific G82E mutation abolishes AGT catalytic activity by interfering with cofactor binding, as does the artificial K209R mutation at the putative site of cofactor Shiff base formation. These results are discussed in the light of the high allelic frequency (ϳ20%) of the P11L polymorphism and its importance in determining the phenotypic manifestations of mutations in PH1.

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“…SPT/AGT exhibits not only the AGT activity but also the SPT activity with both of these two activities being of physiological significance [7]. Assay of the AGT activity of SPT/AGT in human liver extract is associated with a problem that glutamate:glyoxylate aminotransferase (GGT) also catalyzes transamination between alanine and glyoxylate.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondrial production of glyoxylate from hydroxyproline is assumed to play a significant role in carnivores [5], because the hydroxyproline content of collagen reaches about 10–13% [6] and collagen accounts for about 30% of total animal protein. Although SPT/AGT is a bifunctional enzyme involved in the metabolism of both L -serine and glyoxylate, its contribution to L -serine metabolism is independent of mitochondrial or peroxisomal localization [7]. …”

Section: Introductionmentioning

confidence: 99%

Primary Hyperoxaluria Type 1 in Japan

et al. 2005

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Background/Aims: Current status of primary hyperoxaluria (PH) has not been surveyed in Japan. Methods: Japanese patients with PH were reviewed in the published literature. Results: Fifty-nine patients were diagnosed as PH from 1962 to 2003. The median ages both at diagnosis and at the onset of initial symptoms were 17 (range: 0.02–63) and 13 (range: 0–58) years, respectively. Twenty-nine (49%) patients were older than 20 years at diagnosis, among whom 26 (90%) already presented end-stage renal failure (ESRF) or soon evolved into ESRF. Among 30 (51%) diagnosed as PH under 20 years old, only 13 (43%) were already in a terminal stage of renal insufficiency. Ten patients were diagnosed as PH1 by liver biopsy. We identified two types of enzymatic phenotypes in 3 of those patients examined. In 1 case, immunoreactive SPT/AGT protein level was very low due to accelerated proteolysis, while in other 2 cases, the immunoreactivity was detected on mitochondria due to mistargeting. Of 9 cases having been subjected to kidney transplantation at a median age of 20 years (range 7.3–40.0), it was only 2 cases that were reported to be successful, while the median survival time of the kidney grafts being 1.4 years (range 0–7). Of 4 patients having undergone combined liver/kidney transplantations (at the ages of 1.3, 1.4, 9 and 41 years, respectively), the surgery was successful in 3 cases; in the remaining one case, however, rejection required removal of the transplanted kidney was observed. The overall survival ratio of all the 59 PH cases accounted for 77, 71 and 55% at 5, 10 and 20 years, respectively. Conclusion: Assuming that the majority of the 59 patients with PH reported was classified as PH1, it is postulated that morbidity of violent infantile PH1 in Japan might be less than those in the USA and Europe, and symptoms of elderly Japanese PH1 patients seem to be milder than those of Western patients. Establishment of an early detection system of PH1 and more popular application of combined liver/kidney transplantation deserve further study.

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Flux of the l-Serine Metabolism in Rabbit, Human, and Dog Livers

Cited by 50 publications

References 22 publications

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations

Primary Hyperoxaluria Type 1 in Japan

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