Peroxisomal Oxidases and Suggestions for the Mechanism of Action of Insulin and Other Hormones

Hamilton, Gordon A.

doi:10.1002/9780470123034.ch2

Cited by 29 publications

(5 citation statements)

References 243 publications

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“…Ddo genetic inactivation induces a strong increase of D-aspartate levels in the hippocampus without affecting its morphology Based on the evidences that DDO plays a crucial role in the metabolism of D-aspartate (Errico et al, 2006;Hamilton, 1985;Huang et al, 2006), we first analysed the neurochemical consequences of Ddo gene ablation by measuring D-aspartate levels in the hippocampus of 10-12 weeks old mice. HPLC analysis indicated a strong increase of hippocampal D-aspartate content (p b 0.0001) in knockout (Ddo −/− ) mice (384.0 ± 25.2 nmol/g tissue) compared to their wild type (Ddo +/+ ) littermates (29.2 ± 2.9 nmol/g tissue).…”

Section: Resultsmentioning

confidence: 99%

“…High levels of free D-aspartate appear to occur throughout the brain during early development and in newborns but rapidly decrease afterwards (Dunlop et al, 1986;Hashimoto et al, 1995;Neidle and Dunlop, 1990;Wolosker et al, 2000). The postnatal reduction of D-aspartate levels in the CNS has been correlated with the concomitant increase of D-Aspartate Oxidase (DDO) activity (Van Veldhoven et al, 1991), the only known enzyme able to metabolize selectively bicarboxylic D-amino acids (Errico et al, 2006;Hamilton, 1985;Huang et al, 2006). In particular, the adult rat hippocampus shows a very low concentration of D-aspartate but strongly expresses DDO (Schell et al, 1997;Zaar et al, 2002), suggesting that a strict control of the enzyme over its substrate must occur in this area.…”

Section: Introductionmentioning

confidence: 99%

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Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Errico

Nisticò

Palma

et al. 2008

Molecular and Cellular Neuroscience

110

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Errico

Nisticò

Palma

et al. 2008

Molecular and Cellular Neuroscience

110

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“…The current study does not answer the question of where the conversion of d-Met to l-Met occurs in the body. d-Amino acid oxidase is present in peroxisomes across many tissues in mammalian species (Hamilton, 1985) with high activity in bovine kidney (Horiike and Miyake, 1971) and with the enzyme isolated from beef liver offered commercially. The disappearance of d-Met from the whole body (3.7 mmol/h; from Tables 4 and 5) is approximately twice that based on hepatic extraction and estimated blood flow for the same animals (Lapierre et al, 2009) and suggests that other tissues,…”

Section: Studymentioning

confidence: 99%

Is d-methionine bioavailable to the dairy cow?

Lapierre

Holtrop

Calder

et al. 2012

Journal of Dairy Science

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Rumen-protected forms of Met contain an equimolar mixture of the D- and L-isomers. Only L-Met can be directly used for protein synthesis, but it is unclear how much of the D-isomer can be transformed into L-Met in ruminants. Four lactating dairy cows, with an average milk yield of 32.4 kg/d, received a basal diet (12.5% crude protein, supplying 1,718 g/d of metabolizable protein) in 12 equal meals per day plus an abomasal infusion of amino acids (590 g/d, casein profile without Met). They were used in 3 consecutive studies to determine utilization of D-Met. First, the cows each received portal vein infusions for d of 5, 10, or 15 g/d of DL-Met in a Youden square. On the last day of each period, 6 arterial samples were collected at 45-min intervals. Concentrations of L- and D-Met were determined on a chiral column by gas chromatography-mass spectrometry. Portal infusion of 5, 10, and 15 g/d of DL-Met increased plasma total Met concentrations (19.7, 25.0, and 34.4±0.6 μM) and the proportion of Met as D (19.4, 30.5, and 37.3±0.7%). The fractional removal of D-Met was 6 to 7 times lower than the fractional removal of L-Met, with mean half-lives of 52 versus 8 min, respectively. Second, the same cows were infused for 8 h with L[methyl-(2)H(3)]Met at 1.3 mmol/h; at 2 h, cows received a bolus injection i.v. of D-[1-(13)C]Met (6.8 mmol), and arterial samples were collected after 10, 20, 30, 40, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min. Expressed relative to L-[(12)C]Met; that is, as tracer:tracee ratios, enrichments of plasma D-[1-(13)C]Met and L-[1-(13)C]Met averaged 1.77±0.14 and 0.144±0.026, respectively, 10 min after the bolus injection and declined exponentially thereafter. A minimum of 75±3% of the D-[1-(13)C]Met was transformed into L-[1-(13)C]Met. Third, the cows received, in a crossover design, an abomasal infusion for D of either DL-Met or L-Met (1g/d) and, on the last day of each experimental period, blood samples were collected simultaneously from arterial, portal, hepatic, and mammary vessels. Arterial total Met concentrations were higher with DL- versus L-Met infusions (37.4 vs. 25.4±0.5 μM), with 37.1±5.0% as D-Met. The mammary gland did not extract any D-Met. Hepatic removal of D-Met was observed, but was numerically lower than the fractional extraction of L-Met. In conclusion, much of the D-Met is transformed into L-Met by the dairy cow but at a slow rate. No uptake of D-Met occurs across the mammary gland but L-Met synthesized from the D-isomer elsewhere in the body can be utilized for milk protein synthesis.

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“…DASPO is ubiquitously expressed in mammals: the highest amounts of the enzyme have been detected in kidney, liver, and CNS (Hamilton 1985;van Veldhoven et al, 1991); interestingly, the same distribution was reported for the orthologous DAAO (Pollegioni et al, 2007 and references therein). The presence and the physiological role of these two flavoenzymes in the brain prompted the investigation of their localization in different brain areas, tissues and cell populations.…”

Section: Tissue and Cellular Localizationmentioning

confidence: 61%

Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism

Pollegioni

Molla

Sacchi

et al. 2021

Front. Mol. Biosci.

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In recent years, the D-enantiomers of amino acids have been recognized as natural molecules present in all kingdoms, playing a variety of biological roles. In humans, d-serine and d-aspartate attracted attention for their presence in the central nervous system. Here, we focus on d-aspartate, which is involved in glutamatergic neurotransmission and the synthesis of various hormones. The biosynthesis of d-aspartate is still obscure, while its degradation is due to the peroxisomal flavin adenine dinucleotide (FAD)-containing enzyme d-aspartate oxidase. d-Aspartate emergence is strictly controlled: levels decrease in brain within the first days of life while increasing in endocrine glands postnatally and through adulthood. The human d-aspartate oxidase (hDASPO) belongs to the d-amino acid oxidase-like family: its tertiary structure closely resembles that of human d-amino acid oxidase (hDAAO), the enzyme that degrades neutral and basic d-amino acids. The structure-function relationships of the physiological isoform of hDASPO (named hDASPO_341) and the regulation of gene expression and distribution and properties of the longer isoform hDASPO_369 have all been recently elucidated. Beyond the substrate preference, hDASPO and hDAAO also differ in kinetic efficiency, FAD-binding affinity, pH profile, and oligomeric state. Such differences suggest that evolution diverged to create two different ways to modulate d-aspartate and d-serine levels in the human brain. Current knowledge about hDASPO is shedding light on the molecular mechanisms underlying the modulation of d-aspartate levels in human tissues and is pushing novel, targeted therapeutic strategies. Now, it has been proposed that dysfunction in NMDA receptor-mediated neurotransmission is caused by disrupted d-aspartate metabolism in the nervous system during the onset of various disorders (such as schizophrenia): the design of suitable hDASPO inhibitors aimed at increasing d-aspartate levels thus represents a novel and useful form of therapy.

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Peroxisomal Oxidases and Suggestions for the Mechanism of Action of Insulin and Other Hormones

Cited by 29 publications

References 243 publications

Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Increased levels of d-aspartate in the hippocampus enhance LTP but do not facilitate cognitive flexibility

Is d-methionine bioavailable to the dairy cow?

Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism

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