A Study of Amino Acid Oxidase Specificity, Using a New Sensitive Assay<sup>*</sup>

Scannone, Héctor; Wellner, Daniel; Novogrodsky, Abraham

doi:10.1021/bi00899a027

Cited by 35 publications

(18 citation statements)

References 15 publications

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“…The peroxisomal enzyme d -amino acid oxidase (DAAO) was suspected of initiating the metabolism of d -lysine. Indeed, Scannone et al (1964) had previously shown that d -lysine is a substrate of mammalian DAAO. The product of d -lysine oxidative deamination is α-keto-ε-aminocaproate (KAC), which spontaneously cyclizes to the ketimine P2C (Fig.…”

Section: The Nature Of the First Step Of The Pipecolate Pathway In Thmentioning

confidence: 99%

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

2013

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The lysine catabolism pathway differs in adult mammalian brain from that in extracerebral tissues. The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. The two pathways converge at the level of Δ1-piperideine-6-carboxylate (P6C), which is in equilibrium with its open-chain aldehyde form, namely, α-aminoadipate δ-semialdehyde (AAS). A unique feature of the pipecolate pathway is the formation of the cyclic ketimine intermediate Δ1-piperideine-2-carboxylate (P2C) and its reduced metabolite l-pipecolate. A cerebral ketimine reductase (KR) has recently been identified that catalyzes the reduction of P2C to l-pipecolate. The discovery that this KR, which is capable of reducing not only P2C but also other cyclic imines, is identical to a previously well-described thyroid hormone-binding protein [μ-crystallin (CRYM)], may hold the key to understanding the biological relevance of the pipecolate pathway and its importance in the brain. The finding that the KR activity of CRYM is strongly inhibited by the thyroid hormone 3,5,3′-triiodothyronine (T3) has far-reaching biomedical and clinical implications. The interrelationship between tryptophan and lysine catabolic pathways is discussed in the context of shared degradative enzymes and also potential regulation by thyroid hormones. This review traces the discoveries of enzymes involved in lysine metabolism in mammalian brain. However, there still remain unanswered questions as regards the importance of the pipecolate pathway in normal or diseased brain, including the nature of the first step in the pathway and the relationship of the pipecolate pathway to the tryptophan degradation pathway.

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Section: The Nature Of the First Step Of The Pipecolate Pathway In Thmentioning

confidence: 99%

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

2013

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“…The precipitated protein was removed by centrifugation, and the supernatant was extracted two times with 1 ml of water-saturated diethyl ether to remove TCA. D-Serine was determined by incubation of the samples with D-amino acid oxidase, which specifically degrades D-amino acids, generating an ␣-keto acid, NH 3 , and hydrogen peroxide (16). The generation of hydrogen peroxide was quantitated by the use of peroxidase and luminol, which emits light.…”

mentioning

confidence: 99%

Purification of serine racemase: Biosynthesis of the neuromodulator d -serine

Wolosker

Sheth

Takahashi

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

479

361

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High levels of D-serine occur in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate receptors. In glial cultures of rat cerebral cortex, D-serine is enriched in type II astrocytes and is released upon stimulation with agonists of non-N-methyl-D-aspartate glutamate receptors. The high levels of D-serine in discrete areas of rat brain imply the existence of a biosynthetic pathway. We have purified from rat brain a soluble enzyme that catalyzes the direct racemization of L-serine to D-serine. Purified serine racemase has a molecular mass of 37 kDa and requires pyridoxal 5-phosphate for its activity. The enzyme is highly selective toward L-serine, failing to racemize any other amino acid tested. Properties such as pH optimum, K m values, and the requirement for pyridoxal phosphate resemble those of bacterial racemases, suggesting that the biosynthetic pathway for D-amino acids is conserved from bacteria to mammalian brain.D-Amino acids are prominent in bacteria whereas in animal tissues L-amino acids occur exclusively, though there have been occasional reports of D-amino acids, usually in invertebrates (1, 2). Recently, D-serine (3-6) and D-aspartate (7,8) were reported in mammalian tissues, especially in the nervous system. Using highly selective antibodies, we localized D-aspartate to neuroendocrine tissues (9), whereas the immunohistochemical localizations of D-serine closely resemble N-methyl-D-aspartate (NMDA) receptors for the neurotransmitter glutamate, as the distribution of D-serine measured chemically (10, 11). Glutamate cannot activate the NMDA receptor in the absence of glycine, indicating a ''glycine site'' for the receptor (12, 13). D-Serine is up to three times more potent than glycine at this site (14), suggesting that D-serine is the endogenous ligand for this site. D-Serine is localized exclusively to type II astrocytes, a form of glia concentrated in gray matter in the same areas of the brain as NMDA receptors (10). Stimulation of the kainate subtype of glutamate receptors releases D-serine from type II astrocytes, implying that synaptic release of glutamate triggers release of D-serine from the astrocytes to activate NMDA receptors physiologically (10). Although in most parts of the brain the distribution of D-serine resembles NMDA receptors far better than glycine, in some areas glycine and NMDA receptors are colocalized, suggesting that D-serine is the predominant ligand for the receptor in most brain areas but that glycine serves this purpose in some sites (11).Understanding the neurobiology of D-serine requires delineation of its biosynthesis. D-Serine might be formed by direct racemization from L-serine. Dunlop and Neidle (15) reported the transformation of radiolabeled L-serine to D-serine in intact rats, but this might have involved multiple steps rather than any direct enzymatic racemization. In the present study we describe an enzyme activity that directly racemizes L-serine to D-serine and that is localized to the brain. We ...

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“…The assay is based on irreversible inhibition of ¢atalase by H:O., in the presence of aminotriazo!e [4]. A reaction mixtur~ containing 50 #M phosphate, pH 7.3, 20/~M aminotriazole, and 17 U bovine catalase (2 x crystallized) in 30/.tl was mixed with 20/.tl sample and incubated at 37°C in a shaking water bath.…”

Section: 4 Ho: Assaymentioning

confidence: 99%

“…Hemin may mediate its effects through an oxidative process. We measured the generation of H.,O,_ catalyzed by the different metalloporphyrins using the aminotriazole-eatalase inhibition assay that we have previously developed [4]. As seen in Table III, the hierarchy of potency of the different metailoporphyrins to generate H~O2 was as follows:…”

Section: Effect Of Heroin Analoguesmentioning

confidence: 99%

Hemin stimulation of cAMP production in human lymphocytes

1992

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Heroin stimulates cAMP production in human peripheral blood raononuclear cells (PBMC). The kinetics are similar to that of hormone-induced cAMP generation, namely a rapid effect followed by a desensitization phase, Several experimental findings suggest that prostaglandins do not mediate this effect. First, macrophage depleted T and B cells purified by erythrocyte-rosetting were as responsive as unfraetioiaated PBMC to herein, Second, indomethacin, an inhibitor of prostaglandin synthesis, and meclofenamate, a prostaglandin E. receptor antagonist, had no ell'oct on heroin stimulated cAMP production, In addition, propranolol, a,B-adrenergic receptor antagonist, had no effect on herein-stimulated cAMP production, We also examined structural analogues of heroin. Among the metalloporphyrins (Fe, Ni, Co, Zn and Sn) and protoporphyrin IX tested only heroin (Fe-protoporphyrin) was active in stimulating cAMP production, No correlation was found between the ability of metalloporphyrins to stimulate cAMP production and their ability to generate H..O~, The data indicate that heroin stimulates cAMP production by directly affecting lymphocytes and that prostaglandins do not mediate this effect.

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A Study of Amino Acid Oxidase Specificity, Using a New Sensitive Assay^*

Cited by 35 publications

References 15 publications

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

Purification of serine racemase: Biosynthesis of the neuromodulator d -serine

Hemin stimulation of cAMP production in human lymphocytes

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A Study of Amino Acid Oxidase Specificity, Using a New Sensitive Assay*

Cited by 35 publications

References 15 publications

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

Purification of serine racemase: Biosynthesis of the neuromodulator d -serine

Hemin stimulation of cAMP production in human lymphocytes

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Product

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A Study of Amino Acid Oxidase Specificity, Using a New Sensitive Assay^*