L‐Cycloserine: A Potent Anticonvulsant

Chung, Shin-Ho; Johnson, Mark; Gronenborn, Angela M.

doi:10.1111/j.1528-1157.1984.tb04200.x

Cited by 22 publications

(11 citation statements)

References 18 publications

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“…L-Cycloserine has anticonvulsant effects and has been shown to inhibit many PLP-dependent enzymes, for example GABA aminotransferase [123], aspartate and alanine aminotransferases [124], and dialkylglycine decarboxylase [125]. Chung et al show that cycloserine forms an irreversible Schiff base with PLP [126]. L-Cycloserine is therefore a nonspecific inhibitor.…”

Section: Table 3 Serine Analogs As Sr Inhibitorsmentioning

confidence: 96%

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Jiraskova-Vanickova

Ettrich²,

Vorlová³

et al. 2011

CDT

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Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders; however, their effect is often compromised by undesirable side effects. Therefore, alternative ways of modulating NMDA receptor function need to be sought after. The opening of the NMDA receptor ion channel requires occupation of two distinct binding sites, the glutamate site and the glycine site. It has been shown that D-serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a specific enzyme, serine racemase (SR), which was identified a decade ago. SR has therefore emerged as a new potential target for the NMDA-receptor-based diseases. There is evidence linking increased levels of D-Ser to amyotrophic lateral sclerosis and Alzheimer's disease and decreased concentrations of D-serine to schizophrenia. SR is a pyridoxal-5'-phosphate dependent enzyme found in the cytosol of glial and neuronal cells. It is activated by ATP, divalent cations like Mg(2+) or Ca(2+), and reducing agents. This paper reviews the present literature on the activity and inhibition of mammalian SRs. It summarizes approaches that have been applied to design SR inhibitors and lists the known active compounds. Based on biochemical and docking analyses, i) we delineate for the first time the ATP binding site of human SR, and ii) we suggest possible mechanisms of action for the active compounds. In the end, we discuss the SR features that make the discovery of its inhibitors a challenging, yet very important, task of medicinal chemistry.

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Section: Table 3 Serine Analogs As Sr Inhibitorsmentioning

confidence: 96%

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Jiraskova-Vanickova

Ettrich²,

Vorlová³

et al. 2011

CDT

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“…Androgen imprinting takes place during the first week of life, since castration performed at a later age does not induce full feminization of P-450 [37]. Rats treated with testosterone immediately after neonatal castration, and given a second treatment with testosterone in adulthood, display the same P-450 activity as that found in intact adult rats [8]. Treatment of castrated neonates with androgens combined with estrogens prevents the androgenic imprinting of P-450 [39]; in adulthood, these rats have the female type of P-450 activity.…”

Section: Waxman Levin Guengerich Schenkman Kato Wolf Omura Gustafssonmentioning

confidence: 93%

“…One occurs by androgens permanently present in the body since after castration the effect is abolished: adult rat castration decreased the level of the IICll isoform of cytochrome P-450 and correspondingly decreased the ability of the hepatic microsomes to metabolize some xenobiotics and androgens in positions 16a and 2a [14,191. The other parameters characterizing the male type of metabolism like, for example, the low K , for ethylmorphine deethylation [8] and the ratio of rapidly and Table 2. Designation of the main sex-specific isoforms of rat hepatic cytochrome P-450 The purification and characteristics of the enzymes mentioned in the table are described in [22,25, 28, 32, 36, 38, 85 -871.…”

Section: Hormonal Regulation Of Sex-specific Isoforms Of Cytochrome Pmentioning

confidence: 99%

“…Liver microsomal cytochrome P-450 has been shown to decay biphasically in vivo with phase half-lives of 7 -8 h and 44-46 h, referred to as rapid and slow decay, respectively [14]. The ratio of the rapid turnover to the slow turnover forms of cytochrome P-450 varies between 3.4: 1 and 4.4: 1 in the female and is 1.9 : 1 in the male rat liver microsomes [8,141 (Table 1).…”

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confidence: 99%

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Regulation of the expression of the sex‐specific isoforms of cytochrome P‐450 in rat liver

Кобляков¹,

Попова²,

Rossi

1991

European Journal of Biochemistry

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The hepatic metabolism of steroid hormones and of xenobiotics frequently depends on the expression of the sex-specific isoforms of cytochrome P-450 and on differences in sex hormones.Following biochemical, immunological and molecular biological investigations, it was shown that in adult rat liver there exist at least four male-specific and one female-specific isoforms of cytochrome P-450. The designation of these sex-specific genes is IIC11, IIIA2, IIC13 and IIA2 in males, and IIC12 in females. The irreversible programming of the expression of these isoforms of cytochrome P-450 in adulthood occurs during the perinatal period of life, and is named enzyme imprinting. One of the main factors that regulates the expression of the sexspecific isoforms of cytochrome P-450 is the level of androgens in the blood. Castration of adult rats decreased the level of the male isoforms of cytochrome P-450 and the activity of the monooxygenase enzyme system that remained higher than in intact females.The mechanism of enzyme imprinting can be explained as follows: neonatal androgens program the secretion of hypothalamic hormones, somatostatin and growth-hormone-releasing factor. These factors determine the type of growth hormone secretion in adult rats, and this controls the type of sex-specific isoforms of cytochrome P-450 expressed in adulthood.Metabolic regulation similar to that outlined above was shown to occur for several metabolism-dependent chemical carcinogens. Such a pathway may explain the different sensitivity displayed by male and female rats to treatment with these carcinogenic agents. One possible way of modulating the expression of some isoforms of cytochrome P-450 in adult rats is by treating neonates with specific xenobiotics that change the constitutive expression of neonatal androgens. It appears that this enzyme imprinting plays an important role in determining the individual sensitivity to the carcinogenic effects of chemicals.Most environmental compounds that are dangerous for health (carcinogens, mutagens, toxins) are indirectly acting agents and must be activated by the monooxygenase enzyme system in order to induce their effects in target tissues. The catalytic part of monooxygenases is cytochrome P-450, an enzyme highly concentrated in the liver, where the majority of xenobiotics are processed by either detoxification or activation metabolic pathways. It comprises a number of isoforms with overlapping substrate specificity. It is possible that the sensitivity of adult organisms to chemicals depends, among other factors, on the level of expression and substrate-specificity of these enzymes. The expression of some isoforms of the hepatic cytochrome P-450 in adulthood is programmed in the perinatal period of life, a type of regulation termed enzyme imprinting [l], also adopted to explain the sex-dependent regulation of xenobiotic metabolism in the liver.The purpose of this review is to provide an up-to-date description of the factors regulating the developmental im-

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“…It lowered the levels of some gangliosides in vitro (Cinatl et al, ) and in vivo (Sundaram and Lev, , ). L‐cycloserine caused an increase in GABA content, likely as a result of its inhibitory effects on GABA transaminase (Chung et al, ), and this increase in GABA can decrease neuronal firing within the brain (Haas and Wieser, ). L‐cycloserine also inhibits alanine aminotransferase that is expressed in the liver (Cornell et al, ).…”

Section: Srt In Kd: L‐cycloserinementioning

confidence: 99%

Substrate reduction therapy for Krabbe's disease

Sands

Levine

2016

J of Neuroscience Research

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Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose‐sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP‐galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand‐alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult‐onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.

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L‐Cycloserine: A Potent Anticonvulsant

Cited by 22 publications

References 18 publications

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry

Regulation of the expression of the sex‐specific isoforms of cytochrome P‐450 in rat liver

Substrate reduction therapy for Krabbe's disease

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