Interrelationships between ornithine, glutamate and GABA-III. an ornithine aminotransferase activity that is resistant to inactivation by 5-fluoromethylornithine

Daune, Genevieve; Seiler, Nikolaus

doi:10.1016/0197-0186(88)90012-5

Cited by 14 publications

(5 citation statements)

References 26 publications

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“…L-arginine has many other metabolic roles in the brain, including the biosynthesis of GABA via ornithine (and thence glutamate) or via the putrescine pathway (Erdo 1985; Daune and Seiler 1988;De-Mello et al 1993;Seiler and Daune-Anglard 1993). Since the majority of the D-arginine-accumulating neurons in the retina are also GABAergic, we suggest that these neurons use L-arginine as a substrate for the synthesis of GABA.…”

Section: Why Might Non-nitrergic Neurons Transport Arginine?mentioning

confidence: 96%

Immunocytochemical analysis of the transport of arginine analogues into nitrergic neurons and other cells in the retina and pituitary

Pow

Crook

1997

Cell Tissue Res

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Nitric oxide is formed by the action of nitric oxide synthase upon l-arginine. The efficacy of some exogenously applied arginine analogues in inhibiting nitric oxide synthase and thus nitrergic transmission indicates that neurons producing nitric oxide may possess an arginine transport system. To investigate whether arginine analogues are preferentially transported into nitric oxide-utilising cells or into cells making other neurochemicals, we have raised highly specific antisera against a number of arginine analogues including NG-methyl arginine, D-arginine, NGnitro-L-arginine, NG-nitro-L-arginine methyl ester and canavanine. Retinae were incubated in physiological media containing these analogues and rats were given intraperitoneal injections of the analogues to study the pituitary. Immunocytochemistry and NADPH-diaphorase histochemistry revealed that many of these analogues could be transported preferentially, but not exclusively, into nitric oxide-generating cells. However, some nitric oxide-producing cells apparently lacked the ability to take up some arginine analogues. We conclude that nitric oxide-generating cells in the retina and pituitary possess one or more arginine transporters. Other subsets of neurons that use GABA or glutamate as a neurotransmitter may also accumulate arginine analogues, possibly as a substrate for formation of these neurochemicals.

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Section: Why Might Non-nitrergic Neurons Transport Arginine?mentioning

confidence: 96%

Immunocytochemical analysis of the transport of arginine analogues into nitrergic neurons and other cells in the retina and pituitary

Pow

Crook

1997

Cell Tissue Res

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“…OAT is inhibited by aminohexanoate [35], GABA, gabaculine, 5-fluoromethylornithine (5-FMOrn) [20,36,37,38], and l -canaline [39]. A more complete list of inhibitors and their structures is given in Table 2.…”

Section: Introductionmentioning

confidence: 99%

“…An intriguing property of 5-FMOrn is that even at high concentrations, a small OAT activity remains detectable in some tissues (brain and liver), whereas in other tissues inhibition is complete [20]. This activity is associated with kinetic properties that are somewhat different from “standard”; there is yet no satisfactory explanation for this finding.…”

Section: Introductionmentioning

confidence: 99%

Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

Ginguay

Cynober

Curis

et al. 2017

Biology

101

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Ornithine δ-aminotransferase (OAT, E.C. 2.6.1.13) catalyzes the transfer of the δ-amino group from ornithine (Orn) to α-ketoglutarate (aKG), yielding glutamate-5-semialdehyde and glutamate (Glu), and vice versa. In mammals, OAT is a mitochondrial enzyme, mainly located in the liver, intestine, brain, and kidney. In general, OAT serves to form glutamate from ornithine, with the notable exception of the intestine, where citrulline (Cit) or arginine (Arg) are end products. Its main function is to control the production of signaling molecules and mediators, such as Glu itself, Cit, GABA, and aliphatic polyamines. It is also involved in proline (Pro) synthesis. Deficiency in OAT causes gyrate atrophy, a rare but serious inherited disease, a further measure of the importance of this enzyme.

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“…51 5-FMO (18) also irreversibly inhibits OAT, but selectively, and long-term inhibition of OAT does not produce apparent detrimental effects in mice, 52 possibly because 10−20% of OAT is refractory to inactivation by 18. 53 Of the four possible stereoisomers of 5-FMO, only the (2S,5S) isomer inactivates OAT. 54 The crystal structure of human OAT inactivated by 5FMO 55 shows that the PLP is modified to give the expected product of mechanism-based inactivation by an enamine mechanism (19, Scheme 3).…”

Section: ■ Early Inactivators Of Oatmentioning

confidence: 99%

“…The crystal structure of 17 with human OAT confirmed the oxime structure . 5-FMO ( 18 ) also irreversibly inhibits OAT, but selectively, and long-term inhibition of OAT does not produce apparent detrimental effects in mice, possibly because 10–20% of OAT is refractory to inactivation by 18 . Of the four possible stereoisomers of 5-FMO, only the (2 S ,5 S ) isomer inactivates OAT .…”

Section: Early Inactivators Of Oatmentioning

confidence: 99%

Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma

Silverman

2021

ACS Med. Chem. Lett.

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Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.

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Interrelationships between ornithine, glutamate and GABA-III. an ornithine aminotransferase activity that is resistant to inactivation by 5-fluoromethylornithine

Cited by 14 publications

References 26 publications

Immunocytochemical analysis of the transport of arginine analogues into nitrergic neurons and other cells in the retina and pituitary

Immunocytochemical analysis of the transport of arginine analogues into nitrergic neurons and other cells in the retina and pituitary

Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma

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