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Studies on the development of ornithine-keto acid aminotransferase activity in rat liver.

ABSTRACT: 1. During the normal development of the rat, the specific activity of liver ornithine-keto acid aminotransferase exhibits a transient elevation around term, and subsequently increases to adult activity levels during the third postnatal week. 2. The synthetic glucocorticoid triamcinolone, administered as a single injection, produces a marked elevation of the ornithine-keto acid aminotransferase activity within 24hr. if given postnatally before the natural increase in ornithine-keto acid aminotransferase activity has occurred. In foetal and adult animals, triamcinolone does not induce any increase in this enzyme activity. 3. The repeated administration of puromycin completely prevents the rise in ornithine-keto acid aminotransferase activity that follows triamcinolone administration. 4. If adult rats are fed with a protein-free carbohydrate diet, or one free of arginine, the ornithine-keto acid aminotransferase activity diminishes to a fraction of the normal. When such diets are given, a single injection of triamcinolone does not increase the enzyme activity within 24hr. 5. Partial hepatectomy, and repeated injections of growth hormone, depress the ornithine-keto acid aminotransferase activity in adult rats. 6. The findings are discussed in relation to the mechanisms concerned with developmental and adaptive changes in enzyme activities in the liver.

SUBMITTER: Raiha NC

PROVIDER: S-EPMC1198845 | biostudies-other | 1968 Jul

REPOSITORIES: biostudies-other

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Factors influencing the activity of ornithine aminotransferase in isolated rat liver mitochondria.

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Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

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Ornithine aminotransferase versus GABA aminotransferase: implications for the design of new anticancer drugs.

Project description:Ornithine aminotransferase (OAT) and ?-aminobutyric acid aminotransferase (GABA-AT) are classified under the same evolutionary subgroup and share a large portion of structural, functional, and mechanistic features. Therefore, it is not surprising that many molecules that bind to GABA-AT also bind well to OAT. Unlike GABA-AT, OAT had not been viewed as a potential therapeutic target until recently; consequently, the number of therapeutically viable molecules that target OAT is very limited. In this review the two enzymes are compared with respect to their active-site structures, catalytic and inactivation mechanisms, and selective inhibitors. Insight is offered that could aid in the design and development of new selective inhibitors of OAT for the treatment of cancer.

| S-EPMC4415689 | biostudies-literature

Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.

Project description:There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

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Effects of aliphatic diamines on rat liver ornithine decarboxylase activity.

Project description:Rat liver ornithine decarboxylase activity was decreased by administration of putrescine (1,4-diaminobutane) or other diamines, including 1,3-diaminopropane, 1,5-diaminopentane and 1,6-diaminohexane. This effect was seen in control rats and in rats in which hepatic ornithine decarboxylase activity had been increased by administration of growth hormone (somatotropin) or thioacetamide. Loss of activity was not dependent on the conversion of putrescine into polyamines and was short-lived. Within 6h after intraperitoneal administration of 0.8 mmol/kg body wt., ornithine decarboxylase activity had returned to normal values. This return correlated with the rapid loss of the diamines from the liver, and the decrease in activity could be slightly prolonged by treatment with aminoguanidine, a diamine oxidase inhibitor. A decrease in ornithine decarboxylase activity by these diamines was accompanied by the accumulation in the liver of a nondiffusible inhibitor that decreased the activity of a purified ornithine decarboxylase preparation. The possibility that administration of non-physiological diamines that are not converted into polyamines might be useful for the inhibition of polyamine synthesis is discussed.

| S-EPMC1183944 | biostudies-other

Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase.

Project description:Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.

| S-EPMC4538432 | biostudies-literature

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