China
Africa
Explore chapters and articles related to this topic
D-2-hydroxyglutaric (DL-2-hydroxyglutaric) aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The reaction is also catalyzed by a transhydrogenase and in the exchange 4-hydroxybutyric acid is converted to succinic semialdehyde [36]. Succinic semialdehyde is the immediate catabolic product of 4-aminobutyric (GABA), and thus, interference with this pathway and accumulation of GABA would be expected to have neurologic consequences, as in the case of GABA transaminase deficiency [37].
Mechanisms of action
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
GABA, which is the main inhibitory NT in the brain, is synthesised from glutamic acid (glutamate) in GABA-ergic neurons by an enzyme called glutamic acid decarboxylase. GABA is metabolised sequentially by GABA transaminase into succinic-semialdehyde, then into succinic acid by the enzyme succinic-semialdehyde dehydrogenase.
Glutamine, Glutamate, and GABA in Human Diseases
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
Table 4 also lists the circumstances in which brain GABA contents may be elevated in humans. In patients dying with idiopathic Parkinson’s disease, GABA content is significnatly increased in the putamen,56,57 presumably as a secondary effect of nigrostriatal neuronal death and decreased release of dopamine in the striatum. Patients with the rare autosomal recessive disorder succinic semialdehyde dehydrogenase deficiency show marked reduction in the activity of this enzyme in lymphocytes isolated from blood, and they accumulate 7- hydroxybutyric acid in blood, urine, and CSF.58 Although amounts of GABA, the immediate precursor of succinic semialdehyde, have not yet been reported for the CSF and brain of such patients, it would not be surprising if they eventually prove to be elevated.
High-yield synthesis and purification of recombinant human GABA transaminase for high-throughput screening assays
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Mingu Gordon Park, Ah-reum Han, Su Yeon Kim, Tai Young Kim, Ho Min Kim, C. Justin Lee
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter synthesised and released from GABAergic neurons and astrocytes in the mammalian central nervous system (CNS)1–4. GABA is synthesised by glutamate decarboxylase (GAD; EC 4.1.1.15) in GABAergic neurons and by monoamine oxidase (MAO-B; EC 1.4.3.4) or diamine oxidase (DAO; EC 1.4.3.22) in astrocytes4–6. However, the only GABA-catabolizing enzyme in the mammalian CNS is GABA transaminase (GABA-T; EC 2.6.1.19) encoded by the ABAT gene7. GABA-T catalyses the conversion of GABA to succinic semialdehyde (SSA) concomitantly with the conversion of α-ketoglutarate (α-KG) to glutamate. Subsequently, SSA is oxidised to succinic acid (SA) by the enzyme SSA dehydrogenase (SSADH; EC 1.2.1.24). GABA-T and SSADH are mitochondrial enzymes and exist both in GABAergic neurons and astrocytes8–10. Because the transaminase reaction cannot be directly monitored, we can utilise dehydrogenation of SSA from GABA-T reaction to indirectly monitor GABA-T activity by detecting a conversion of NADP+ to NADPH11.
Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs
Published in Expert Review of Anti-infective Therapy, 2020
Liliana Rodrigues, Pedro Cravo, Miguel Viveiros
Valproic acid, or valproate, is a fatty acid derivative and anticonvulsant used in the treatment of epilepsy and bipolar disorders [132]. This drug has been also investigated for neuroprotective, anti-manic, and anti-migraine effects. Currently, it is a compound of interest in oncology drug research for its anti-proliferative effects and is the subject of many clinical trials. The mechanism of action of valproate is relatively unknown, but it is suggested that the drug’s action is a result of several pathways: i) inhibition of succinic semialdehyde dehydrogenase and increasing GABAergic neurotransmission; impact on fatty acid metabolism, which alters membrane fluidity; and noncompetitive inhibition of brain microsomal long-chain fatty acyl-CoA synthetase, which decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins [133–135]. Valproate has been previously tested in M. tuberculosis. In 2015, Schieber et al. demonstrated that this drug stimulates the autophagosome formation in vitro and, in 2018, Rao and collaborators showed that it improves the action of isoniazid and rifampicin in the macrophage [136,137]. However, the specific target in M. tuberculosis has not been identified to date. Our study predicted a possible acyl-CoA dehydrogenase FadE19 (Rv2500c) as a potential M. tuberculosis target.
Stargardt macular dystrophy and evolving therapies
Published in Expert Opinion on Biological Therapy, 2018
Rehan M. Hussain, Thomas A. Ciulla, Audina M. Berrocal, Ninel Z. Gregori, Harry W. Flynn, Byron L. Lam
Vision Medicine’s VM200 molecule for STGD1 is currently in preclinical trials. This oral aldehyde trap sequesters the toxic compound, all-trans retinal, to potentially prevent retinal cell death [39]. Specifically, VM200 is a primary amine that reacts with the aldehyde group of all-trans retinal to form an inactive Schiff base, thus making it unable to form A2E. VM200 was shown to preserve retinal structure in ABCA4−/− Rdh8−/− mice, as measured by SD-OCT. According to unpublished data from Case Western Reserve University, VM200 has also demonstrated ability to preserve retinal function, as mice treated with it were noted to have increased concentration of 11-cis-retinal (a biomarker of intact photoreceptors) compared to controls [40]. No significant toxicities were noted in 2-week and 13-week long studies. The molecule of VM200 is an enantiomer of pregabalin, which is used to treat neuropathic pain, though its affinity for the pregabalin target is 10-fold less than that of pregabalin. VM200 could also have therapeutic potential in other inborn errors of aldehyde metabolism including Sjogren-Larsson Syndrome, Best Disease, and Succinic semialdehyde-dehydrogenase deficiency. Preclinical studies are continuing [40].