Disease relevance of DL-Gabaculine

• A gabaculine-tolerant Synechococcus strain, GR6, was found to produce a GSA-AT less sensitive to the inhibitor [1].
• Studies on the kinetics and stoichiometry of inactivation of Pseudomonas omega-amino acid:pyruvate transaminase by gabaculine [2].
• Inhibition of haem synthesis in the transformed E. coli cells expressing cytochrome b5, by the use of gabaculin or succinylacetone, prevented the assembly of the cytochrome b5 holoprotein but had little effect on the accumulation of cytochrome apoprotein [3].
• Gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid, 1), a naturally occurring neurotoxin isolated from Streptomyces toyocaenis, has been shown to be a mechanism-based inactivator of gamma-aminobutyric acid aminotransferase (GABA-AT) (Rando, R. R. Biochemistry 1977, 16, 4604) [4].
• The effect of the tetrapyrrole biosynthesis inhibitor gabaculine on the expression of specific genes involved in phycocyanin biosynthesis was investigated in cultures of Synechococcus PCC6301 in nitrogen chlorosis, and during recovery to nitrogen sufficiency [5].

High impact information on DL-Gabaculine

• The structure of the complex with gabaculine, a substrate analogue, shows unexpectedly that the substrate binding site involves residues from the N-terminal domain of the molecule, notably Arg-32 [6].
• A similar conclusion is reached from examination of cytochrome c6 synthesis in gabaculine-treated cells where inhibition of heme attachment did not prevent either of the two processing steps [7].
• The in vitro findings are entirely transferable to the in vivo situation: 4-aminohex-5-ynoic acid and gabaculine cause a long-lasting inhibition of ornithine aminotransferase in brain and liver, and reduce significantly in vivo ornithine degradation, whereas 4-aminohex-5-enoic acid is inactive both in vivo and in vitro toward this enzyme [8].
• The structure of AHBA synthase from Amycolatopsis mediterranei has been determined to 2.0 A resolution, with bound cofactor, PLP, and in a complex with PLP and an inhibitor (gabaculine) [9].
• 3-Amino-2,3-dihydrobenzoic acid is an inhibitor of the aminotransferase activity [10].

Chemical compound and disease context of DL-Gabaculine

• However, in Synechococcus 6301 strain GR6, a cyanobacterium that is resistant to 100 microM gabaculine, this enzyme has undergone two changes in structure: a deletion of three amino acids from positions 5 to 7 and the substitution of isoleucine for methionine at position 248 [11].

Biological context of DL-Gabaculine

• However, inhibition was overcome after an extended lag period, following which cell growth proceeded at a similar rate to that of control cells not exposed to gabaculine [12].
• We also observed a decrease in the global energetic creatine-phosphocreatine pool, which also could be related to the sedative properties of gabaculine, measurable by the diminution of cortical electrical activity and mean arterial blood pressure [13].
• The results suggest that gabaculine-induced sniffing and head movement were mediated by nigral GABAergic synapses and were independent of any dopaminergic system, and that the high ambulation at 24 h after operation may have been due to a non-specific effect of abnormal GABA elevation in thalamus and/or nigra [14].
• Gabaculine (250 muM), a GABA transaminase inhibitor, suppressed OMP-induced oxygen consumption but not L-leucine- or glucose-stimulated respiration [15].

Anatomical context of DL-Gabaculine

• Inhibitors or ornithine--2-oxo acid transaminase (L-canaline or gabaculine) decreased the uptake of ornithine by hepatocytes and inhibited the alpha-methylisocitrate insensitive urea synthesis from ornithine and NH4Cl [16].
• Rather, it appeared that ketamine might be interfering with the transport of gabaculine into the cellular structures [17].
• Comparison of the amino acid levels in the two types of organelles and of the effects of gabaculine thereon indicated that the neurosome portion of synaptoneurosomes constituted the major influencing component of the organelles [18].
• Amino acid content of nerve endings (synaptosomes) in different regions of brain: effects of gabaculine and isonicotinic acid hydrazide [19].
• The other analogues investigated in this study exhibited different patterns of transport; gabaculine was taken up into glial cells, whilst diaminobutyric acid was taken up into neurons, glial cells and retinal pigment epithelia [20].

Associations of DL-Gabaculine with other chemical compounds

• The effects of light, 2-amino-4-phosphonobutyric acid (APB), and kainic acid on rat retinal gamma-aminobutyric acid (GABA)-ergic transmission were studied by measuring levels of retinal GABA following subcutaneous injection of gabaculine, an irreversible inhibitor of GABA-transaminase [21].
• Di-n-propylacetate (DPA), aminooxyacetic acid (AOAA), and gabaculine were administered alone or in combination to Swiss mice [22].
• In dark-aged artichoke tissues, gabaculine also effectively blocked cytochrome P-450 induction, peroxidase activity and 5-aminolaevulinic acid synthesis, thus suggesting the involvement of a C5 pathway in cytoplasmic and microsomal haemoprotein synthesis in this higher plant [23].
• Five inhibitors of the GABA degrading enzyme GABA-aminotransferase (GABA-T), viz., gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA, ethanolamine O-sulphate, and aminooxyacetic acid, as well as GABA itself and the antiepileptic sodium valproate were administered to mice in doses equieffective to raise the electroconvulsive threshold by 30 V [24].
• Correlated with the rise in endogenous GABA level after vigabatrin or gabaculine treatment, the intensity of BOLD-weighted fMRI signals in rat somatosensory cortex during forepaw stimulation was found to be reduced significantly [25].

Gene context of DL-Gabaculine

• However, when the GTR was expressed in the presence of 3-amino-2,3- dihydrobenzoic acid (gabaculine), an inhibitor of heme synthesis, the purified GTR had 60 to 70% less bound heme than control GTR, and it was inhibited by hemin in vitro [26].
• Growth and chlorophyll accumulation in equivalent strains with the hemL gene containing either the deletion or the transition characteristic of Synechococcus 6301 GR6 were inhibited by 10 microM gabaculine [11].
• Intrastriatal injections of 100 micrograms gabaculine induced a rapid and complete inhibition of GABA-T [27].
• A glutamate-1-semialdehyde aminotransferase, the terminal enzyme in the conversion of glutamate to ALA in chloroplasts, was detected in 6803 cell extracts by the conversion of glutamate-1-semialdehyde to ALA and by the inhibition of this reaction by gabaculin [28].
• In cells depleted of tetrapyrrole pathway intermediates by gabaculine treatment, cytochrome f synthesis was significantly reduced [29].

Analytical, diagnostic and therapeutic context of DL-Gabaculine

• We then investigated whether GABA is involved by measuring the rate of its accumulation following intraventricular injection of gabaculine [30].
• Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less [31].
• The gabaculine inhibition was reversible for up to 1 h after its addition, if the gabaculine was removed by gel filtration before the enzyme was incubated with substrate [32].
• Four-day-old suckling pigs received oral administration of 0.0 or 0.83 mg gabaculine/kg body wt every 4 h during a 12-h period from 6 A.M. to 6 P.M. Blood was collected from piglet's jugular vein at 6 A.M. and 6 P.M. after a 2-h isolation from sows [33].

References