PubMed · 2564063
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1989-03-11. Vigabatrin.. https://pubmed.ncbi.nlm.nih.gov/2564063/
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Although standard anticonvulsants are effective in achieving complete seizure control in the majority of patients, an appreciable proportion (about 20 to 25%) is at least in part resistant to conventional pharmacotherapy. Efficacy of carbamazepine, phenytoin, phenobarbital and valproate is very similar. Should one drug fail because of inadequate efficacy and unacceptable adverse effects, an alternative monotherapy should be used. Surgical treatment is a possible therapeutic option for only some of these patients. The development of newer, more effective drugs, such as vigabatrin, lamotrigine, gabapentin and oxcarbazepine, for monotherapy is desirable. The search for new antiepileptic agents is reasonable in order to reduce the proportion of drug-resistant patients. The choice of conventional or new drugs should include not only expected efficacy and risk of adverse effects, but also pharmacokinetic properties and expense. Consequently, no general rule is appropriate, and each decision and recommendation for treatment should be individualized.
A human brain cDNA library constructed in the lambda ZAP II vector was screened using a fragment of pig brain cDNA encoding 4-aminobutyrate aminotransferase (pGaba-t). A cDNA that encodes the human brain Gaba-t (hGaba-t) has been isolated from the library and sequenced. Using the GenBank and EMBL databases, comparison of the predicted amino-acid sequence of hGaba-t with the pig enzyme revealed 95.4% homology.
4-Aminobutyrate aminotransferase undergoes a reversible process of association/dissociation at low pH. At pH 5.0, monomeric species exist predominantly in solution as revealed by FPLC and time-dependent emission anisotropy measurements. The observed rotational correlation time at pH 5.0, phi obs = 25 ns, corresponds to a compact spherical unit of 52 kDa. An increase in the net charge of the macromolecule at pH 5.0 is responsible for destabilization of the dimeric structure, (WEL approximately 41.84 kJ/mol), but the dissociation of the protein does not perturb the secondary structure as revealed by CD measurements. The fluorescent probe 1-anilinonaphthalene-8-sulfonate (ANS), bound to hydrophobic sites of the enzyme, was used to monitor the kinetics of protein dissociation by stopped-flow spectroscopy. The dissociation of the dimeric structure at pH 5.0 was characterized by a relaxation time of 18 ms. The rate of association of monomeric subunits at pH 7.0 was too fast to be detected in the stopped-flow instrument. These observations have some bearing on the mechanism of reconstitution of dimeric structures of 4-aminobutyrate aminotransferase in the cell.