PubMed · 4262852
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J T Dickinson, G W Jaquiss. 1972. Alloplastic implants 1972.. https://pubmed.ncbi.nlm.nih.gov/4262852/
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A series of experiments has been conducted to investigate the possibility that substrate channelling might occur in the bifunctional forms of enzymes carrying out C-terminal amidation, a post-translational modification essential to the biological activity of many neuropeptides. C-terminal amidation entails sequential action by peptidylglycine mono-oxygenase (PAM, EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5), with the mono-oxygenase catalysing conversion of a glycine-extended pro-peptide into the corresponding alpha-hydroxyglycine derivative, which is then converted by the lyase into amidated peptide plus glyoxylate. Since the mono-oxygenase and lyase reactions exhibit tandem reaction stereospecificities, channelling of the alpha-hydroxy intermediate might occur, as is the case for some other multifunctional enzymes. Selective inhibition of the mono-oxygenase domain by competitive ester inhibitors, as well as mechanism-based mono-oxygenase inactivation by the novel olefinic inhibitor 5-acetamido-4-oxo-6-phenylhex-2-enoate (N-acetylphenylalanyl acrylate), has little to no effect on the kinetic parameters of the lyase domain of the AE from Xenopus laevis. Similarly, inhibition of the lyase domain by the potent dioxo inhibitor 2,4-dioxo-5-acetamido-6-phenylhexanoate has little effect on the activity of the monooxygenase domain in the bifunctional enzyme. A series of experiments on intermediate accumulation and conversion were also carried out, along with kinetic investigations of the reactivities of the monofunctional and bifunctional forms of PAM and PGL towards substrates and inhibitors. Taken together, the results demonstrate the kinetic independence of the mono-oxygenase and lyase domains, and provide no evidence for substrate channelling between these domains in the bifunctional amidating enzyme.
Copolymers of N-(2-hydroxypropyl)methacrylamide with p-nitrophenyl esters of unsaturated phenoxyacetic acids and N-methacryloylglycylleucine and with acrylic acid were synthesized as polymer carriers for obtaining water-soluble polymer forms of an antibiotic gramicidin-S. The kinetics of the aminolysis of copolymers of N-(2-hydroxypropyl) methacrylamide (HPMA) which contain reactive p-nitrophenoxycarbonyl groups by gramicidin-S were investigated. It was established that aminolysis rate depends on the structure of the bridge group which binds p-nitrophenoxycarbonyl group to the main chain of the copolymer. On the basis of these copolymers of HPMA polymer amide and salt derivatives of gramicidin-S were obtained and their composition was determined. It was shown, that the antibacterial activity of these polymer derivatives of gramicidin-S depends on the bond type of the antibiotic with the polymer and attains a relatively high level for polymer salts of gramicidin-S.
A novel approach to immobilize nonuniform initial drug concentration profiles in multilaminated matrix devices utilizing photopolymerization techniques is presented. Solution polymerization of 2-hydroxyethyl methacrylate (HEMA) and diethylene glycol dimethacrylate (DEGDMA) in the presence of a model compound, acid orange 8 (AO8), was conducted using UV light and photoinitiators to construct a laminated matrix device. In this process, each layer was polymerized with a different AO8 concentration to form a nonuniform initial concentration profile in the matrix devices. The AO8 diffusion coefficients measured in this work were used in a concurrently developed model to predict the effects of nonuniform AO8 concentration profiles on AO8 release patterns. The release data predicted by the model agreed well with the experimentally determined data. The results indicate that a zero-order release pattern can be approximated by employing a suitable nonuniform initial drug concentration profile.