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Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
D-cycloserine (DCS) is an analog of D-Alanine, which targets the biosynthesis of the peptidoglycan layer of cell wall by inhibiting d-Alanine: d-alanine ligase. Furthermore, DCS prevents D-Alanine racemase, which is an enzyme essential for the interconversion of L-Alanine and D-Alanine.20
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
d-Cycloserine (CS) is a water-soluble weak acid (log P −2.4, pKa 4.21–8.36, MW 102.09). Terizidone (TZ) is a condensation product of two CS molecules with terephthalaldehyde, which acts as a pro-drug. CS is a natural product analog of d-alanine originating from Streptomyces garyphalus. It is a competitive inhibitor of the enzymes alanine racemase and d-alanine:d-alanine ligase, disrupting peptidoglycan synthesis.191 Wild-type MIC99s range from 8 to 32 μg/mL.85 Resistance to CS is uncommon and usually associated with mutations in the alr (alanine racemase) locus.192
The Effects of Synthetic Phosphonates on Living Systems
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
The phosphonate antibiotics are primarily of natural occurrence. These antibiotics are produced by various strains of the Streptomycetes and are discussed in Chapter 2, Section II. A. However, there are several compounds of synthetic origin with potential use as antibiotics. L-alanyl-L-l-aminoethylphosphonic acid (alafosfalin) interferes with cell wall synthesis.113,114 This effect apparently occurs following transport of the peptide and intracellular cleavage by peptidase and is the result of the inhibition of alanine racemase in susceptible organisms.115
D-Alanine Is Reduced by Ocular Hypertension in the Rat Retina
Published in Current Eye Research, 2020
Takashi Kanamoto, Hiroaki Sakaue, Yasushi Kitaoka, Ryo Asaoka, Kei Tobiume, Yoshiaki Kiuchi
The decrease in the D/L-ratio of retinal alanine following ocular hypertension may be mediated by changes in the activity of the D/L-alanine–regulating enzymes, D-amino acid oxidase (DAO)32 and alanine racemase.33 It is possibly speculated that ocular hypertension increase the enzymatic activity of DAO or decrease alanine racemase, leading to changes in D/L alanine. There has been no evidence to show the role of alanine in neurodegeneration, but it was reported that alanine, a marker of synaptic and metabolic pathways, was significantly changed in Alzheimer disease.34 Furthermore, it was also reported that D-alanine levels was elevated in the gray matter of Alzheimer brains.35 It is suspected that changes in D/L alanine may be associated with neuronal degeneration.
The problem of racemization in drug discovery and tools to predict it
Published in Expert Opinion on Drug Discovery, 2019
Andrew Ballard, Stefania Narduolo, Hiwa O. Ahmad, David A. Cosgrove, Andrew G. Leach, Niklaas J. Buurma
The remaining five compounds are surveyed in more detail. Compound 26 is an inhibitor of alanine racemase, an enzyme that provides the D-Alanine required for cell wall biosynthesis [51]. It is likely that its ability to racemize is not a problem in this context. Compound 29 is a local anesthetic that can be administered intravenously and the single isomer version was promoted as providing reduced toxicity and improved efficacy [52]. In this case, studies of 29 in a range of species suggest that there is no racemization in vivo [53]. Compound 30 inhibits carbonic anhydrase and is used intraocularly via topical application and hence is likely to be protected from the racemizing medium of the plasma [54]. Antihistamine 9 had its in vivo racemization studied as described above. It is likely that the steric bulk of the three rings (two phenyl and one piperazine) that must become co-planar inhibits racemization in this case. Whereas such effects can be reproduced reasonably well by quantum mechanical calculations, the group-contribution approach that we have used here does not account for the effects of steric hindrance. Finally, 31 is a relatively recently approved treatment for Parkinson’s disease that is used in tablet form for oral administration and for which the two stereoisomers show different profiles but rates of racemization have not been reported [55].
Bioactive cyclic molecules and drug design
Published in Expert Opinion on Drug Discovery, 2018
Research in the latter part of the 20th century identified many classes of natural products with a majority being classified into one of four major groups from their structures and biosynthetic mechanisms. These were the terpenoids, alkaloids, polyketides, and non-ribosomal peptides (the NRPs). Although there is not enough space to show many clinically important cyclic peptides, one immunosuppressive agent should be commented on, cyclosporin (aka ciclosporin) shown in Figure 56. The structure of the compound was first reported as an iodo derivative (X-ray) in 1976 [15] and more than 30 variations have been isolated from submerged cultures of T. inflatum all synthesized by the same three enzymes with their genes being organized in a large secondary metabolite cluster. Cyclosporins have been isolated from at least 17 different fungal taxa[16], and all have the necessary ‘flexability’ to cross cell membranes and to interact with peptidyl prolyl cis/trans isomerase. Since the molecule contains D-alanine as well as two other non-proteinogenic amino acids, a D-alanine racemase is part of the genetic cluster, but will also racemize serine, Abu and leucine. The final assembly utilizes a large (15K aminoacid) NRPS complex known as CySyn, which starts with the D-Ala precursor and then follows along with the other 10 aminoacids, followed by cyclization. D-Ala in the cyclic compound is probably a method of stopping proteolytic cleavage of the active molecule.