Inhibition of serine and proline racemases by substrate-product analogues

Harty, Matthew; Nagar, Mitesh; Atkinson, Logan; LeGay, Christina M.; Derksen, Darren J.; Bearne, Stephen L.

doi:10.1016/j.bmcl.2013.10.061

Cited by 17 publications

(13 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, the increased growth rate was observed in the presence of L-arginine in the assay medium, and other amino acids exhibited similar catabolic patterns during incubation. A log-phase culture has released a reasonable quantity of ammonia from L-serine catabolism as compared with other amino acids, suggestive of its growth-associated biofuel production, which may be due to oxidization of L-serine in the Stickland reactions [45][46][47] and the presence of L-serine/ L-threonine symporter and also L-arginine/L-ornithine antiporter [36]. Pyruvate is a metabolic intermediate produced from dehydration of L-serine in A. sticklandii, which can be subsequently transformed into biofuel components.…”

Section: Discussionmentioning

confidence: 99%

Growth‐associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids

Sangavai

Chellapandi

2020

J Basic Microbiol

View full text Add to dashboard Cite

Acetoanaerobium sticklandii DSM 519 is a hyperammonia‐producing anaerobe that catabolizes proteins and amino acids into organic solvents and volatile acids via the Stickland reactions. However, the specific growth rate and metabolic capability of this organism on proteins and amino acids are not yet known. Therefore, the present study was intended to evaluate its specific growth rate and metabolic potential on gelatin and amino acids in the experimental media. We carried out metabolic assay experiments to calculate its ability to utilize pure gelatin, single amino acids, and amino acid pairs at different growth phases. The results of this study show that complete assimilation of gelatin was achieved by its log‐phase culture. The subsequent fermentation of amino acids was much faster than gelatin hydrolysis. The rate of gelatin degradation was associated with the growth and catabolic rates of this organism. Many amino acids were not assimilated completely for its growth and energy conservation. A log‐phase culture of this organism preferably utilized l‐cysteine, l‐arginine, and l‐serine, and released more fraction of ammonia. As shown by our analysis, the catabolic rates of these amino acids were determined by the rates of respective enzymes involved in amino acid catabolic pathways and feedback repression of ammonia. The growth kinetic data indicated that at the initial growth stage, a metabolic shift in its solventogenesis and acidogenesis phases was associated with catabolism of certain amino acids. Thus, the results of this study provide a new insight to exploit its log‐phase culture as a starter for the production of biofuel components from gelatin processing industries.

show abstract

Section: Discussionmentioning

confidence: 99%

Growth‐associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids

Sangavai

Chellapandi

2020

J Basic Microbiol

View full text Add to dashboard Cite

show abstract

“…This organism has a typical operon that performs the reductive ring cleavage of d -proline into 5-aminovalerate, which is subsequently excreted [54] , [56] . Proline reductase, proline racemase and proline racemase are key enzymes involved in proline catabolism [57] , [58] , [59] , [60] .…”

Section: General Metabolismmentioning

confidence: 99%

“…Threonine dehydratase catalyzes threonine to ammonia and 2-ketobutyrate, which are oxidized to propionate and CO 2 or reductively aminated to 2-aminobutyrate [64] . l -Serine catabolism is rapidly mediated in the exponential growth phase by the presence of iron-dependent serine dehydratase and serine racemase [60] , [67] . This organism is able to catabolize both d -serine and l -serine due to its genome contains d -serine ammonia-lyase and d -serine ammonia-lyase.…”

Section: General Metabolismmentioning

confidence: 99%

Amino acid catabolism-directed biofuel production in Clostridium sticklandii: An insight into model-driven systems engineering

Sangavai

Chellapandi

2017

Biotechnology Reports

View full text Add to dashboard Cite

show abstract

“…While this work was in preparation, three papers aiming at the identification of novel SR inhibitors were published. Harty et al 26 . designed substrate analogues as potential inhibitors, Vorlova et al 25 synthesized a series of malonate analogues, and Mori et al 24 identified novel potential inhibitors of SR by in silico ligand-based screening.…”

Section: Introductionmentioning

confidence: 99%

“…Crystal structures of eukaryotic SR were solved from different sources, human, rat 20 and Schizosaccharomyces Pombe 21,22 , in holo form or in complex with the inhibitor malonate ( Figure 1). Despite the availability of structural data and the identification of a few inhibitors [23][24][25][26] , the development of specific and more potent SR inhibitors remains very challenging 13 . While this work was in preparation, three papers aiming at the identification of novel SR inhibitors were published.…”

Section: Introductionmentioning

confidence: 99%

Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target

Beato

Pecchini

Cocconcelli

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

D-Serine is the co-agonist of NMDA receptors and binds to the so-called glycine site. D-Serine is synthesized by human serine racemase (SR). Over activation of NMDA receptors is involved in many neurodegenerative diseases and, therefore, the inhibition of SR might represent a novel strategy for the treatment of these pathologies. SR is a very difficult target, with only few compounds so far identified exhibiting weak inhibitory activity. This study was aimed at the identification of novel SR inhibitor by mimicking malonic acid, the best-known SR inhibitor, with a cyclopropane scaffold. We developed, synthesized, and tested a series of cyclopropane dicarboxylic acid derivatives, complementing the synthetic effort with molecular docking. We identified few compounds that bind SR in high micromolar range with a lack of significant correlation between experimental and predicted binding affinities. The thorough analysis of the results can be exploited for the development of more potent SR inhibitors.

show abstract

Inhibition of serine and proline racemases by substrate-product analogues

Cited by 17 publications

References 38 publications

Growth‐associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids

Growth‐associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids

Amino acid catabolism-directed biofuel production in Clostridium sticklandii: An insight into model-driven systems engineering

Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target

Contact Info

Product

Resources

About