Document Detail


Enzymatic synthesis of chiral intermediates for Omapatrilat, an antihypertensive drug.
MedLine Citation:
PMID:  11337276     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Biocatalytic processes were used to prepare chiral intermediates required for the synthesis of Omapatrilat 1 by three different routes. The synthesis and enzymatic conversion of 2-keto-6-hydroxyhexanoic acid 3 to L-6-hydroxynorleucine 2 was demonstrated by reductive amination using beef liver glutamate dehydrogenase. To avoid the lengthy chemical synthesis of the ketoacid 3, a second route was developed to prepare the ketoacid by treatment of racemic 6-hydroxy norleucine [readily available from hydrolysis of 5-(4-hydroxybutyl) hydantoin 4] with D-amino acid oxidase from porcine kidney or Trigonopsis variabilis followed by reductive amination to convert the mixture completely to L-6-hydroxynorleucine in 98% yield and 99% enantiomeric excess (e.e.). The enzymatic synthesis of (S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (allysine ethylene acetal, 5) was demonstrated using phenylalanine dehydrogenase (PDH) from T. intermedius. Phenylalanine dehydrogenase was cloned and overexpressed in Escherichia coli and Pichia pastoris. Using PDH from E. coli or P. pastoris, the enzymatic process was scale-up to prepare kg quantity of allysine ethylene acetal 5. The reaction yields of >94% and e.e. of >98% were obtained for allysine ethylene acetal 5. An enzymatic process was developed for the synthesis of [4S-(4a,7a,10ab)]1-octahydro-5-oxo-4 [[(phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,1-b] [1,3]thiazepine-7-carboxylic acid [BMS-199541-01]. The enzymatic oxidation of the epsilon-amino group of lysine in the dipeptide dimer N(2)-[N[[(phenyl-methoxy)carbonyl] L-homocysteinyl] L-lysine)-1,1-disulphide [BMS-201391-01] to produce BMS-199541-01 using a novel L-lysine epsilon-aminotransferase (LAT) from Sphingomonas paucimobilis SC 16113 was demonstrated. This enzyme was overexpressed in E. coli and a process was developed using the recombinant enzyme.
Authors:
R N Patel
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Biomolecular engineering     Volume:  17     ISSN:  1389-0344     ISO Abbreviation:  Biomol. Eng.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-05-04     Completed Date:  2001-07-12     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  100928062     Medline TA:  Biomol Eng     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  167-82     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Oxidoreductases / chemistry,  metabolism
Antihypertensive Agents / chemical synthesis*,  chemistry,  metabolism
Bioreactors
D-Amino-Acid Oxidase / chemistry,  metabolism
Enzymes / chemistry,  pharmacology
Escherichia coli / genetics,  metabolism
Fermentation
Glutamate Dehydrogenase / chemistry,  metabolism
L-Lysine 6-Transaminase
Pichia / genetics,  metabolism
Pyridines / chemical synthesis*,  chemistry,  metabolism
Recombinant Proteins / chemistry,  metabolism
Stereoisomerism
Thiazepines / chemical synthesis*,  chemistry,  metabolism
Transaminases / chemistry,  metabolism
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Enzymes; 0/Pyridines; 0/Recombinant Proteins; 0/Thiazepines; 36NLI90E7T/omapatrilat; EC 1.4.-/Amino Acid Oxidoreductases; EC 1.4.1.2/Glutamate Dehydrogenase; EC 1.4.3.-/phenylalanine oxidase; EC 1.4.3.3/D-Amino-Acid Oxidase; EC 2.6.1.-/Transaminases; EC 2.6.1.36/L-Lysine 6-Transaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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