The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences

Caldwell, John; Hutt, Andrew J.; Fournel‐Gigleux, Sylvie

doi:10.1016/0006-2952(88)90762-9

Cited by 365 publications

(178 citation statements)

References 30 publications

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“…interessante de medicamento que ainda é vendido como mistura racêmica. Relatos tem comprovado que a forma S do ibuprofeno é 160 vezes mais ativa que a forma R na síntese de prostaglandina in vitro 11,12 . Um grande investimento em pesquisas tem sido feito para desenvolver diferentes processos para obtenção da forma enantiomérica ativa deste fármaco.…”

Section: Introductionunclassified

Potencial de biocatálise enantiosseletiva de lipases microbianas

Carvalho¹,

Calafatti²,

Marassi³

et al. 2005

Quím. Nova

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Recebido em 18/5/04; aceito em 12/11/04; publicado na web em 13/4/05 POTENTIAL OF ENANTIOSELECTIVE BIOCATALYSIS BY MICROBIAL LIPASES. Microbial lipases have a great potential for commercial applications due to their stability, selectivity and broad substrate specificity because many non-natural acids, alcohols or amines can be used as the substrate. Three microbial lipases isolated from Brazilian soil samples (Aspergillus niger; Geotrichum candidum; Penicillium solitum) were compared in terms of their stability and as biocatalysts in the enantioselective esterification using racemic substrates in organic medium. The lipase from Aspergillus niger showed the highest activity (18.2 U/mL) and was highly thermostable, retaining 90% and 60% activity at 50 o C and 60 o C after 1 hour, respectively. In organic medium, this lipase provided the best results in terms of enantiomeric excess of the (S)-active acid (ee = 6.1%) and conversion value (c = 20%) in the esterification of (R,S)-ibuprofen with 1-propanol in isooctane. The esterification reaction of the racemic mixture of (R,S)-2-octanol with decanoic acid proceeded with high enantioselectivity when lipase from Aspergillus niger (E = 13.2) and commercial lipase from Candida antarctica (E = 20) were employed.Keywords: lipases; enantioselectivity; (R,S)-ibuprofen. INTRODUÇÃOA biocatálise é hoje um dos campos mais promissores dentro das novas tecnologias para síntese de compostos de alto valor agregado. A exploração da biodiversidade na busca de novos catalisadores por técnicas de seleção de microrganismos, de plantas ou células animais representam os métodos tradicionais de descoberta de novas enzimas para o desenvolvimento da biocatálise em escala industrial 1 . Os microrganismos neste caso são de particular interesse devido ao curto período de geração, à grande diversidade de processos metabólicos e enzimas envolvidas e, não há um número limitado de microrganismos na natureza que possam ser testados, os quais são bastante diferentes entre si. Microrganismos isolados em território brasileiro têm demonstrado excelente potencial biocatalisador frente a diferentes substratos orgânicos de interesse, como por ex. na hidrólise de óleos marinhos 2,3 , na síntese de ésteres de ácidos graxos poliinsaturados 4 e de ésteres de aroma 5 .Dentre as enzimas hidrolíticas de maior interesse estão as lipases (glicerol ester hidrolase E C. 3.1.1.3), que são biocatalisadores versáteis capazes de catalisar diferentes reações, tanto em meio aquoso como em meio orgânico, com teor de água restrito. Entre as lipases de vegetais, animais e microbianas, estas últimas são as mais utilizadas e, na sua grande maioria, não são nocivas a saúde humana, sendo reconhecidas como "Generally Regarded as Save -GRAS" 6 . Do ponto de vista industrial, os fungos são especialmente valorizados porque as enzimas por eles produzidas normalmente são extracelulares, o que facilita sua recuperação do meio de fermentação 7 . Os trabalhos replatados em literatura sobre lipases fúngicas são numerosos, sendo que os mais ...

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Section: Introductionunclassified

Potencial de biocatálise enantiosseletiva de lipases microbianas

Carvalho¹,

Calafatti²,

Marassi³

et al. 2005

Quím. Nova

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“…Such bi-directional chiral inversion has previously been reported for the model substrate 2-PPA but in that case, the rate was faster in the (R) to (S) direction, resulting in an overall increase of the (S)-enantiomer with time (Hutt et al 1993 ;Hanlon et al 1994). The chiral inversion of the (S) to the (R) enantiomer of ketoprofen has only recently been reported in mammalian systems (Jamali et al 1997), although there was precedent for the inversion of ibuprofen in man in this direction (Lee et al 1985 ;Caldwell et al 1988).…”

Section: Discussionmentioning

confidence: 91%

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Thomason

Rhys‐Williams

Lloyd

et al. 1998

Journal of Applied Microbiology

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The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids : ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and amethoxyphenylpropionic acid. The results demonstrated that V. lecanii is capable of inverting the chirality of all the 2-arylpropionic acids investigated. All were inverted in the (R) to (S) direction with the exception of ketoprofen, where inversion was observed in the reverse direction. Using the structurally related compounds as substrates, the size of the alkyl substituent at the a-carbon at the methyl group, and the presence of the methyl group at the chiral centre, were found to be critical. These results suggest that V. lecanii could be used as a basis for the production of pure enantiomers of the 2-arylpropionic acids in commercial biotransformations.

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“…In this context, it may b e interesting to note that a similar preference for the (2R)-enantiomer was observed for the activation of 2-phenylpropionic acids such as 2-(4-isobutylphenyl)-propionic acid (Ibuprofen) (Knights et al, 1988;Knihinicki et al, 1989). Together with a racemase acting on the CoA thioester (Shieh and Chen, 1993) [possibly the amethylacyl-CoA racemase (Schmitz e t al., 1994)] and acyl-CoA hydrolases, this results in an ATP-driven inversion of the (2R)-enantiomer in vivo (Lee e t al., 1984;Caldwell et al, 1988;Chen et al, 1991). A detailed kinetic analysis of the activation of branched-chain fatty acids is under way in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Stereochemistry of Peroxisomal and Mitochondrial β‐oxidation of α‐methylacyl‐CoAs

Schmitz

Conzelmann

1997

European Journal of Biochemistry

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The stereochemistry of Poxidation of a-methyl-branched fatty acids was analyzed, in rat liver and in human cells, with (2R)-and (2S)-2-methyltetradecanoic acid as model substrates. In rat liver, formation of the a$-unsaturated compound was found to be concentrated in mitochondria while in human cells, this activity co-distributed mainly with peroxisomal marker enzymes. In both cases, the dehydrogenating enzymes were absolutely specific for the (2s)-enantiomer. In human liver, activation was some three times faster with the (2R)-than with the (2s)-isomer while in rat liver both were activated at about the Same rate.Keywords : branched-chain fatty acid ; p-oxidation ; acyl-CoA oxidase ; peroxisome ; racemase.Various branched-chain fatty acids arise in the catabolism of isoprenoids. A prominent and quantitatively important example is phytanic acid (3,7,11,15-tetramethylhexadecarioic acid), which is derived from the chlorophyll component phytol. For degradation, it must, as a P-methyl fatty acid, first be shortened by one methylene unit, in a process called a-oxidation (for review, see Steinberg, 1995), then the resulting pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) can be further degraded by @-oxidation, yielding alternatingly propionyl CoA and acetyl CoA. Some pristanic acid is also derived directly from dietary sources (Hansen and Morrison, 1964). Interest in the catabolism of branched-chain fatty acids has been revived by the observation that phytanic acid (Poulos et al., 1984) as well as pristanic acid (Poulos et al., 1988) may accumulate in the sera of patients with deficient peroxisome assembly.Phytanic acid occurs naturally as a mixture of the (3R)-and (3s)-diastereomers (Ackman and Hansen, 1967). Since a-oxidation does not affect the hydrogen atom in P-position (Avigan et al., 1966;Fingerhut et al., 1993), the resulting product, pristanic acid, is likewise a mixture of diastereomers (Ackman and Hansen, 1967). We have previously shown that, in both rat liver (Schmitz et al., 1994) and human tissues (Schmitz et al., 1995), a-methyl-branched fatty acids are racemized as coenzyme A thioesters by a specific a-methylacyl-CoA racemase. It was not known, however, whether this racemase is indeed required for catabolism of branched-chain fatty acids or whether both enantiomers can be degraded directly. We have therefore analyzed the stereochemistry of p-oxidation of a-methyl-branched fatty acids. MATERIALS AND METHODSMaterials. The chemicals used were purchased from the following companies: farnesol, (I-ethoxycarbonylethy1iden)-tri- phenylphosphoran, ferrocene, NaPF,, trifluoroacetic acid anhydride, diisobutylaluminium hydride, Pd on charcoal, H,O, (30 % solution), sucrose, Tris, heptadecanoic acid, pentadecanoic acid and (R)-1 -phenylethylamine from Aldrich; dichloromethane, diethyleneglycol dimethyl ether (diglyme), acetic acid ethyl ester and TiO(S0,) from Riedel-de Haen; phenazine methosulfate, 2,6-dichloroindophenol, iodonitrotetrazolium violet, coenzyme A (Li, salt), Nycodenz and protein-A-agarose...

show abstract

The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences

Cited by 365 publications

References 30 publications

Potencial de biocatálise enantiosseletiva de lipases microbianas

Potencial de biocatálise enantiosseletiva de lipases microbianas

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Stereochemistry of Peroxisomal and Mitochondrial β‐oxidation of α‐methylacyl‐CoAs

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