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PubMed2006

Production of (R)-3-amino-3-phenylpropionic acid and (S)-3-amino-3-phenylpropionic acid from (R,S)-N-acetyl-3-amino-3-phenylpropionic acid using microorganisms having enantiomer-specific amidohydrolyzing activity.

(R)-3-Amino-3-phenylpropionic acid ((R)-beta-Phe) and (S)-3-amino-3-phenylpropionic acid ((S)-beta-Phe) are key compounds on account of their use as intermediates in synthesizing pharmaceuticals. Enantiomerically pure non-natural amino acids are generally prepared by enzymatic resolution of the racemic N-acetyl form, but despite the intense efforts this method could not be used for preparing enantiomerically pure beta-Phe, because the effective enzyme had not been found. Therefore, screening for microorganisms capable of amidohydrolyzing (R,S)-N-acetyl-3-amino-3-phenylpropionic acid ((R,S)-N-Ac-beta-Phe) in an enantiomer-specific manner was performed. A microorganism having (R)-enantiomer-specific amidohydrolyzing activity and another having both (R)-enantiomer- and (S)-enantiomer-specific amidohydrolyzing activities were obtained from soil samples. Using 16S rDNA analysis, the former organism was identified as Variovorax sp., and the latter as Burkholderia sp. Using these organisms, enantiomerically pure (R)-beta-Phe (>99.5% ee) and (S)-beta-Phe (>99.5% ee) with a high molar conversion yield (67%-96%) were obtained from the racemic substrate.

Cell-Free System↗

PubMedDate not supplied

Stereoselective metabolism of 2-phenylpropionic acid in rat. I. In vitro studies on the stereoselective isomerization and glucuronidation of 2-phenylpropionic acid.

Optical isomerization of 2-phenylpropionic acid (hydratropic acid, HTA) was studied in the organs of male rat in vitro. (R)-(-)-HTA was not isomerized by rat liver homogenate even after the addition of CoA, ATP, and Mg2+ to the incubation mixture; however, it was isomerized slowly but significantly in liver slices. This suggests that some additional factor(s) are required for the optical isomerization of HTA in rat liver homogenate. Kidney slices showed about 3-fold higher isomerizing activity of (R)-(-)-HTA than liver slices. (S)-(+)-HTA was also slightly isomerized to (R)-(-)-HTA in kidney slices suggesting that the isomerization of HTA is stereoselective but not stereospecific. The liver and the kidney were considered to be the major organs for isomerization of HTA, since the isomerizing activity of the small intestine was low and other tissues examined were inactive. Change of the incubation medium of liver slices from Krebs-Ringer bicarbonate buffer to Krebs-Ringer buffer without bicarbonate, 0.25 M sucrose solution with 0.05 M Tris-HCl buffer (pH 7.4) or 0.9% NaCl solution with 0.05 M Tris-HCl buffer (pH 7.4) increased the isomerization rate of (R)-(-)-HTA to (S)-(+)-HTA, but decreased the glucuronide formation. During incubation of racemic HTA with liver slices, (S)-(+)-enantiomer percentage in HTA acyl glucuronide (HTA-G) increased with time, whereas that of the free HTA remained nearly constant. These results suggested the stereoselective hydrolysis of (R)-(-)-HTA-G in liver slices, which was confirmed by the results from incubation of HTA-G with rat liver preparations. Kidney homogenate also preferentially hydrolyzed (R)-(-)-HTA-G.

Animals↗

PubMedDate not supplied

Stereoselective metabolism of 2-phenylpropionic acid in rat. II. Studies on the organs responsible for the optical isomerization of 2-phenylpropionic acid in rat in vivo.

The contribution of the liver and kidney to the optical isomerization of (R)-(-)-2-phenylpropionic acid (hydratropic acid (HTA] was examined by iv injection of racemic HTA (20 mg/kg) to nephrectomized and bile duct-ligated rats (NEBL-rats), eviscerated rats with nonfunctioning livers (EVIS-rats), rats with ligated bilateral ureters and bile ducts (BUBL-rats), and sham-operated rats. The decrease of (R)-(-)-enantiomer percentage of HTA in plasma of EVIS-rats from 53% (5 min) to 45% (60 min) clearly proved the contribution of the kidney on the optical isomerization of (R)-(-)-HTA in vivo. In NEBL-rats, the decrease of (R)-(-)-enantiomer percentage of HTA in plasma was only 2% in 55 min, but the (R)-(-)-enantiomer percentages of HTA acyl glucuronide (HTA-G) in plasma and liver at 1 hr after dosing were 40% and 30%, respectively. Therefore, the contribution of the liver on the isomerization was also suggested. Only a trace amount of HTA-G was detected in the EVIS-rats plasma and kidney, confirming the low glucuronic acid-conjugating activity of HTA in rat kidney. But, in the BUBL-rats, stereoselective hydrolysis of (R)-(-)-HTA-G in the kidney was suggested. Both the stereoselective glucuronidation of (S)-(+)-HTA and the stereoselective hydrolysis of (R)-(-)-HTA-G in rat liver might be responsible for the enrichment of (S)-(+)-HTA-G in the liver.

Animals↗

PubMed1992

Formation of glycine conjugate and (-)-(R)-enantiomer from (+)-(S)-2-phenylpropionic acid suggesting the formation of the CoA thioester intermediate of (+)-(S)-enantiomer in dogs.

It has been proposed that the chiral inversion of the 2-arylpropionic acids is due to the stereospecific formation of the (-)-R-profenyl-CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (-)-R-profenyl-CoA, i.e., the racemates and the (-)-(R)-isomers. We have examined this problem in dogs with respect to 2-phenylpropionic acid(2-PPA). Regardless of the optical configuration of 2-phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)-(S)-enantiomer by chiral HPLC. Both (-)-(R)- and (+)-(S)-2-phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2-phenylpropionic acid and its glucuronide excreted in urine after administration of (-)-(R)- and (+)-(S)-2-phenylpropionic acid. The (+)-(S)-enantiomer underwent chiral inversion to the (-)-(R)-antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2-phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)-(S)-2-phenylpropionic acid is a substrate for the glycine N-acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs.

Animals↗

PubMed1990

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat.

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.

Animals↗

PubMed1993

Production of S-(+)-2-phenylpropionic acid from (R,S)-2-phenylpropionitrile by the combination of nitrile hydratase and stereoselective amidase in Rhodococcus equi TG328.

A new soil isolate, tentatively identified as Rhodococcus equi TG328, was found to be effective in the production of S-(+)-2-phenylpropionic acid from (R,S)-2-phenylpropionitrile. The conversion is catalysed by two enzymes. First, a nitrile hydratase converts the (R,S)-nitrile to (R,S)-2-phenylpropionamide. Second, a stereoselective amidase converts the S-(+)-amide to S-(+)-2-phenylpropionic acid. Conditions for optimal enzyme production and accumulation of S-(+)-2-phenylpropionic acid by resting cells were studied. The reaction of resting cells for 30 h at 10 degrees C with (R,S)-2-phenylpropionitrile resulted in the production of 100 g of S-(+)-2-phenylpropionic acid per litre of reaction mixture. The enantiometric excess of the purified S-(+)-2-phenylpropionic acid was 99.4%. The amount of S-(+)-2-phenylpropionic acid accumulated was enhanced by lower reaction temperatures. In addition, unreacted R-(-)-2-phenylpropionamide with 99.0% enantiometric excess was isolated.

Acetonitriles↗

PubMed1999

Degradation of 3-phenylpropionic acid by Haloferax sp. D1227.

Haloferax sp. D1227, isolated from soil contaminated with highly saline oil brine, is the first halophilic archaeon to demonstrate the utilization of aromatic compounds (i.e., benzoic acid, cinnamic acid, and 3-phenylpropionic acid) as sole carbon and energy sources for growth. The degradation of 3-phenylpropionic acid in this strain was studied to examine the strategies utilized by Archaea to metabolize aromatic compounds. Based on our findings of (1) the extracellular accumulation of cinnamic acid, benzoic acid, 3-hydroxybenzoic acid, and gentisic acid in cultures of Haloferax D 1227 grown on 3-phenylpropionic acid, (2) the presence of an 3-phenylpropionylCoA dehydrogenase, (3) the ATP, CoA, and NAD-dependent conversion of cinnamic acid to benzoylCoA, and (4) the presence of gentisate 1,2-dioxygenase, we propose that Haloferax D1227 metabolizes 3-phenylpropionic acid by initial 2-carbon shortening of the side chain to benzoylCoA via a mechanism similar to fatty acid beta-oxidation, followed by aromatic degradation using a gentisate pathway. The upper aliphatic pathway from 3-phenylpropionic acid to benzoic acid is regulated separately from the lower gentisate pathway.

Biodegradation, Environmental↗

PubMed1982

3-Hydroxy- and 3-keto-3-phenylpropionic acids: novel metabolites of benzoic acid in horse urine.

The metabolism of benzoic acid has been examined in the horse, using 14C- and deuterium-labelled compounds. Chromatographic analysis of the urine showed the presence of hippuric acid, benzoyl glucuronide and benzoic acid and a discrete band which accounted for 2% of the dose administered. This material was isolated by solvent extraction and HPLC and, following treatment with diazomethane, examined by GC/MS. The major component of this fraction was 3-hydroxy-3-phenylpropionic acid methyl ester, which was accompanied by very much smaller amounts of cinnamic acid methyl ester and acetophenone. The two latter minor components have been shown to be artefacts produced during workup and analysis. Cinnamic acid methyl ester arises by the thermal decomposition of 3-hydroxy-3-phenylpropionic acid methyl ester on the GC column. It is proposed that acetophenone has formed, during workup, by decarboxylation of 3-keto-3-phenylpropionic acid. It is suggested that 3-hydroxy and 3-keto-3-phenylpropionic acids, which are also endogenous in horse urine, have arisen by an addition of a 2 carbon fragment to benzoyl CoA, in a sequence analogous to the reactions of fatty acid biosynthesis. Some implications of the metabolic interrelationships between xenobiotic acids and fatty acids are discussed.

Animals↗

PubMed1986

Stereospecific induction of rat liver bilirubin UDPglucuronosyltransferase and lauric acid 12-hydroxylation by the isomers of 2-phenylpropionic acid.

The inductive effects of racemic 2-phenylpropionic acid and its isomers on rat liver bilirubin UDP-glucuronosyltransferase activity and lauric acid 12-hydroxylation (cytochrome P-452-dependent) were compared. The (S)-(+)-enantiomer and the racemic mixture gave the greatest induction of both enzyme activities, whereas (R)-(-)-2-phenylpropionic acid produced increases of only one-third of those of its antipode. The determination of the enantiomeric composition of the excreted 2-phenylpropionic acid after a single oral dose indicated that the (R)-(-)-enantiomer given as such or in the racemate was inverted to its antipode, which strongly suggests that (S)-(+)-2-phenylpropionic acid is responsible for the inductive effects observed. The demonstration of the same stereospecificity for the induction of bilirubin UDPglucuronosyltransferase and lauric acid 12-hydroxylation further indicates a close mechanistic link between these two processes.

Animals↗

PubMed1982

Nitrogen-15 nuclear magnetic resonance of arsanilazotyrosine-248 carboxypeptidase A and its complex with beta-phenylpropionate. Structure and dynamics in solution.

Nitrogen-15 nuclear magnetic resonance has been used to study the structure of arsanilazocarboxypeptidase A and its complex with the inhibitor beta-phenylpropionate. Derivatives selectively enriched with 15N were prepared to facilitate observation of the 15N resonances. The results are consistent with the conclusions reached previously from absorption spectroscopic studies and, in addition, provide new information regarding the properties of the azoenzyme and its inhibitor complex. Direct evidence has been obtained for formation of an intramolecular complex between the catalytically essential zinc ion and azoTyr-248, and it has been possible to estimate the degree of complexation. Moreover, the zinc complex involves the distal (N beta) nitrogen of the azo linkage, whereas a model compound, tetrazolyl-N-acetyltyrosine, complexes to zinc through the proximal (N alpha) nitrogen. The 15N NMR spectra give specific information regarding the intramolecular hydrogen bonding in the azoenzyme. The free azophenol form of the azoenzyme, like that of the model compound arsanilazo-N-acetyltyrosine, exists predominantly with the tyrosine phenolic proton intramolecularly hydrogen bonded to N beta of the azo linkage to form a six-membered ring structure. A similar hydrogen bond is also present in the apoazoenzyme and in the azoenzyme-Gly + L-Tyr) complex, but not in the complex between the azoenzyme and beta-phenylpropionate. In the latter complex, there appears to be a new and strong hydrogen bond between the phenolic proton of Tyr-248 and the carboxylate group of enzyme-bound beta-phenylpropionate. Thus, azoenzyme-bound beta-phenylpropionate, but not azoenzyme-bound Gly + L-Tyr, is apparently able to compete effectively with, and displace, the azo nitrogen as the hydrogen-bond acceptor of the phenolic proton of Tyr-248.

Arsanilic Acid↗

PubMed2003

Effects of recombinant human growth hormone and nandrolone phenylpropionate on the healing of ischemic colon anastomosis in rats.

PURPOSE: Recombinant human growth hormone and nandrolone phenylpropionate are two different anabolic agents. This study was designed to investigate the effects of these anabolic agents on the healing of ischemic colon anastomosis in rats. METHODS: Seventy adult male Wistar rats were divided into five groups (n = 14). Group I was the sham laparotomy group. In the other groups, surgical procedures consisting of transsection and anastomosis were made at a distance 3 cm from the peritoneal reflection. Group II was the nonischemic control group. Ischemic colon model was produced in the remaining groups. Group III was the untreated control group. Groups IV and V received recombinant human growth hormone and nandrolone phenylpropionate, respectively. Bursting pressure and hydroxyproline levels were measured on the third and seventh postoperative days to evaluate anastomotic healing. RESULTS: Recombinant human growth hormone increased both collagen deposition and bursting pressure significantly at postoperative Days 3 and 7 compared with the sham and untreated control groups (P < 0.005). When compared with the untreated control, nandrolone phenylpropionate significantly increased collagen deposition at postoperative Days 3 and 7 (P < 0.005) and bursting pressure only at postoperative Day 3 (P < 0.005). CONCLUSIONS: Recombinant human growth hormone has more favorable therapeutic effects on the healing of ischemic colonic anastomoses than nandrolone phenylpropionate. Recombinant human growth hormone also improves healing of nonischemic colonic anastomosis.

Anastomosis, Surgical↗

PubMed1965

The metabolism of beta-phenylpropionic acid by an Achromobacter.

1. When a species of Achromobacter grew with beta-phenylpropionate as carbon source, 2-hydroxy-beta-phenylpropionate and 2,3-dihydroxy-beta-phenylpropionate appeared in the growth medium. The concentrations of these compounds were maximal during exponential growth. 2. The cells contained an oxygenase that required Fe(2+) ions and cleaved the benzene nucleus between the adjacent carbon atoms that bear the side chain and one hydroxyl group of 2,3-dihydroxy-beta-phenylpropionate. 3. The ring-fission product, formed with the consumption of 1mol. of oxygen/mol. of substrate, was isolated and a chemical structure assigned. Sephadex-treated cell extracts converted 1mol. of this compound into 1mol. of 4-hydroxy-2-oxovalerate without oxygen consumption; succinic acid was also formed. 4. When Mn(2+) ions or Mg(2+) ions were added, dialysed extracts converted 4-hydroxy-2-oxovalerate into pyruvate and acetaldehyde, but the reaction did not proceed to completion.

Alcaligenes↗

PubMed2005

3-phenylpropionate catabolism and the Escherichia coli oxidative stress response.

Cells have devised a variety of protection systems against the toxic effects of dioxygen. Dioxygenases are part of this defence mechanism. In Escherichia coli, the positive regulator HcaR, a member of the LysR family of regulators, controls expression of the neighbouring genes, hcaA1, hcaA2, hcaC, hcaB and hcaD, coding for the 3-phenylpropionate dioxygenase complex and 3-phenylpropionate-2',3'-dihydrodiol dehydrogenase, that oxidizes 3-phenylpropionate to 3-(2,3-dihydroxyphenyl) propionate. Differences between expression of hcaR and expression of its target, hcaA, suggest that HcaR is involved in control of other cellular processes or that other regulatory proteins modulate hcaA expression. Protein expression profiling was used to identify other HcaR targets. Two-dimensional gel electrophoresis was used to compare the proteomes of wild-type E. coli and strains in which hcaR was disrupted. Several polypeptides whose production was up- or downregulated in the hcaR mutant were involved in the oxidative stress response. Subsequent experiments demonstrated that hcaR disruption was involved in regulation of genes involved in the oxidative stress response. Modification of the stress response also occurred in an hcaA1A2CD mutant strain. Using gel retardation, the HcaR binding site was estimated to be located about -70 to -55 bp upstream of the hcaA transcription start site. The expression of hcaR was repressed in the absence of oxygen by the ArcA/ArcB two-component system.

Amino Acid Sequence↗

PubMed1986

Isolation and characterization of Escherichia coli mutants defective for phenylpropionate degradation.

Mutants of Escherichia coli defective in catabolism of 3-phenylpropionate, 3-(3-hydroxyphenyl)propionate, or both were isolated after mutagenesis with ethylmethane sulfonate. Nine phenotypically distinct classes of mutants were identified, including strains lacking each of the first five enzyme activities for the degradation of these compounds and mutants pleiotropically negative for some of these activities. Characterization of these mutants was greatly facilitated by the use of indicator media in which accumulation of 3-(2,3-dihydroxyphenyl)propionate or 2-hydroxy-6-ketononadienedioic acid led to the formation of dark red or bright yellow colors, respectively, in the medium. Assays with wild-type and mutant strains indicated that 3-phenylpropionate (or its dihydrodiol), but none of the hydroxylated derivatives tested, induced the synthesis of enzymes for its conversion to 3-(2,3-dihydroxyphenyl)propionate. The remaining enzymes were induced by the 2- or 3-hydroxy or 2,3-dihydroxy derivatives of 3-phenylpropionate, with the 2-hydroxy compound acting as an apparent gratuitous inducer. Metabolism to nonaromatic intermediates appeared to be unnecessary for full induction of any pathway enzyme. One unusual class of mutants, in which 2-keto-4-pentenoate hydratase appeared to be uninducible, indicated a level of control not previously shown in meta-fission catabolic pathways.

Enzyme Induction↗

PubMed2001

Regulation of the early steps of 3-phenylpropionate catabolism in Escherichia coli.

Microbial catabolism of phenylpropanoid compounds plays a key role in the degradation of aromatic molecules originating from the degradation of proteins and plant constituents. In this study, the regulation of the early steps in the utilisation of 3-phenylpropionate, a phenylpropanoid compound, was investigated. Expression of the hcaA gene product, which is involved in 3-phenylpropionate catabolism in Escherichia coli, was positively regulated by HcaR, a regulatory protein similar to members of the LysR regulators family. Remarkably, the expression of hcaA in the presence of 3-phenylpropionate was sharply and transiently induced at the end of the exponential growth phase. This occurred in a rpoS-independent manner. This transient induction was also mediated by HcaR. The expression of this positive regulator is negatively autoregulated, as for other members of the LysR family. The expression of hcaR is strongly repressed in the presence of glucose. Glucose-dependent repression of hcaR expression could only be partially overcome by adding exogenous cAMP.

Bacterial Proteins↗

PubMed1975

[A change in the activity of the beta-phenylpropionic acid conversion enzyme in Escherichia coli under the influence of transmissive plasmids of Salmonella heidelberg].

The activity of the enzyme of the conversion of beta-phenylpropionic acid was studied in the strains of Escherichia coli serotypes 055:K59:H2 and O111:K58:H2 used as recipients via transmission of R- and Col-plasmids by conjugation in vitro. The activity of this enzyme was determined by modified method of Ben Hamida [3]. The wild type strain of Salmonella heidelberg carrying ColIb plasmid and preliminary obtained R1-19 plasmid from E. coli J 5-3 was used as a donor. The activity of the enzyme of conversion of beta-phenylpropionic acid in recombinants carrying R1-19ColIb plasmids was 3-5 times lower as compared with the original recipient. The colour reaction drived under the growth of original bacterial strains in the nutrient broth agar contained beta-phenylpropionic acid at the final concentration of 20 mg% was completely inhibited with that recombinants. The activity of this enzyme in recombinants carrying only R1-19 or ColIb plasmid remains unchanged.

Conjugation, Genetic↗

PubMed1993

Experience with the 3-phenylpropionic acid loading test for diagnosis of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

MCADD is an autosomal recessively transmitted inborn error of C6-C12-carboxylic acid metabolism, causing episodically attacks of life threatening hypoketotic hypoglycemia or Reye-syndrome-like disease. Diagnosis is made best by investigating urinary organic acids before and after a load with 3-phenylpropionate. From 1986 until now 29 patients with MCADD were detected in Freiburg by selective screening for inherited metabolic disorders; 27 of them were confirmed by challenging with 3-phenylpropionic acid. The remaining two patients were not available for further investigations. The 3-phenylpropionate loading test is recommended in patients suffering from recurrent attacks of hypoketotic hypoglycemia and in families, where sudden infant death syndrome (SIDS) or near miss SIDS has occurred.

Acyl-CoA Dehydrogenase↗

PubMed1994

Effects of the anabolic steroid nandrolone phenylpropionate on craniofacial growth in rats.

Primary testosterone and its derivatives are anabolic steroids used in the treatment of osteoporosis and Turner syndrome. They also enhance fast-twitch muscle weight in female rats. The present study examines the effect of an anabolic steroid on craniofacial growth and development in rats. Five-week-old female Sprague-Dawley rats (125) were divided into experimental and control groups. The experimental group was injected subcutaneously with 1 mg nandrolone phenylpropionate in the interscapular region on alternate days, whereas those in the control group were injected with a vehicle, arachis oil. Rats were sacrificed at 60 and 120 days of age. Cephalometric analysis of soft X-ray cephalograms showed that chronic administration of the anabolic steroid, nandrolone phenylpropionate, resulted in: (1) about a 20% increase in body weight, (2) an increase in total skull length, (3) elongation of the maxillary and mandibular incisors, (4) an increase in the depth of the antegonial notch, and (5) downward-forward growth of the viscerocranium against the neurocranium. These results suggest that nandrolone phenylpropionate may accelerate craniofacial growth and/or induce high functional activity of the masticatory muscles in female rats.

Anabolic Agents↗