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PubMed2004

Genetic diversity in Rhizopus oryzae strains as revealed by the sequence of lactate dehydrogenase genes.

Twenty-seven strains of Rhizopus oryzae accumulating predominantly lactic acid were shown to possess two ldh genes, ldhA and ldhB, encoding NAD-dependent lactate dehydrogenases. Variation in nucleotide sequence was identified for each gene from different strains, and similar phylogenetic trees were obtained based on the nucleotide sequences of both genes. The other 21 strains of R. oryzae accumulating predominantly fumaric and malic acids contained a single ORF of ldhB. Compared to the strains accumulating predominantly lactic acid, a lower degree of sequence divergence was found in ldhB, resulting in a separate cluster in the phylogenetic tree. The high similarity (>90%) spanning the ORF and adjacent regions demonstrates that ldhA and ldhB are derived from the same ancestor gene. The strains accumulating predominantly fumaric and malic acids lack functional ldhA, which plays a role in lactic acid synthesis and may form a lineage separated from the strains accumulating predominantly lactic acid in the genus Rhizopus.

DNA, Fungal↗

PubMed1997

Catabolite regulation of two Escherichia coli operons encoding nitrite reductases: role of the Cra protein.

The Escherichia coli nir and nrf operons, which encode alternative nitrite reductases expressed during anaerobic growth, are subject to catabolite regulation. Transcription from the nir promoter is maximal when bacteria are grown in rich media such as Lennox broth supplemented with glucose. Conversely, expression of the nrf operon is suppressed by rich media, but stimulated during growth in minimal medium with glycerol and fumarate. The role of the catabolite repressor-activator (Cra) protein in catabolite regulation of the nir and nrf promoters was investigated. Transcription from the nir promoter was repressed by Cra when cells were grown in minimal medium with glycerol and fumarate. Crude protein extracts from a strain overproducing Cra encoded on a multicopy plasmid retarded a nir promoter fragment in a mobility shift assay, confirming that the observed Cra-dependent repression was due to the direct interaction of Cra with the regulatory region of the nir operon. Furthermore, the inclusion of fructose 1-phosphate, an effector of Cra DNA-binding activity, in the assay decreased the ability of Cra to retard the nir promoter fragment. In contrast, transcription from the nrf promoter was not regulated by Cra under any of the growth conditions tested.

Bacterial Proteins↗

PubMed1998

Expression of the succinate dehydrogenase genes (sdhCAB) from the facultatively anaerobic paenibacillus macerans during aerobic growth

Paenibacillus (formerly Bacillus) macerans is capable of succinate oxidation under oxic conditions and fumarate reduction under anoxic conditions. The reactions are catalyzed by different enzymes, succinate dehydrogenase (Sdh) and fumarate reductase (Frd). The genes encoding Sdh (sdhCAB) were analyzed. The gene products of sdhA and sdhB were similar to the subunits of known Sdh and Frd enzymes. The hydrophobic subunit SdhC showed close sequence similarity to the class of Sdh/Frd enzymes containing diheme cytochrome b. From the sdhCAB gene cluster two transcripts were produced, one comprising sdhCAB, the other sdhAB. The transcripts were found only during aerobic growth, and the amount was directly proportional to Sdh activity, but inversely proportional to Frd activity.

Journal Article↗

PubMed1999

Chlorobium ferrooxidans sp. nov., a phototrophic green sulfur bacterium that oxidizes ferrous iron in coculture with a "Geospirillum" sp. strain.

A green phototrophic bacterium was enriched with ferrous iron as sole electron donor and was isolated in defined coculture with a spirilloid chemoheterotrophic bacterium. The coculture oxidized ferrous iron to ferric iron with stoichiometric formation of cell mass from carbon dioxide. Sulfide, thiosulfate, or elemental sulfur was not used as electron donor in the light. Hydrogen or acetate in the presence of ferrous iron increased the cell yield of the phototrophic partner, and hydrogen could also be used as sole electron source. Complexed ferric iron was slowly reduced to ferrous iron in the dark, with hydrogen as electron source. Similar to Chlorobium limicola, the phototrophic bacterium contained bacteriochlorophyll c and chlorobactene as photosynthetic pigments, and also resembled representatives of this species morphologically. On the basis of 16S rRNA sequence comparisons, this organism clusters with Chlorobium, Prosthecochloris, and Pelodictyon species within the green sulfur bacteria phylum. Since the phototrophic partner in the coculture KoFox is only moderately related to the other members of the cluster, it is proposed as a new species, Chlorobium ferrooxidans. The chemoheterotrophic partner bacterium, strain KoFum, was isolated in pure culture with fumarate as sole substrate. The strain was identified as a member of the epsilon-subclass of the Proteobacteria closely related to "Geospirillum arsenophilum" on the basis of physiological properties and 16S rRNA sequence comparison. The "Geospirillum" strain was present in the coculture only in low numbers. It fermented fumarate, aspartate, malate, or pyruvate to acetate, succinate, and carbon dioxide, and could reduce nitrate to dinitrogen gas. It was not involved in ferrous iron oxidation but possibly provided a thus far unidentified growth factor to the phototrophic partner.

Bacteria, Anaerobic↗

PubMed1999

Anaerobic degradation of m-cresol by Desulfobacterium cetonicum is initiated by formation of 3-hydroxybenzylsuccinate.

The anaerobic bacterium Desulfobacterium cetonicum oxidized m-cresol completely with sulfate as electron acceptor. During growth, 3-hydroxybenzylsuccinate (identified by gas chromatography/mass spectroscopy and by comparison of high-performance liquid chromatography retention time and UV spectrum with a chemically synthesized reference compound) accumulated in the medium. This finding indicates that the methyl group of m-cresol is activated by addition to fumarate as in the case of anaerobic toluene metabolism. In cell-free extracts of D. cetonicum, the formation of 3-hydroxybenzylsuccinate from m-cresol and fumarate was detected at an activity of 0.5 nmol min(-1) (mg protein)(-1). This reaction depended strictly on anoxic assay conditions. Treatment with air resulted in a complete loss of activity; however, some activity could be recovered after restoring anoxic conditions. The activity was slightly membrane-associated. 3-Hydroxybenzylsuccinate was degraded via CoA thioesterification and further oxidation to 3-hydroxybenzoyl-CoA as subsequent steps in the degradation pathway.

Anaerobiosis↗

PubMed2003

Glucose fermentation by Propionibacterium microaerophilum: effect of pH on metabolism and bioenergetic.

pH affected significantly the growth and the glucose fermentation pattern of Propionibacterium microaerophilum. In neutral conditions (pH 6.5-7.5), growth and glucose fermentation rate (qs) were optimum producing propionate, acetate, CO(2), and formate [which together represented 90% (wt/wt) of the end products], and lactate representing only 10% (wt/wt) of the end products. In acidic conditions, propionate, acetate, and CO(2) represented nearly 100% (wt/wt) of the fermentation end products, whereas in alkaline conditions, a shift of glucose catabolism toward formate and lactate was observed, lactate representing 50% (wt/wt) of the fermentation end products. The energy cellular yields ( Y(X/ATP)), calculated (i) by taking into account extra ATP synthesized through the reduction of fumarate into succinate, was 6.1-7.2 g mol(-1). When this extra ATP was omitted, it was 11.9-13.1 g mol(-1). The comparison of these values with those of Y(X/ATP) in P. acidipropionici and other anaerobic bacteria suggested that P. microaerophilum could not synthesize ATP through the reduction of fumarate into succinate and therefore differed metabolically from P. acidipropionici.

Carbon Dioxide↗

PubMed1998

Metabolic transition in the development of Hymenolepis diminuta (Cestoda).

Cysticercoids as well as 6-, 10-, and 14-day Hymenolepis diminuta were evaluated in terms of enzymatic activities related to phosphoenolpyruvate (PEP) utilization and mitochondrial succinate accumulation. The data obtained support a transition toward anaerobic electron-transport-dependent succinate accumulation, characteristic of adult H. diminuta, with development from cysticercoid to adult. This transition was reflected most prominently in the increasing activities of PEP carboxykinase (PEPCK), malate dehydrogenase, NADPH-->NAD+ transhydrogenase, and fumarate reductase. Developmental increases in PEPCK/pyruvate kinase (PK), fumarate reductase (FR)/NADH oxidase (NO), and FR/succinate dehydrogenase (SDH) activity ratios were also apparent. Evaluations of "egg-free" immature, mature, and pregravid-gravid segments of adult H. diminuta revealed that in general the greater levels of activity were associated with the immature and mature segments. Whereas FR/NO and FR/SDH ratios remained relatively constant in segment comparisons, the greatest PEPCK/PK ratio was associated with the pregravid-gravid segment.

Anaerobiosis↗

PubMed1998

The succinate/fumarate transporter Acr1p of Saccharomyces cerevisiae is part of the gluconeogenic pathway and its expression is regulated by Cat8p.

The product of the ACR1 gene is essential for growth of Saccharomyces cerevisiae on ethanol or acetate as sole carbon source, and its expression is subject to glucose repression. It was previously shown that Acr1p is a membrane protein which specifically transports succinate and fumarate. Its suggested function is to shuttle cytosolic succinate from the glyoxylate cycle into the mitochondria in exchange for fumarate, an activity that is essential during gluconeogenic growth on C2 compounds. In this study we show that ACR1 is coregulated with the genes coding for the key enzymes of the glyoxylate cycle and gluconeogenesis: ICL1, MLS1 and PCK1, FBP1 respectively. We demonstrate that derepression of ACR1 is strictly dependent on the Zn2Cys6-type transcriptional activator Cat8p. A detailed deletion analysis of the ACR1 promoter revealed that 69% of the derepression of ACR1 is mediated by three cis-acting elements, located between positions -679 and -569 relative to the translational start, which show a high degree of similarity to the UAS/CSRE elements of PCK1, FBP1, ICL1 and MLS1. Our results, in conjunction with previous biochemical data, clearly identify Acr1p as an element which is directly involved in gluconeogenesis, functioning as the mitochondrial carrier which links the anaplerotic reactions of the glyoxylate cycle to the TCA cycle.

Basic-Leucine Zipper Transcription Factors↗

PubMed2006

Desulfomicrobium thermophilum sp. nov., a novel thermophilic sulphate-reducing bacterium isolated from a terrestrial hot spring in Colombia.

A moderately thermophilic, sulphate-reducing bacterium, designated strain P6-2(T), was isolated from a terrestrial hot spring located at a height of 2,500 m in the Andean region, Colombia (5 degrees 43'69''N, 73 degrees 6'10''W). Cells of strain P6-2(T) were rod-shaped, stained Gram-negative and were motile by means of a single polar flagellum. The strain grew lithotrophically with H(2) as the electron donor and organotrophically on lactate, pyruvate, ethanol, malate, fumarate, n-propanol and succinate in the presence of sulphate as the terminal electron acceptor. Fumarate and pyruvate was fermented. Strain P6-2(T) grew optimally at 55 degrees C (range 37-60 degrees C), pH 6.6 (range 5.8-8.8) in the presence of 0.5% NaCl (range 0-4.5%) with lactate and sulphate and produced acetate, CO(2) and H(2)S as the major end-products. Sulphate, sulphite and thiosulphate could be used as electron acceptors but not elemental sulphur or nitrate. The G + C content of the genomic DNA was 58.7 mol%. The 16S rRNA sequence analysis indicated that strain P6-2(T) was a member of the class Deltaproteobacteria, domain Bacteria with Desulfomicrobium baculatum being the closest relative (similarity value of 94%). Phylogeny of genes encoding alpha- and beta-subunits of the dissimilatory sulphite reductase (dsrAB genes) supported its affiliation to members of the genus Desulfomicrobium. On the basis of this evidence, we propose to assign strain P6-2(T) as new species of the genus Desulfomicrobium, D. thermophilum sp. nov., with strain P6-2(T) as the type strain (= DSM 16697(T) = CCUG 49732(T)).

1-Propanol↗

PubMed2005

Isolation and characterization of Sulfurospirillum carboxydovorans sp. nov., a new microaerophilic carbon monoxide oxidizing epsilon Proteobacterium.

A new microaerophilic, Gram-negative, motile, 2-3 microm long and 0.3 microm wide, vibrioid to spirillum-shaped, CO oxidizing bacterium, designated strain MV, isolated from marine sediment (The North Sea) is described. Strain MV was able to couple the oxidation of CO to the reduction of elemental sulphur, DMSO and thiosulphate. Growth occurred with up to 100% (v/v) CO in the headspace. Acetate was needed as carbon source. No growth on CO was observed with nitrate and selenate as electron acceptor. Sulphite, elemental sulphur, DMSO, thiosulphate, nitrate, nitrite, perchloroethylene, arsenate and selenate were used as electron acceptors with pyruvate as energy and carbon source. Microaerophilic growth was observed. In non-agitated cultures growth occurred at atmospheric oxygen concentrations in the headspace. Hydrogen (with acetate as carbon source), formate (with acetate as carbon source), pyruvate, lactate, succinate, fumarate, malate alpha-ketoglutaric acid, aspartate and yeast extract (1% (w/v)) supported growth with nitrate as electron acceptor. Fumarate and malate were fermented. Vitamins were not required for growth. The strain was cytochrome C oxidase and catalase positive. The DNA mol G+C content was 30.5%. 16S rRNA gene sequence comparison showed that strain MV grouped within the genus Sulfurospirillum with Sulfurospirillum arcachonense (sequence similarity 98.3%) as closest relative. The relative DNA-DNA relatedness between strain MV and S. arcachonense was 33.1%. Based on a detailed phenotypic and phylogenetic analysis, inclusion of strain MV in the genus Sulfurospirillum as a well separated new species is proposed. As species name we propose Sulfurospirillum carboxydovorans. The type strain is strain MV (ATCC BAA-937 = DSM 16295, GenBank accession number: AY740528).

Aldehyde Oxidoreductases↗

PubMed1986

Adenylylation state of glutamine synthetase and permeability properties of Pseudomonas fluorescens.

The state of adenylylation, n, of glutamine synthetase (GS) in Pseudomonas fluorescens has been determined as a function of growth conditions. Compared to the behavior of Escherichia coli, atypical responses to either carbon or nitrogen starvation were observed when P. fluorescens was grown with either succinate, malate, or fumarate as the sole source of carbon and energy. Under conditions of carbon starvation (high NH4+, low dicarboxylic acid substrate), the value of n falls rapidly from 10 to 1.0 during prolonged incubation in the stationary phase, whereas the value of n is unexpectedly high (ca. 10) in extracts of nitrogen-starved cells. These abnormal responses are attributable to particular permeability properties of P. fluorescens cells compared to E. coli. The unusual changes in nitrogen-starved cells are related to the release of alpha-ketoglutarate by such cells during incubation or washing procedures. These changes can be prevented by the addition of cetyltrimethylammonium bromide (CTAB) to the cultures 5 min prior to harvesting the cells, or by freezing the cell pellets just after centrifugation and sonication within 3 min of suspension in buffer, or by suspending freshly harvested cells in buffer containing alpha-ketoglutarate and orthophosphate (i.e., effectors that favor deadenylylation of glutamine synthetase). The abnormal changes which occur during carbon starvation in the presence of excess NH4+ can be prevented by addition of ATP and glutamine to the buffer in which the freshly harvested cells are suspended prior to sonication. The results suggest that during the stationary phase of growth on succinate, fumarate, or malate (but not on glucose), the cellular membrane becomes permeable to small molecules that regulate the adenylylation cascade, and indeed, it was observed that such whole cells expressed, without any chemical or physical treatment, more than 50% of the glutamine synthetase activity they contained. Such cells may be useful in studies to examine the effects of multiple metabolites on the regulation of glutamine synthetase adenylylation in situ.

Adenosine Monophosphate↗

PubMed1989

Effect of esters of succinic acid and other citric acid cycle intermediates on insulin release and inositol phosphate formation by pancreatic islets.

Esters of carboxylic acids are permeable to cells and once inside the cell are hydrolyzed to carboxylic acids. Methyl and ethyl esters of succinate and other citric acid cycle intermediates were tested to find out whether they are insulin secretagogues. Monomethyl succinate stimulated insulin release from pancreatic islets in a concentration-dependent manner with maximal release attained at a concentration of 10 mM. Dimethyl succinate (10 mM) was as effective as monomethyl succinate, but pyruvate methyl ester, monoethyl succinate, and dimethyl fumarate were ineffective as primary secretagogues. However, dimethyl fumarate potentiated both leucine- and leucine-plus-glutamine-induced insulin release. Glucose, leucine, leucine plus glutamine, and monomethyl succinate increased inositol tris-, bis- and monophosphate formation in pancreatic islets and antimycin A inhibited this formation. Since mitochondrial metabolism is probably essential for glucose-induced insulin release and the metabolism of succinate and leucine (without or with glutamine) involves mitochondrial respiration exclusively, these results might indicate that mitochondrial metabolism generates conditions or factors that are transmitted to the cytosol to increase inositol trisphosphate formation and thus calcium mobilization and insulin release. Since succinate is believed to enter metabolism at site II of the mitochondrial respiratory chain, it is interesting that rotenone, an inhibitor of NADH dehydrogenase and site I of the respiratory chain, was a potent inhibitor of monomethyl succinate-induced insulin released. Rotenone also inhibited leucine (plus or minus glutamine)-induced insulin release. These results indicate that beta cell metabolism of monomethyl succinate and leucine, like glucose, influences dehydrogenases that produce NADH.

Animals↗

PubMed1990

Heterogeneous pools of cholesterol side-chain cleavage activity in adrenal mitochondria from adrenocorticotropic hormone-treated rats: reconstitution of the isocitrate response with succinate and low concentrations of isocitrate.

Cholesterol side-chain cleavage in isolated adrenal mitochondria requires unique energy requirements that may determine not only electron transport to P450 but also cholesterol availability. In mitochondria from ACTH-treated rats, two approximately equal pools of reactive cholesterol are indicated by the partial effectiveness of succinate (SU; Type A), and the metabolism of residual cholesterol by 1 mM isocitrate (IC; Type B). Type A metabolism is associated with relatively few initial cholesterol-P450scc complexes and is rapidly and selectively lost when mitochondria are preincubated without an energy source. We now show that cholesterol metabolism supported by IC resolves into equal high and low affinity components (EC50 = 10 and 250 microM) exhibiting, respectively, Type A and Type B characteristics. SU and 50 microM IC, in combination, provided nearly the same activity characteristics as 1 mM IC, including resistance to preincubation and increased turnover of cholesterol-P450scc complexes. Much higher (three to six times) and more sustained pregnenolone formation was seen, with all reductants, following either enhancement of the reactive cholesterol pool or addition of 20-alpha-hydroxycholesterol, indicating that adrenocorticotropic hormone-mitochondria are limited by substrate availability. ATP generation was most effectively supported by SU, and IC was maximally active at 50 microM, emphasizing differences between respiratory and steroidogenic energy requirements. ATP production and the maintenance of uniform suppression after in vivo cycloheximide treatment indicate the integrity of the mitochondrial interaction with all reductants. Inhibitors of SU oxidation (KCN, malonate) strongly inhibited SU-supported cholesterol metabolism but had little effect on SU synergism with IC. Fumarate (but not alpha-ketoglutarate or oxaloacetate) was equally effective as a synergist, but was totally ineffective as a reductant. SU or fumarate, therefore, act by a nonreductive pathway to boost NADPH production from low concentrations of IC. This decrease in apparent Km for IC may be mediated by stimulation of mitochondrial uptake of the reductant through the specific transporters.

Adrenal Glands↗

PubMed1986

Electron-transfer complexes of Ascaris suum muscle mitochondria. II. Succinate-coenzyme Q reductase (complex II) associated with substrate-reducible cytochrome b-558.

A succinate-coenzyme Q reductase (complex II) was isolated in highly purified form from Ascaris muscle mitochondria by detergent solubilization, ammonium sulfate fractionation and gel filtration on a Sephadex G-200 column. The enzyme preparation catalyzes electron transfer from succinate to coenzyme Q1 with a specific activity of 1.2 mumol coenzyme Q1 reduced per min per mg protein at 25 degrees C. The isolated complex II is essentially free of NADH-ferricyanide reductase, reduced CoQ2-cytochrome c reductase and cytochrome c oxidase and consists of four major polypeptides with apparent molecular weights of 66 000, 27 000, 12 000 and 11 000 and two minor ones with Mr of 36 000 and 16 000. The complex II contained cytochrome b-558, a major constituent cytochrome of Ascaris mitochondria, at a concentration of 3.6 nmol per mg protein, but neither other cytochromes nor quinone. The cytochrome b-558 in the complex II was reduced with succinate. In the presence of Ascaris NADH-cytochrome c reductase (complex I-III) (Takamiya, S., Furushima, R. and Oya, H. (1984) Mol. Biochem. Parasitol. 13, 121-134), the cytochrome b-558 in complex II was also reduced with NADH and reoxidized with fumarate. These results suggest the cytochrome b-558 to function as an electron carrier between NADH dehydrogenase and succinate dehydrogenase in the Ascaris NADH-fumarate reductase system.

Animals↗

PubMed1993

Differential susceptibilities of the prosthetic heme of hemoglobin-based red cell substitutes. Implications in the design of safer agents.

One approach to the development of an effective red cell substitute has been chemical modification of human hemoglobin to optimize oxygen transport and plasma half-life. Human hemoglobin A0 and two of these modified hemoglobins, one prepared from the cross-linking of the alpha-chains at lysine residue 99 by bis(3,5-dibromosalicyl)fumarate (Hb-DBBF) and the other by acylation of lysine residue 82 of the beta-chain by mono-(3,5-dibromosalicyl)fumarate (Hb-FMDA), were tested by HPLC for their susceptibility to oxidative damage caused by H2O2. Such oxidative insult may occur during ischemia and reperfusion of tissues after transfusion of red cell substitutes to patients with hypovolemic shock and trauma. Hb-DBBF was extremely susceptible to damage of its heme and protein moieties with stoichiometric amounts of H2O2, whereas Hb-FMDA was highly resistant, even at 10-fold molar excess and at an acidic pH of 4.7. Hemoglobin A0 was of intermediate susceptibility, exhibiting alteration of heme and protein moieties at acidic but not neutral pH. Since the degradation of heme can release the potentially toxic agent iron, Hb-FMDA may be a more promising candidate than Hb-DBBF for development as a red cell substitute. A similar approach may be used to assess the susceptibility of other hemoglobin-based red cell substitutes to oxidative damage in order to determine the molecular basis of heme and protein alteration.

Aspirin↗

PubMed1990

Submicromolar Ag+ increases passive Na+ permeability and inhibits the respiration-supported formation of Na+ gradient in Bacillus FTU vesicles.

The effect of Ag+ on Na+ pumping by Na(+)-motive NADH-quinone reductase and terminal oxidase has been studied in Bacillus FTU inside-out vesicles. Very low concentrations of Ag+ (C1/2 = 1 x 10(-8) M or 2 x 10(-12) g ion.mg protein-1) are shown to inhibit the uphill Na+ uptake coupled to the oxidation of NADH by fumarate or of ascorbate + TMPD by oxygen but exert no effect on the H+ uptake by the H(+)-motive respiratory chain. Low Ag+ also induces a specific increase in the Na+ permeability of the vesicles. HQNO, added before and not after Ag+, prevents the Ag(+)-induced permeability increase, with effective HQNO concentrations being similar to those inhibiting the uphill Na(+)-uptake coupled to the NADH-fumarate oxidoreduction. Reduction of terminal oxidase by ascorbate + TMPD in the presence of cyanide sensitizes the Na+ permeability to Ag+. It is suggested that low [Ag+], known as a specific inhibitor of electron transport by the Na(+)-motive NADH-quinone reductase, uncouples the electron and Na+ transports so that the Ag(+)-modified NADH-quinone reductase operates as an Na+ channel rather than an Na+ pump. This effect is discussed in connection with the antibacterial action of Ag+.

Bacillus↗

PubMed1984

Pharmacologic inhibition of scar contracture of intracardiac prosthetic patches.

Significant fibrosis and contracture often cause complications of pericardial and Dacron grafts within the heart. Both continue to be utilized because more suitable materials are unavailable. Newer prosthetic materials and the administration of drugs that might minimize intracardiac fibrosis and contracture after implantation were studied. Measured patches of three prosthetic materials were implanted into the right atrium of 18 dogs: 6 with expanded polytetrafluoroethylene (PTFE or Gore-Tex--W. L. Gore & Associates, Elkton, Md.), 6 with glutaraldehyde-preserved bovine pericardium, and 6 with Dacron patches. The animals were sacrificed after 8 weeks and gross and microscopic pathologic examinations were performed. The patch materials did not intrinsically shrink but all demonstrated marked distortion from the growth of surrounding scar tissue. In a fourth group of eight dogs with intraatrial Dacron patches, four were treated for 8 weeks with oral 3-aminopropionitrile fumarate, and four were not treated. A blinded observed evaluated the adhesions on a scale of 0 = no adhesions or patch distortion, to 4 = dense adhesions with marked distortion of the patches. The untreated dogs had dense adhesions of the lung and pericardium and the patches were encased in scar tissue with marked distortion. The average score was 3.5. The treated dogs had only minimal pleural adhesions and only a thin neointimal covering of the patch with virtually no distortion. The average score was 1.0 (P = 0.0032). The tensile strength of the healed atriotomies was evaluated with stress testing. The intact atrial wall ruptured at a force of 2.60 +/- 0.37 kg/m/sec2, the untreated atriotomy wound at 2.38 +/- 0.18 kg/m/sec2, and the treated atriotomy wound at 2.60 +/- 0.17 kg/m/sec2. There was no statistically significant difference among these groups. No other side effects of the 3-aminopropionitrile fumarate were noted, with only a single superficial wound infection caused by early postoperative trauma. Pharmacologic inhibition of scar formation minimized distortion and contracture of intracardiac prosthetic patches and decreased adhesions. Though further experimental evaluations are necessary, prolonged low-dose oral administration of beta-aminoproprionitrile (BAPN) may be beneficial in preventing complications of prosthetic implants and reoperative cardiac surgery in children.

Aminopropionitrile↗

PubMed1988

Topical beta-aminopropionitrile and biochemistry of granuloma tissue.

The changes of connective tissue in granuloma development were studied up to 20 days following subcutaneous implantation of polyvinyl alcohol (PVA) sponges in rats. The total protein and collagen content were found to increase from the 4th to 12th days of implantation while the content of DNA continuously decreased with the age of the granuloma. Administration of beta-aminopropionitrile (beta APN) fumarate on the intact skin overlying the implanted PVA sponge in the presence and absence of dimethyl sulfoxide (DMSO) during the growth phase of granuloma development (4th through 12th days after implantation) was accompanied by significant inhibition of collagen polymerization. This was documented by a significant increase of collagen extractable into 1 N NaCl, by a significantly reduced content of aldehydes in collagens extractable into neutral salt solution, and by a significant increase of alpha subunits and alpha/beta ratio. Topical beta APN administration had no effect on the content of DNA, noncollagenous proteins, or total hydroxyproline. We conclude that topically administered beta APN fumarate onto the intact skin penetrates the stratum corneum and effectively inhibits collagen crosslinking in the underlying granuloma tissue. The extent of the effectiveness was found to be significantly greater in the presence of DMSO.

Administration, Cutaneous↗