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PubMed2005

NTP carcinogenesis studies of 2,2-bis(bromomethyl)-1,3-propanediol, nitromethane, and 1,2,3-trichloropropane (cas nos. 3296-90-0, 75-52-5, and 96-18-4) in guppies (Poecilia reticulata) and medaka (Oryzias latipes) (Waterborne Studies).

The NTP chose to initiate studies in fish as an exploration of alternate or additional models for examining chemical toxicity and carcinogenicity. The use of small fish species in carcinogenicity testing offered potential advantages as a bioassay test system, including significant savings in cost and time over rodent studies. Large numbers of small fish could be easily maintained in a limited area. The two species chosen for study were guppy (Poecilia reticulata) and medaka (Oryzias latipes), both of which are hardy, easily maintained, and have a low occurrence of background lesions. The three chemicals chosen for study in fish had already been studied by the NTP in rodents, permitting a comparison of results between the two models. Two of the chemicals used (2,2-bis(bromomethyl)-1,3-propanediol and 1,2,3-trichloropropane) were mutagenic and multisite carcinogens in rats and mice. The third chemical, nitromethane, was nonmutagenic with a more modest carcinogenic response in rodents. Male and female guppies and medaka were exposed to 2,2-bis(bromomethyl)- 1,3-propanediol (greater than 99% pure), nitromethane, (greater than 99% pure), or 1,2,3-trichloropropane (99% pure) in aquaria water for up to 16 months. OVERALL STUDY DESIGN: Groups of approximately 220 guppies (two replicates of 110) were maintained in aquaria water containing nominal concentrations of 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 30, or 70 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. Groups of approximately 340 medaka (two replicates of 170) were maintained in aquaria water containing 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 20, or 40 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. The overall study durations were 16 months for all guppy studies, 14 months for 2,2-bis(bromomethyl)-1,3-propanediol-exposed medaka, and 13 months for nitromethane- and 1,2,3-trichloropropane-exposed medaka. Ten guppies and 10 medaka from each group replicate were sacrificed at 9 months for histopathologic analysis. Approximately one third of the remaining fish from each group were placed in chemical-free water at 9 months and constituted a stop-exposure study component. The remainder of the fish were exposed for the duration of the study and constituted the core study component. A stop-exposure component was added to determine if stopping the exposure at 9 months and transferring to chemical-free aquaria might allow for better survival and tumor development. The sex of guppies and medaka was determined at histopathologic analysis. 2,2-BIS(BROMOMETHYL)-1,3-PROPANEDIOL - 16-MONTH STUDY IN GUPPIES: 2,2-Bis(bromomethyl)-1,3-propanediol was chronically toxic to guppies in the 60 and 150 mg/L core and stop-exposure groups. Due to mortality, exposure of core study animals in the 150 mg/L group was terminated on day 443, after approximately 64 weeks on study, and fish were maintained in 2,2-bis(bromomethyl)- 1,3-propanediol-free water in the exposure system until the end of the study at 69 weeks. Nominal exposure concentrations of 24, 60, and 150 mg/L provided actual aquaria water exposure concentrations of 20.0, 53.5, and 139.0 mg/L 2,2-bis(bromomethyl)- 1,3-propanediol, respectively. There were no treatment-related differences between the control and exposed groups in body weights or lengths. At 9 months, hepatocellular adenomas occurred in one 24 mg/L male and in one 150 mg/L male. In the core study, the incidence of hepatocellular adenoma or carcinoma (combined) in 150 mg/L males was greater than that in the controls; multiple adenomas occurred in two 150 mg/L males and in one 150 mg/L female. Cholangioma occurred in a small number of exposed males and females. In the stop-exposure study, incidences of hepatocellular adenoma (including multiple) and of hepatocellular carcinoma were greater in 150 mg/L males than in controls. One cholangioma and one cholangiocarcinoma occurred in the 150 mg/L female group. 14-MONTH STUDY IN MEDAKA: Exposure to 2,2-bis(bromomethyl)-1,3-propanediol did not result in any significant reduction in survival, although the mortality of fish was somewhat greater in the 60 and 150 mg/L core study groups than in the control and 24 mg/L groups. After reallocation, mortality of medaka in the 60 and 150 mg/L core groups was slightly increased over the corresponding stop-exposure groups. Nominal exposure concentrations of 24, 60, and 150 mg/L provided actual exposure concentrations of 19.4, 56.9, and 137.8 mg/L 2,2-bis(bromomethyl)- 1,3-propanediol, respectively. Core study animals in the 60 and 150 mg/L groups were significantly larger, in both body length and weight, than control group fish. In the core study, the incidence of hepatocellular adenoma or carcinoma (combined) was increased in 150 mg/L males. Cholangiocarcinomas occurred in a few exposed males and females, with all but one occurring in 150 mg/L fish. One cholangioma occurred in a 150 mg/L female, and one occurred in a control female. In the stop-exposure study, incidences of hepatocellular adenoma or carcinoma (combined) were marginally increased in the 150 mg/L group of males and in the 60 and 150 mg/L groups of females as compared with controls. Cholangiocarcinoma occurred in one male and one female in the 150 mg/L groups and in one control female. NITROMETHANE - 16-MONTH STUDY IN GUPPIES: Although the cause of death could not be confirmed in many cases, mortality in the 70 mg/L groups appeared to indicate that this level of nitromethane exposure was chronically toxic. This is confirmed by the similar survival rate of guppies from all treatments following removal from treatment aquaria and placement in stop-exposure. Due to the high mortality of fish in the 70 mg/L core study groups, these fish were removed from treatment (day 396) and fixed for histological analyses after approximately 57 weeks on study. The controls and other exposed groups were sacrificed at 70 weeks. Nominal exposure concentrations of 10, 30, and 70 mg/L provided actual exposure concentrations of 9.9, 28.7, and 66.4 mg/L nitromethane, respectively. There were no treatment-related differences between the control and exposed groups in body lengths or weights. 13-MONTH STUDY IN MEDAKA: Nitromethane in the aquaria supported a substantial microfaunal growth which, without frequent cleaning, affected water quality and treatment concentrations. To maintain acceptable water quality and treatment concentrations potentially affected by the rapid microfaunal growth, the study aquaria were brushed once and siphoned three times each day. Due to this frequent activity, a number of fish probably died due to mechanical injury. Unfortunately, the cause of death could not be confirmed in many cases; the mortality from this activity is believed to have been approximately uniform among treatments and should not have affected the comparison of survival between treatments. Based on mortality in this study and the previous life-span evaluation, the life phase of this study was terminated approximately 13.5 months after hatching. Nominal exposure concentrations of 10, 20, and 40 mg/L resulted in actual exposure concentrations of 9.3, 20.8, and 41.7 mg/L nitromethane, respectively. No differences between control and exposed groups were found in body lengths or weights at the 9-month interim evaluation. Due to mortality, unequal numbers of fish were distributed among the core study and stop-exposure aquaria at 9 months. Differences in lengths and weights were found at 13 months. The biological significance of this finding is unknown. At 9 months, a single cholangiocarcinoma occurred in a 40 mg/L male. Hepatocellular adenomas occurred in two 20 mg/L males and in one 40 mg/L female. In the core study, one cholangioma occurred in a 20 mg/L male, and cholangiocarcinomas were seen in a few exposed males, but none occurred in control males. 1,2,3-TRICHLOROPROPANE - 16-MONTH STUDY IN GUPPIES: The survival of exposed guppies was less than that of the control group at 9 months. Reduced survival was evident at 6 months in the 18.0 mg/L groups and at 7 months in the 4.5 and 9.0 mg/L groups. Survival was significantly reduced in the 18.0 mg/L core study group within 1 month of the 9-month interim evaluation, and mortality in this group was 42.6% between 9 months and study termination. Nominal exposure concentrations of 4.5, 9.0, and 18.0 mg/L resulted in actual exposure concentrations of 4.4, 8.8, and 18.2 mg/L 1,2,3-trichloropropane, respectively. Guppies in the 18.0 mg/L core study group were significantly longer and weighed more than the controls. Fish in the 18.0 mg/L stop-exposure group also weighed more than the controls. Mortality of fish during the study resulted in unequal numbers of individuals distributed to core study and stop-exposure aquaria at 9 months. This appears to have influenced the length and weight of fish measured at study termination (i.e., the smaller tank population allowed the fish to grow more). Observed differences in weight and length between controls and 18.0 mg/L fish was most likely an artifact of the reduced numbers of fish in the 18.0 mg/L aquaria. At 9 months, multiple hepatocellular adenomas occurred in one 4.5 mg/L male, and one hepatocellular adenoma occurred in a control male. In the core study, increased incidences of cholangiocellular (bile duct) and hepatocellular neoplasms occurred in exposed groups of males and females. Cholangioma and cholangiocarcinoma were seen in several exposed males and females. In the stop-exposure study, increased incidences of hepatocellular neoplasms occurred in 18.0 mg/L males and increased incidences of cholangiocellular (bile duct) neoplasms occurred in 18.0 mg/L females. (ABSTRACT TRUNCATED)

Animal Feed↗

PubMed1974

Evolution of L-1, 2-propanediol catabolism in Escherichia coli by recruitment of enzymes for L-fucose and L-lactate metabolism.

A mutant strain of Escherichia coli capable of growth on l-1,2-propanediol was isolated previously. The mutant is characterized by constitutive production of a propanediol:nicotinamide adenenine dinucleotide (NAD) oxidoreductase which is essential for the new growth property. In the present study, it is shown that phage P1 cotransduces the genetic locus conferring this property and the genes for the utilization of l-fucose. A further indication of a relationship between these two growth properties is provided by the observation that wild-type E. coli excretes propanediol during fermentation of l-fucose. Under these conditions, a propanediol dehydrogenase (lactaldehyde reductase) is induced. This enzyme migrates on diethylaminoethyl-cellulose with the propanediol dehydrogenase produced constitutively by the mutant strain. A key event in the establishment of the ability to grow on propanediol is evidently a shift in the expression and function of propanediol dehydrogenase; an enzyme catalyzing formation of a reduced fermentation product anaerobically in wild-type cells functions aerobically to oxidize this same product in the mutant. l-Lactaldehyde, which is thus derived from propanediol, is converted to l-lactate by another dehydrogenase (l-lactaldehyde:NAD oxidoreductase) which is constitutively produced by both wild-type and mutant cells. The normal function of this enzyme is not yet established. l-Lactate is converted to pyruvate by an inducible NAD-independent l-lactate dehydrogenase. Thus, the carbons of propanediol are brought into the central metabolic network of the cell.

Aerobiosis↗

PubMed1977

Regulatory changes in the fucose system associated with the evolution of a catabolic pathway for propanediol in Escherichia coli.

Wild-type strains of Escherichia coli are unable to use L-1,2-propanediol as a carbon and energy source. Strain 3, a mutant selected for the ability to grow on this compound at progressively more rapid rates, synthesizes constitutively a nicotinamide adenine dinucleotide-linked propanediol oxidoreductase. This enzyme is normally synthesized during anaerobic growth on L-fucose when it functions as a lactaldehyde reductase. Propanediol, the end product of this fermentation process, escapes irretrievably into the medium. The propanediol-utilizing mutant can no longer grow on fucose in either the presence or absence of molecular oxygen. In the present study nine independent lines of propanediol-positive mutants were characterized. One mutant, strain 418, attained a propanediol growth rate close to that of strain 3 without loss of the ability to grow on fucose. In all cases examined, however, prolonged selection on propanediol did result in the emergence of fucose-negative mutants. All of these mutants had enzyme patterns similar to that of strain 3; namely, fucose permease, fucose isomerase, and fuculose kinase were noninducible, whereas fuculose 1-phosphate aldolase was constitutive. In strain 418 and in the fucose-positive predecessors of the other mutants, the first four enzymes in the pathway remained inducible, as in the wild-type strain. Improvements in the growth rate on propanediol appeared to reflect principally the increased activity level of the oxidoreductase during the early stages of evolution. According to transductional analysis, the mutations affecting the ability to grow on propanediol and those that affect the expression of the first enzymes in the fucose pathway were very closely linked. The loss of the ability to grow on fucose is thought to be a mechanistic consequence incidental to the remodeling of the regulatory system in favor of the utilization of the novel carbon source.

Alcohol Oxidoreductases↗

PubMed1982

[Substrate specificity of adenosylcobalamin-dependent glycerol dehydratase. Interaction with enantiomers of 1,2-propanediol].

Adenosylcobalamin-dependent glycerol dehydratase was shown to catalyze the conversion of both enantiomers of 1.2-propanediol. The kinetic constants for the dehydration reaction of (R)- and (S)-1.2-propanediol appear to be different. The enzyme preferentially binds 1.2-propanediol in the (S)-configuration; however, the rate of (S)-1,2-propanediol dehydration is 2 times less than that of (R)-1.2-propanediol. The catalytic conversion of 1.2-propanediol enantiomers is accompanied by the enzyme inactivation. During dehydration of (R)-1.2-propanediol the enzyme is inactivated at a higher rate than during the (S)-enantiomer dehydration. The turnover number of the enzyme calculated as a ratio of the rate constants of catalysis and inactivation does not practically depend on the substrate configuration. Consequently, the changes in the configuration of the substrate, 1.2-propanediol, similarly affect the rate-limiting steps of the catalytic and inactivation processes. It is assumed that the (R)- and (S)-enantiomers of 1.2-propanediol are bound at the substrate site of glycerol dehydratase by three identical points.

Cobamides↗

PubMed1990

Cobalamin-dependent 1,2-propanediol utilization by Salmonella typhimurium.

The enteric bacterium Salmonella typhimurium utilizes 1,2-propanediol as a sole carbon and energy source during aerobic growth, but only when the cells are also provided with cobalamin as a nutritional supplement. This metabolism is mediated by the cobalamin-dependent propanediol dehydratase enzyme pathway. Thirty-three insertion mutants were isolated that lacked the ability to utilize propanediol, but retained the ability to degrade propionate. This phenotype is consistent with specific blocks in one or more steps of the propanediol dehydratase pathway. Enzyme assays confirmed that propanediol dehydratase activity was absent in some of the mutants. Thus, the affected genes were designated pdu (for defects in propanediol utilization). Seventeen mutants carried pdu::lac operon fusions, and these fusions were induced by propanediol in the culture medium. All of the pdu mutations were located in a single region (41 map units) on the S. typhimurium chromosome between the his (histidine biosynthesis) and branch I cob (cobalamin biosynthesis) operons. They were shown to be P22-cotransducible with a branch I cob marker at a mean frequency of 12%. Mutants that carried deletions of the genetic material between his and cob also failed to utilize propanediol as a sole carbon source. Based upon the formation of duplications and deletions between different pairs of his::MudA and pdu::MudA insertions, the pdu genes were transcribed in a clockwise direction relative to the S. typhimurium genetic map.

Chromosome Deletion↗

PubMed1979

Fermentation of 1,2-propanediol with 1,2-ethanediol by some genera of Enterobacteriaceae, involving coenzyme B12-dependent diol dehydratase.

Klebsiella pneumoniae (Aerobacter aerogenes) ATCC 8724 was able to grow anaerobically on 1,2-propanediol and 1,2-ethanediol as carbon and energy sources. Whole cells of the bacterium grown anaerobically on 1,2-propanediol or on glycerol catalyzed conversion of 1,2-diols and aldehydes to the corresponding acids and alcohols. Glucose-grown cells also converted aldehydes, but not 1,2-diols, to acids and alcohols. The presence of activities of coenzyme B(12)-dependent diol dehydratase, alcohol dehydrogenase, coenzyme-A-dependent aldehyde dehydrogenase, phosphotransacetylase, and acetate kinase was demonstrated with crude extracts of 1,2-propanediol-grown cells. The dependence of the levels of these enzymes on growth substrates, together with cofactor requirements in in vitro conversion of these substrates, indicates that 1,2-diols are fermented to the corresponding acids and alcohols via aldehydes, acyl-coenzyme A, and acyl phosphates. This metabolic pathway for 1,2-diol fermentation was also suggested in some other genera of Enterobacteriaceae which were able to grow anaerobically on 1,2-propanediol. When the bacteria were cultivated in a 1,2-propanediol medium not supplemented with cobalt ion, the coenzyme B(12)-dependent conversion of 1,2-diols to aldehydes was the rate-limiting step in this fermentation. This was because the intracellular concentration of coenzyme B(12) was very low in the cells grown in cobalt-deficient medium, since the apoprotein of diol dehydratase was markedly induced in the cells grown in the 1,2-propanediol medium. Better cell yields were obtained when the bacteria were grown anaerobically on 1,2-propanediol. Evidence is presented that aerobically grown cells have a different metabolic pathway for utilizing 1,2-propanediol.

Aerobiosis↗

PubMed2002

PduA is a shell protein of polyhedral organelles involved in coenzyme B(12)-dependent degradation of 1,2-propanediol in Salmonella enterica serovar typhimurium LT2.

Salmonella enterica forms polyhedral organelles involved in coenzyme B(12)-dependent 1,2-propanediol degradation. These organelles are thought to consist of a proteinaceous shell that encases coenzyme B(12)-dependent diol dehydratase and perhaps other enzymes involved in 1,2-propanediol degradation. The function of these organelles is unknown, and no detailed studies of their structure have been reported. Genes needed for organelle formation and for 1,2-propanediol degradation are located at the 1,2-propanediol utilization (pdu) locus, but the specific genes involved in organelle formation have not been identified. Here, we show that the pduA gene encodes a shell protein required for the formation of polyhedral organelles involved in coenzyme B(12)-dependent 1,2-propanediol degradation. A His(6)-PduA fusion protein was purified from a recombinant Escherichia coli strain and used for the preparation of polyclonal antibodies. The anti-PduA antibodies obtained were partially purified by a subtraction procedure and used to demonstrate that the PduA protein localized to the shell of the polyhedral organelles. In addition, electron microscopy studies established that strains with nonpolar pduA mutations were unable to form organelles. These results show that the pduA gene is essential for organelle formation and indicate that the PduA protein is a structural component of the shell of these organelles. Physiological studies of nonpolar pduA mutants were also conducted. Such mutants grew similarly to the wild-type strain at low concentrations of 1,2-propanediol but exhibited a period of interrupted growth in the presence of higher concentrations of this growth substrate. Growth tests also showed that a nonpolar pduA deletion mutant grew faster than the wild-type strain at low vitamin B(12) concentrations. These results suggest that the polyhedral organelles formed by S. enterica during growth on 1,2-propanediol are not involved in the concentration of 1,2-propanediol or coenzyme B(12), but are consistent with the hypothesis that these organelles moderate aldehyde production to minimize toxicity.

Bacterial Proteins↗

PubMed1992

A single regulatory gene integrates control of vitamin B12 synthesis and propanediol degradation.

The cob operon of Salmonella typhimurium encodes enzymes required for synthesis of adenosyl-cobalamin (vitamin B12). The pdu operon encodes enzymes needed for use of propanediol as a carbon source, including an adenosyl-cobalamin-dependent enzyme, propanediol dehydratase. These two operons both map near min 41 of the S. typhimurium linkage map and are transcribed divergently. Here we report that the cob and pdu operons form a single regulon. Transcription of this regulon is induced by either glycerol or propanediol. The metabolism of these compounds is not required for induction. Propanediol induces the regulon either aerobically or anaerobically during growth on poor carbon sources. Aerobically glycerol induces only if its metabolism is prevented by a mutational block such as a glpK mutation. Under anaerobic conditions, glycerol induces in both glpK+ and glpK mutant strains during growth on poor carbon sources. A new class of mutations, pocR, prevents induction of the cob/pdu regulon by either propanediol or glycerol and causes a Cob- Pdu- phenotype. The pocR gene is located between the cob and pdu operons and appears to encode a trans-acting protein that acts as a positive regulator of both operons. Transcription of the pocR regulatory gene is induced, even without the PocR protein, during aerobic growth on poor carbon sources and during anaerobic respiration. With the functional PocR protein, transcription of the pocR gene is autoinduced by propanediol but not by glycerol. The growth conditions that increase pocR gene expression correlate with growth conditions that allow high induction of the cob/pdu regulon. A model for control of this regulon suggests that the PocR protein is a transcriptional activator of both the cob and pdu operons and that both glycerol and propanediol can individually serve as effectors of the PocR protein. We suggest that global control mechanisms cause variation in the level of the PocR protein; an increased level of the PocR protein permits higher induction by propanediol or glycerol.

Bacterial Proteins↗

PubMed1998

Studies of regulation of expression of the propionate (prpBCDE) operon provide insights into how Salmonella typhimurium LT2 integrates its 1,2-propanediol and propionate catabolic pathways.

Expression of the prpBCDE operon of Salmonella typhimurium LT2 required (i) the synthesis of propionyl-coenzyme A (CoA) by the PrpE protein or the acetyl-CoA-synthesizing systems of the cell and (ii) the synthesis of 2-methylcitrate from propionyl-CoA and oxaloacetate by the PrpC protein. We propose that either 2-methylcitrate or a derivative of it signals the presence of propionate in the environment. This as yet unidentified signal is thought to serve as a coregulator of the activity of PrpR, the member of the sigma-54 family of transcriptional activators needed for activation of prpBCDE transcription. The CobB protein was also required for expression of the prpBCDE operon, but its role is less well understood. Expression of the prpBCDE operon in cobB mutants was restored to wild-type levels upon induction of the propanediol utilization (pdu) operon by 1,2-propanediol. This effect did not require catabolism of 1,2-propanediol, suggesting that a Pdu protein, not a catabolite of 1,2-propanediol, was responsible for the observed effect. We explain the existence of these redundant functions in terms of metabolic pathway integration. In an environment with 1,2-propanediol as the sole carbon and energy source, expression of the prpBCDE operon is ensured by the Pdu protein that has CobB-like activity. Since synthesis of this Pdu protein depends on the availability of 1,2-propanediol, the cell solves the problem faced in an environment devoid of 1,2-propanediol where propionate is the sole carbon and energy source by having cobB located outside of the pdu operon and its expression independent of 1,2-propanediol. At present, it is unclear how the CobB and Pdu proteins affect prpBCDE expression.

Acyl Coenzyme A↗

PubMed1992

Rheological measurements of the influence of 1,2-propanediol on actin/alpha-actinin gel structure: the effects of temperature and protein concentrations.

In previous studies, we demonstrated that 1,2-propanediol induces shortening and bundling of actin filaments, both in vitro and in vivo, and that it enhances actin/alpha-actinin interaction, especially at low temperature. 1,2-Propanediol also promotes homogeneous microporous networks which can be vitrified by rapid cooling. In the present study, dynamical rheological measurements were performed under various sets of experimental conditions including temperature (4 or 20 degrees C), protein concentrations (actin and alpha-actinin), and 1,2-propanediol presence or absence. Gelation kinetics were monitored, and the resulting actin mechanical properties investigated, in order to untangle the respective effects of the experimental parameters. Whether in the presence or absence of solvent, low temperature brings about a rigidification of the sample, as does high protein concentration, as expected. However, 1,2-propanediol itself involves either softening of the sample (at high temperature and low protein concentration or at low temperature and high protein concentration) or rigidification in the case of low temperature and low protein concentration. These effects result from the competition between actin/alpha-actinin affinity (enhanced by both low temperature and 1,2-propanediol), bundling of filaments (fostered by alpha-actinin for alpha-actinin/actin ratios used), rate of actin polymerization (higher at high temperature), shortening effect of 1,2-propanediol on actin filaments, and chain mobility (lower at high protein concentration). As discussed, only the combination of low temperature and low protein concentration induces full crosslinking of the system into a viscoelastic solid under the influence of 1,2-propanediol.

Actinin↗

PubMed2000

High production of 1,3-propanediol from industrial glycerol by a newly isolated Clostridium butyricum strain.

Batch and continuous cultures of a newly isolated Clostridium butyricum strain were carried out on industrial glycerol, the major by-product of the bio-diesel production process. For both types of cultures, the conversion yield obtained was around 0.55 g of 1,3-propanediol formed per 1 g of glycerol consumed whereas the highest 1,3-propanediol concentration, achieved during the single-stage continuous cultures was 35-48 g l-1. Moreover, the strain presented a strong tolerance at the inhibitory effect of the 1,3-propanediol, even at high concentrations of this substance at the chemostat (e.g. 80 g l-1). 1,3-Propanediol was associated with cell growth whereas acetate and butyrate seemed non growth-associated products. At low and medium dilution rates (until 0.1 h-1), butyrate production was favoured, whereas at higher rates acetate production increased. The maximum 1,3-propanediol volumetric productivity obtained was 5.5 g l-1 h-1. A two-stage continuous fermentation was also carried out. The first stage presented high 1,3-propanediol volumetric productivity, whereas the second stage (with a lower dilution rate) served to further increase the final product concentration. High 1,3-propanediol concentrations were achieved (41-46 g l-1), with a maximum volumetric productivity of 3.4 g l-1 h-1. A cell concentration decrease was reported between the second and the first fermentor.

Bioreactors↗

PubMed1975

Effect of 1,2-propanediol on the rumen mucosal growth of kids.

Intra-abomasally administered 1,2-propanediol, 150 to 160 g per Japanese meat-type kid in 3 to 4 wk, increased the ratio of rumen to body weight, of rumen to total stomach, and of rumen mucosa to muscle over the control which received only water. Intra-abomasal administration of glycerol, glucose, fructose, 1.3-butanediol, xylitol, lactic acid, sodium propionate, or sodium butyrate showed no increases over the control. Only propanediol chemically stimulated rumen mucosal growth. Intraruminal administration of propanediol showed the same stimulation as intra-abomasal. Intraruminal administration of minerals or of polyethylene glycol (Carbowax 4,000) and intraruminal insertion of plastic cubes were not effective, but the latter showed a cooperative effect to accelerate rumen growth with propanediol stimulation. Average fresh tissue weights of rumen mucosa in kids of 2.7 kg body weight of control, of propanediol-treatment, and of plastic cube plus propanediol-treatment were 6.4, 10.4, and 14.8 g, and those of rumen muscle were 7.9, 8.3, and 11.1 g. Propanediol may be involved directly in the local control of rumen epithelial growth.

Abomasum↗

PubMed1997

Genetic characterization of the pdu operon: use of 1,2-propanediol in Salmonella typhimurium.

Salmonella typhimurium is able to catabolize 1,2-propanediol for use as the sole carbon and energy source; the first enzyme of this pathway requires the cofactor adenosyl cobalamin (Ado-B12). Surprisingly, Salmonella can use propanediol as the sole carbon source only in the presence of oxygen but can synthesize Ado-B12 only anaerobically. To understand this situation, we have studied the pdu operon, which encodes proteins for propanediol degradation. A set of pdu mutants defective in aerobic degradation of propanediol (with exogenous vitamin B12) defines four distinct complementation groups. Mutations in two of these groups (pduC and pduD) eliminate propanediol dehydratase activity. Based on mutant phenotypes, a third complementation group (pduG) appears to encode a cobalamin adenosyl transferase activity. No function has been assigned to the pduJ complementation group. Propionaldehyde dehydrogenase activity is eliminated by mutations in any of the four identified complementation groups, suggesting that this activity may require a complex of proteins encoded by the operon. None of the mutations analyzed affects either of the first two genes of the operon (pduA and pduB), which were identified by DNA sequence analysis. Available data suggest that the pdu operon includes enough DNA for about 15 genes and that the four genetically identified genes are the only ones required for aerobic use of propanediol.

Adenosine↗

PubMed2001

Microbial formation, biotechnological production and applications of 1,2-propanediol.

This short review covers metabolic pathways, genetics and metabolic engineering of 1,2-propanediol formation in microbes. 1,2-Propanediol production by bacteria and yeasts has been known for many years and two general pathways are recognized. One involves the metabolism of deoxyhexoses, where lactaldehyde is formed during the glycolytic reactions and is then reduced to 1,2-propanediol. The second pathway derives from the formation of methylglyoxal from dihydroxyacetonephosphate and its subsequent reduction to 1,2-propanediol. The enzymes involved in the reduction of methylglyoxal can generate isomers of lactaldehyde or acetol, which can be further reduced by specific reductases, giving chiral 1,2-propanediol as the product. The stereospecificity of the enzymes catalyzing the two reduction steps is important in deriving a complete pathway. Through genetic engineering, appropriate combinations of enzymes have been brought together in Escherichia coli and yeast to generate 1,2-propanediol from glucose. The optimization of these strains may yield microbial processes for the production of this widely used chemical.

Bacteria↗

PubMed2005

Metabolic engineering of Clostridium acetobutylicum for the industrial production of 1,3-propanediol from glycerol.

Clostridium butyricum is to our knowledge the best natural 1,3-propanediol producer from glycerol and the only microorganism identified so far to use a coenzyme B12-independent glycerol dehydratase. However, to develop an economical process of 1,3-propanediol production, it would be necessary to improve the strain by a metabolic engineering approach. Unfortunately, no genetic tools are currently available for C. butyricum and all our efforts to develop them have been so far unsuccessful. To obtain a better "vitamin B12-free" biological process, we developed a metabolic engineering strategy with Clostridium acetobutylicum. The 1,3-propanediol pathway from C. butyricum was introduced on a plasmid in several mutants of C. acetobutylicum altered in product formation. The DG1(pSPD5) recombinant strain was the most efficient strain and was further characterized from a physiological and biotechnological point of view. Chemostat cultures of this strain grown on glucose alone produced only acids (acetate, butyrate and lactate) and a high level of hydrogen. In contrast, when glycerol was metabolized in chemostat culture, 1,3-propanediol became the major product, the specific rate of acid formation decreased and a very low level of hydrogen was observed. In a fed-batch culture, the DG1(pSPD5) strain was able to produce 1,3-propanediol at a higher concentration (1104 mM) and productivity than the natural producer C. butyricum VPI 3266. Furthermore, this strain was also successfully used for very long term continuous production of 1,3-propanediol at high volumetric productivity (3 g L-1 h-1) and titer (788 mM).

Cell Culture Techniques↗

PubMed1984

Genetic and structural evidence for the presence of propanediol oxidoreductase isoenzymes in Escherichia coli.

The synthesis of propanediol oxidoreductase, an enzyme permitting the anaerobic metabolism of fucose and rhamnose, has been described as being controlled by the prd locus closely linked to the fuc locus in wild-type cells of Escherichia coli. However, strain AA-787, deleted in the fuc and prd loci, grew anaerobically on rhamnose, displaying propanediol oxidoreductase activity. From the deleted strain we derived a constitutive producer of propanediol oxidoreductase able to grow on 1,2-propanediol by oxidizing the diol to lactaldehyde which was further metabolized to lactate. Transduction experiments showed that this ability to use propanediol was closely linked to the rha locus. Peptide mapping of fucose- and rhamnose-induced propanediol oxidoreductase of wild-type cells established structural differences between the two enzymes, indicating two structural genes, one for each sugar metabolizing system.

Alcohol Oxidoreductases↗

PubMed1978

Evolution of propanediol utilization in Escherichia coli: mutant with improved substrate-scavenging power.

Wild-type strains of Escherichia coli are unable to use L-1,2-propanediol as a carbon and energy source. A series of mutants, able to grow on this compound at progressively faster rates, had been isolated by repeated transfers to a medium containing 20 mM L-1,2-propanediol. These strains synthesize at high constitutive levels a propanediolmicotinamide adenine dinucleotide oxidoreductase, an enzyme serving as a lactaldehyde during L-fucose fermentation by wild type cells. In this study, a mutant that can grow rapidly on the novel carbon source was subjected to further selection in a medium containing L-1,2-propanediol never exceeding 0.5 mM to obtain a derivative that has an increased power to extract the substrate from the medium. The emerging mutant exhibited four changes at the enzymatic level: (i) fuculose 1-phosphate aldolase activity is lost; (ii) the constitutive propanediol oxidoreductase activity is increased in its level; (iii) lactaldehyde dehydrogenase becomes constitutive and shows an elevated specific activity in crude extracts; and (iv) at low concentrations of propanediol, the facilitated diffusion across the cell membrane is enhanced. Changes two to four seem to act in concert in the trapping of propanediol by hastening its rate of entry and conversion to an ionized metabolite, lactate.

Alcohol Oxidoreductases↗

PubMed1981

Metabolism of L-fucose and L-rhamnose in Escherichia coli: differences in induction of propanediol oxidoreductase.

Escherichia coli is capable of growing on L-fucose or L-rhamnose as a sole source of carbon and energy. When grown under anaerobic conditions on either sugar, a nicotinamide adenine dinucleotide-linked L-lactaldehyde:propanediol oxidoreductase activity is induced. The functioning of this enzyme results in the regeneration of oxidized nicotinamide adenine dinucleotide. Conditions of induction of the enzyme activity were studied and were found to display different characteristics on each sugar. In the rhamnose-grown cells, the increase in enzyme activity detected under inducing conditions was accompanied by the synthesis of propanediol oxidoreductase, as measured by the appearance in the extracts of a protein that reacts with propanediol oxidoreductase antibodies. In contrast, in fucose-grown cells, the level of propanediol oxidoreductase as measured by enzyme antibody-reacting material was high under noninducing and inducing conditions. Thus, the increase in enzyme activity detected in going from noninducing to inducing conditions in fucose-grown cells did not depend on the appearance of the specific protein but on the activation of the propanediol oxidoreductase already present in the cells in an inactive form. The propanediol oxidoreductase of both homologous systems should consequently be regulated by different control mechanisms.

Alcohol Oxidoreductases↗