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PubMed1976

Oxidation of methanol by facultative and obligate methylotrophs.

1. The newly isolated methanol obligate Methylomonas sp. and the methanol facultative Pseudomonas sp. oxidize methanol at an unchanged rate over concentration range from 0.1 to 600 mM; the oxidation rate by the obligate methylotroph is 2.5 times higher (300 nmoles O2/min/mg dry wt.). Low-molecular alcohols, formaldehyde and formate serve as respiratory substrates for the intact cells of both methylotrophs. 2. Methanol dehydrogenase of both methylotrophs isolated should be classified as the phenazine methosulphate-dependent pteridine-type enzyme of double methanol-and formaldehyde-dehydrogenase function. This soluble enzyme is stimulated about 10-fold by NH+4, which results in enhancement of V max, and shows the same specificity and the same affinity toward methanol and formaldehyde (K m about 5 X 10(-5) M). Heat-inactivation of the 10-fold purified enzyme is associated with the release of a watersoluble pigment with maximum fluorescence at 420-430 nm. 3. NAD-deendent formate dehydrogenase was found to catalyse the third step of methanol oxidation in both methylotrophs.

Methanol↗
PubMed1993

Methanol toxicity. Agency for Toxic Substances and Disease Registry.

Methanol is used in a variety of commercial and consumer products. Increased use of methanol as a motor fuel may lead to higher ambient air levels and a greater potential for ingestion from siphoning accidents. Methanol toxicity initially is not characterized by severe toxic manifestations. Pathophysiologically, methanol toxicity represents a classic example of "lethal synthesis," in which toxic metabolites can cause fatality after a characteristic latent period. Methanol is well absorbed following inhalation, ingestion or cutaneous exposure. It is oxidized in the liver to formaldehyde, then to formic acid, which contributes to the profound metabolic acidosis occurring in acute methanol poisoning. The metabolic products of methanol can produce a syndrome of delayed-onset acidosis, obtundation, visual disturbance and death. Intravenous sodium bicarbonate therapy should be considered if the patient's blood pH is below 7.2. Symptoms and history determine whether intravenous ethanol therapy and hemodialysis should be instituted.

Acute Disease↗
PubMed1993

[Blood methanol as a marker of alcoholism. A diagnostic component within the scope of expert assessment of driving competence in alcoholic intoxication].

A blood methanol test which was done in addition to routine diagnosis of the blood methanol level of persons with alcohol driving delicts in the past who were alcoholized during the medical-psychological investigation (MPU) produced differently significant cues for (pre) alcoholism in nearly all persons. As a result 15 out of 40 persons reached a blood methanol level of 10 mg% and more (24 more persons a level between 1.5 and 9.9 mg%). This is a clear indicator of pathological alcohol drinking. Persons with a breath alcohol concentration from 0.2 to 0.99/1000 showed an average blood ethanol concentration of less than 10 mg%, but above 1.5 mg%, where as those persons with an alcohol level above this limit had a blood methanol concentration significantly above 10 mg%. The arithmetical mean and the standard deviation were significantly elevated compared to the range of reference, an effect that didn't show as clearly with the median of the Gamma-glutamyltransferase (GGT). The mean corpuscular volume of erythrocytes (MCV) reacted less sensitively. The correlation between the five parametres (blood ethanol at the last alcohol driving delict, breath alcohol concentration, GGT, MCV, blood methanol) were all significantly positive with one exception: the correlation between the breath alcohol and the blood methanol level. Altogether the results support the hypotheses that the protective assertions of the subjects concerned are hard to believe, even those of persons with a lower blood alcohol level. An additional test of the blood methanol level should be done, however, with persons reaching an alcoholization between 0.2 and 1.0/1000 during the MPU.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMedDate not supplied

Comparison of supercritical CHF3 and CO2 and methanol-modified CHF3 and CO2 for extraction of sulfonamides from chicken liver.

Supercritical CHF3 and methanol-modified CHF3 were compared with supercritical CO2 and methanol-modified CO2 for extraction of sulfonamides from fortified chicken liver admixed with Hydromatrix. Results showed that solvating power and selectivity were higher for supercritical and methanol-modified CHF3 than for supercritical and methanol-modified CO2. Visual observation showed that chicken liver extract obtained with methanol-modified CHF3 was cleaner than that obtained with methanol-modified CO2. Fat precipitated in the solvent trap when CO2 was used as the extraction medium. Also, simple off-line collection of fortified chicken liver extract obtained with CO2 in a solid-phase extraction cartridge (packed with either C18 or alumina) followed by phosphate buffer-methanol (50 + 50) rinse yielded an extract that required no further cleanup for analysis.

Animals↗
PubMed1996

Mass methanol poisoning: a clinico-biochemical analysis of 10 cases.

Methanol is a common ingredient in many household products and intoxication can arise easily from inadvertent exposure through ingestion, inhalation or percutaneous absorption. We analysed ten cases of methanol poisoning who presented with visual, neurological and gastrointestinal symptoms, of whom one died and nine were successfully detoxified with ethanol and bicarbonate infusions. Clinical symptoms were not found to correlate with the severity of poisoning. Serum methanol level was found to correlate significantly with arterial pH (correlation coefficient -0.74, p = 0.014) and serum standard bicarbonate levels (correlation coefficient -0.87, p = 0.001). We found that an arterial pH of < 7.33 or a serum standard bicarbonate of < 20 mmol/L correlated well with a serum methanol level of > 45 mg/dL ie severe poisoning (X2 test with Yate's correction factor, p < 0.02). We conclude that arterial pH or serum standard bicarbonate levels can be used as surrogate indicators of the severity of methanol poisoning. They can be used to guide physicians in the method of detoxification (ie whether intravenous or oral ethanol or dialysis should be used) whilst awaiting serum methanol levels in cases where the index of suspicion for methanol poisoning is high. Some cases of severe poisoning can be successfully treated with oral ethanol if the intravenous form is not available.

Bicarbonates↗
PubMed2004

Synergistic effect of methanol extract of Abies webbiana leaves on sleeping time induced by standard sedatives in mice and anti-inflammatory activity of extracts in rats.

During the determination of LD50 values of extracts of Abies webbiana, it was observed that the methanol extract (MEAW) produces sedation of animals. This led to investigation of the effect of MEAW on sleeping time in mice. When various doses of the methanol extract (100, 150, and 200 mg/kg body weight) were administered alone, no hypnotic activity was observed. However, these exhibited significant synergistic effects (P < 0.001) at those dose levels in mice when administered prior to the administration of standard sedatives (pentobarbitone sodium: 50 mg/kg and diazepam: 6 mg/kg, respectively). In addition anti-inflammatory effects of methanol, chloroform, and petroleum ether extracts of Abies webbiana leaves in rats were performed to assess scientific validity of the medicinal claim of Indian folk medicine. The effects of leaf extracts (methanol, chloroform, and petroleum ether) against inflammation were studied by carrageenan-induced paw edema model in rats. The methanol extract (400 mg/kg p.o.) of leaves of Abies webbiana showed the best significant anti-inflammatory activity as compared to that of diclofenac sodium (150 mg/kg p.o.). The LD50 values of methanol, chloroform, and petroleum ether extracts were found to be 986, 1387, and > 3200 mg/kg, respectively. Thus, the therapeutic index of methanol extract may be favorable to open a new vista on combination therapy of hypnotics and may also against inflammation.

Abies↗
PubMed2000

High level secretion of recombinant human serum albumin by fed-batch fermentation of the methylotrophic yeast, Pichia pastoris, based on optimal methanol feeding strategy.

The dynamic programming method was applied to obtain the optimal specific growth rate, mu, in the fed-batch fermentation using the recombinant human serum albumin (rHSA)-producing yeast, Pichia pastoris. Based on the relationship between the specific production rate, varrho, and the specific growth rate, mu, a simple mathematical model describing the growth and rHSA production was constructed and used for calculations. Two constraints, final volume and maximum methanol feed rate, were adopted for calculations and the optimal mu resulted as follows. That is, mu was initially at the maximum value, mu(max), then decreased gradually. Finally, mu decreased to the mu(min) that gave a maximum varrho. The decline of mu was revealed to be caused by the constraint for maximum methanol feeding rate, F(max), and F(max) was constant until mu decreased to mu(min). We tried to realize the optimal mu in the fed-batch fermentation by manipulating the methanol feeding rate and obtained it. However, the observed varrho was differed from the expected one. The discrepancy between the expected varrho and observed varrho after the change of mu suggests the inapplicability of the relationship between mu and varrho to dynamic situations where mu changes. To confirm this, simulation and fed-batch fermentation runs were carried out at a methanol feeding rate that would cause a continuous change in mu. The rHSA production was simulated well, suggesting the applicability of the relationship between mu and varrho in such situations. Discontinuity in the change in methanol feeding rate of the optimal feed pattern at the time mu changed is considered to be the cause for the discrepancy between the expected and observed varrho. Therefore, a new methanol feeding strategy that could mimic the changes in mu and varrho of the optimal strategy without a discontinuity in the feeding rate was sought using a mathematical model of fermentation by trial and error. This modification in the methanol feeding rate resulted in a considerably improved varrho and 18% increase in total rHSA production compared with those obtained by the optimal strategy.

Journal Article↗
PubMed2006

Kinetics and mechanism of methane, methanol, and dimethyl ether C-H activation with electrophilic platinum complexes.

The relative rates of C-H activation of methane, methanol, and dimethyl ether by [(N-N)PtMe(TFE-d(3))](+) ((N-N) = ArN=C(Me)-C(Me)=NAr; Ar = 3,5-di-tert-butylphenyl, TFE-d(3) = CF(3)CD(2)OD) (2(TFE)) were determined. Methane activation kinetics were conducted by reacting 2(TFE)-(13)C with 300-1000 psi of methane in single-crystal sapphire NMR tubes; clean second-order behavior was obtained (k = 1.6 +/- 0.4 x 10(-3) M(-1) s(-1) at 330 K; k = 2.7 +/- 0.2 x 10(-4) M(-1) s(-1) at 313 K). Addition of methanol to solutions of 2(TFE) rapidly establishes equilibrium between methanol (2(MeOD)) and trifluoroethanol (2(TFE)) adducts, with methanol binding preferentially (K(eq) = 0.0042 +/- 0.0006). C-H activation gives [(N-N)Pt(CH(2)OD)(MeOD)](+) (4), which is unstable and reacts with [(RO)B(C(6)F(5))(3)](-) to generate a pentafluorophenyl platinum complex. Analysis of kinetics data for reaction of 2 with methanol yields k = 2.0 +/- 0.2 x 10(-3) M(-1) s(-1) at 330 K, with a small kinetic isotope effect (k(H)/k(D) = 1.4 +/- 0.1). Reaction of dimethyl ether with 2(TFE) proceeds similarly (K(eq) = 0.023 +/- 0.002, 313 K; k = 5.5 +/- 0.5 x 10(-4) M(-1) s(-1), k(H)/k(D) = 1.5 +/- 0.1); the product obtained is a novel bis(alkylidene)-bridged platinum dimer, [(diimine)Pt(mu-CH(2))(mu-(CH(OCH(3)))Pt(diimine)](2+) (5). Displacement of TFE by a C-H bond appears to be the rate-determining step for all three substrates; comparison of the second-order rate constants (k((methane))/k((methanol)) = 1/1.3, 330 K; k((methane))/k((dimethy)(l e)(ther)) = 1/2.0, 313 K) shows that this step is relatively unselective for the C-H bonds of methane, methanol, or dimethyl ether. This low selectivity agrees with previous estimates for oxidations with aqueous tetrachloroplatinate(II)/hexachloroplatinate(IV), suggesting a similar rate-determining step for those reactions.

Journal Article↗
PubMed2006

Determination of the adsorption isotherm of methanol on the surface of ice. An experimental and grand canonical Monte Carlo simulation study.

The adsorption isotherm of methanol on ice at 200 K has been determined both experimentally and by using the Grand Canonical Monte Carlo computer simulation method. The experimental and simulated isotherms agree well with each other; their deviations can be explained by a small (about 5 K) temperature shift in the simulation data and, possibly, by the non-ideality of the ice surface in the experimental situation. The analysis of the results has revealed that the saturated adsorption layer is monomolecular. At low surface coverage, the adsorption is driven by the methanol-ice interaction; however, at full coverage, methanol-methanol interactions become equally important. Under these conditions, about half of the adsorbed methanol molecules have one hydrogen-bonded water neighbor, and the other half have two hydrogen-bonded water neighbors. The vast majority of the methanols have a hydrogen-bonded methanol neighbor, as well.

Journal Article↗
PubMed2005

Modeling SN2 reactions in methanol solution by ab initio calculation of nucleophile solvent-substrate clusters.

[Structure: see text]. Ab initio calculations were used to study the S(N)2 reactions of the CH3OCH2I molecule with a methoxide ion (CH3O-) and a methanol molecule by systematically building up the reaction system with explicit incorporation of the methanol solvent molecules. For the reaction of CH3OCH2I with a methoxide ion, the explicit incorporation of the methanol molecules to better solvate the methoxide ion led to an increase in the barrier to reaction. For the reaction of CH3OCH2I with a methanol molecule, the explicit incorporation of the methanol molecules led to a decrease in the barrier to reaction because of an inclination of this reaction to proceed with the nucleophilic displacements accompanied by proton transfer through the H-bonding chain. The H-bonding chain served as both acid and base catalysts for the displacement reaction. A ca. 10(15)-fold acceleration of the methanol tetramer incorporated S(N)2 reaction was predicted relative to the corresponding methanol monomer reaction. The properties of the reactions examined are discussed briefly.

Journal Article↗
PubMed2006

Rh-promoted methanol decomposition on cerium oxide thin films.

Methanol adsorption and reaction have been studied on Rh-deposited cerium oxide thin films under UHV conditions using temperature-programmed desorption and synchrotron soft X-ray photoelectron spectroscopy. The methanol behavior was examined as a function of the Ce oxidation state, methanol exposure, and Rh particle size and coverage. When Rh nanoparticles were deposited on the ceria films, methanol decomposed on Rh to CO and H below 200 K. H atoms recombined and desorbed between 200 and 300 K. CO evolved from Rh deposited on fully oxidized ceria between 400 and 500 K. However, on reduced ceria films, the CO on Rh further decomposed to atomic C. Methanol adsorbed on the ceria films deprotonated to form methoxy as the only intermediate on the surface. This methoxy decomposed and desorbed as CO and H2 at higher temperatures regardless of the ceria oxidation state. Compared with the methanol reaction on Rh-free ceria thin films, formaldehyde formation from methoxy was completely suppressed after Rh deposition. Our results indicate that Rh can promote the decomposition of methoxy adsorbed on the ceria and that decomposition of methoxy intermediates occurred at the metal/oxide interfaces. On the other hand, the reduced ceria can promote total methanol decomposition on Rh.

Journal Article↗
PubMed2005

A reflection absorption infrared spectroscopy and density-functional theory investigation of methanol dehydrogenation on Rh(111)V alloy surfaces.

The dehydrogenation reaction of methanol on a Rh(111) surface, a Rh(111)V subsurface alloy, and on a Rh(111)V islands surface has been studied by thermal-desorption spectroscopy, reflection absorption infrared spectroscopy, and density-functional theory calculations. The full monolayer of methanol forms a structure with a special geometry with methanol rows, where two neighboring molecules have different oxygen-rhodium distances. They are close enough to form a H-bonded bilayer structure, with such a configuration, where every second methanol C-O bond is perpendicular to the surface on both Rh(111) and on the Rh(111)V subsurface alloy. The Rh(111)V subsurface alloy is slightly more reactive than the Rh(111) surface which is due to the changes in the electronic structure of the surface leading to slightly different methanol species on the surface. The Rh(111)V islands surface is the most reactive surface which is due to a new reaction mechanism that involves a methanol species stabilized up to about 245 K, partial opening of the methanol C-O bond, and dissociation of the product carbon monoxide. The latter two reactions also lead to a deactivation of the Rh(111)V islands surface.

Journal Article↗
PubMed1993

Corrinoid-Dependent Methyl Transfer Reactions Are Involved in Methanol and 3,4-Dimethoxybenzoate Metabolism by Sporomusa ovata.

Washed and air-oxidized proteins from Sporomusa ovata cleaved the C-O bond of methanol or methoxyaromatics and transferred the methyl to dl-tetrahydrofolate. The reactions strictly required a reductive activation by titanium citrate, catalytic amounts of ATP, and the addition of dl-tetrahydrofolate. Methylcorrinoid-containing proteins carried the methanol methyl, which was transferred to dl-tetrahydrofolate at a specific rate of 120 nmol h mg of protein. Tetrahydrofolate methylation diminished after the addition of 1-iodopropane or when the methyl donor methanol was replaced by 3,4-dimethoxybenzoate. However, whole Sporomusa cells utilize the methoxyl groups of 3,4-dimethoxybenzoate as a carbon source by a sequential O demethylation to 4-hydroxy-3-methoxybenzoate and 3,4-dihydroxybenzoate. The in vitro O demethylation of 3,4-[4-methoxyl-C]dimethoxybenzoate proceeded via two distinct corrinoid-containing proteins to form 5-[C]methyltetrahydrofolate at a specific rate of 200 nmol h mg of protein. Proteins from 3,4-dimethoxybenzoate-grown cells efficiently used methoxybenzoates with vicinal substituents only, but they were unable to activate methanol. These results emphasized that specific enzymes are involved in methanol activation as well as in the activation of various methoxybenzoates and that similar corrinoid-dependent methyl transfer pathways are employed in 5-methyl-tetrahydrofolate formation from these substrates. Methyl-tetrahydrofolate could be demethylated by a distinct methyl transferase. That enzyme activity was present in washed and air-oxidized cell extracts from methanol-grown cells and from 3,4-dimethoxybenzoate-grown cells. It used cob(I)alamin as the methyl acceptor in vitro, which was methylated at a rate of 48 nmol min mg of protein even when ATP was omitted from the assay mixture. This methyl-cob(III)alamin formation made possible a spectrophotometric quantification of the preceding methyl transfers from methanol or methoxybenzoates to dl-tetrahydrofolate.

Journal Article↗
PubMed1988

Identification of putative methanol dehydrogenase (moxF) structural genes in methylotrophs and cloning of moxF genes from Methylococcus capsulatus bath and Methylomonas albus BG8.

An open-reading-frame fragment of a Methylobacterium sp. strain AM1 gene (moxF) encoding a portion of the methanol dehydrogenase structural protein has been used as a hybridization probe to detect similar sequences in a variety of methylotrophic bacteria. This hybridization was used to isolate clones containing putative moxF genes from two obligate methanotrophic bacteria, Methylococcus capsulatus Bath and Methylomonas albus BG8. The identity of these genes was confirmed in two ways. A T7 expression vector was used to produce methanol dehydrogenase protein in Escherichia coli from the cloned genes, and in each case the protein was identified by immunoblotting with antiserum against the Methylomonas albus methanol dehydrogenase. In addition, a moxF mutant of Methylobacterium strain AM1 was complemented to a methanol-positive phenotype that partially restored methanol dehydrogenase activity, using broad-host-range plasmids containing the moxF genes from each methanotroph. The partial complementation of a moxF mutant in a facultative serine pathway methanol utilizer by moxF genes from type I and type X obligate methane utilizers suggests broad functional conservation of the methanol oxidation system among gram-negative methylotrophs.

Alcohol Oxidoreductases↗
PubMed2003

The anaerobic conversion of methanol under thermophilic conditions: pH and bicarbonate dependence.

The thermophilic (55 degrees C) anaerobic conversion of methanol was studied in an unbuffered medium (pH 4+/-0.2) and in a phosphate buffered medium (pH 6.4+/-0.1), in both cases without bicarbonate addition. Our cultivated sludge consortium was unable to degrade methanol under acidic conditions. During the 160 d of continuous operation of an up-flow anaerobic sludge blanket (UASB) reactor (R1), at an organic loading rate (ORL) of 6 gCOD/(l.d) and pH around 4, only 5% of the applied methanol load was consumed and no methane (CH4) was detected. However, hydrogenotrophic methanogens were found to be resistant to exposure to such conditions. At the end of the trial, the hydrogenotrophic methanogenic activity of the sludge was 1.23+/-0.16 gCOD/(gVSS.d) at neutral pH. With methanol as the test substrate, the addition of bicarbonate led to acetate accumulation. A second reactor (R2) was operated for 303 d at OLRs ranging from 5.5 to 25.4 gCOD/(l.d) in order to assess the conversion of methanol at neutral pH (phosphate buffered) in a bicarbonate deprived medium. The reactor performance was poor with a methanol-COD removal capacity limited to about 9.5 gCOD/(l.d). The system appeared to be quite susceptible to any type of disturbance, even at low OLR. The fraction of methanol-COD converted to CH4 and acetate was found to be unaffected by the OLR applied. At the end of the trial, the outcome of the competition was about 50% methanogenesis and 50% homoacetogenesis.

Journal Article↗
PubMed1997

Methanol causes posteriorization of cervical vertebrae in mice.

Inhalation of methanol by pregnant mice before gestation day nine (gd 9) produces fetal skeletal alterations, principally in the cervical region. The appearance of these defects suggests homeotic shifts in segment identity, patterning, or both. To explore this possibility, detailed morphological analyses of the effects of methanol on fetal skeletal development were done. Pregnant mice were gavaged with 0, 4.0, or 5.0 g/kg methanol (MeOH) split in two doses on gd 7, the most sensitive day for induction of skeletal alterations with methanol. Dams were killed on gd 18 and the fetuses were counted, weighed, and examined externally. Fetuses were double stained with alcian blue and alizarin red for examination of cartilaginous and ossified vertebral and rib characteristics, and in selected fetuses cervical vertebrae were disarticulated for more detailed analysis. Observations indicative of methanol-induced homeotic transformations were as follows: [tabular data: see abstract volume] Examination of disarticulated vertebrae revealed foramina and other distinguishing characteristics on vertebrae anterior to those on which they normally appear. These results demonstrate that maternal methanol exposure can alter segment patterning in the developing mouse embryo, producing posteriorization of cervical vertebrae.

Abnormalities, Drug-Induced↗
PubMed2003

Effects of methanol concentration on expression levels of recombinant protein in fed-batch cultures of Pichia methanolica.

The methylotrophic yeast Pichia methanolica can be used to express recombinant genes at high levels under the control of the methanol-inducible alcohol oxidase (AUG1) promoter. Methanol concentrations during the induction phase directly affect cellular growth and protein yield. Various methanol concentrations controlled by an on-line monitoring and control system were investigated in mixed glucose/methanol fed-batch cultures of P. methanolica expressing the human transferrin N-lobe protein. The PMAD18 P. methanolica strain utilized is a knock-out for the chromosomal AUG1 gene locus, resulting in a slow methanol utilization phenotype. Maximum growth of 100 g of dry cell weight per liter of culture was observed in cultures grown at 1.0% (v/v) methanol concentration. Maximum recombinant gene expression was observed for cultures controlled at 0.7% (v/v) methanol concentration, resulting in maximum volumetric production of 450 mg of transferrin per liter after 72 h of elapsed fermentation time.

Bioreactors↗
PubMed2004

Methanol induction optimization for scFv antibody fragment production in Pichia pastoris.

Fibronectin splice variant ED B (extracellular domain B) is a promising marker for angiogenesis in growing solid tumors. Currently, recombinant antibodies against ED B are being investigated concerning their potential use, for either therapeutic or diagnostic purposes. Single-chain antibody fragments directed against the ED B can be efficiently expressed in Pichia pastoris; thus, a recombinant strain of the methylotropic yeast P. pastoris was used for this work. Three different forms of scFv antibody fragment are found in the supernatant from this fermentation: covalent homodimer, associative homodimer, and monomer. Both homodimeric forms can be converted to the monomeric form (under reducing conditions) and be efficiently radiolabeled, whereas the monomeric form of scFv already present in the supernatant cannot. It was also found that the fraction of protein in the monomeric form is highly dependent on the mode of induction rather than scFv concentration. This suggests that the monomeric form of the scFv present in the supernatant might be a result of events occurring at the expression, secretion, or folding level. A high cell density fermentation protocol was developed by optimizing methanol induction, yielding the highest scFv antibody fragment production rate and product quality; cell concentration at the induction point and specific methanol uptake rate were found to be the most important control variables. A decrease in specific methanol uptake rate led to a higher specific production rate for the scFv antibody fragment (5.4 microg g(cell) h(-1)). Product quality, i.e., percentage of product in a homodimeric form, also increased with the decrease in methanol uptake rate. Furthermore, the volumetric productivity depended on cell concentration at the induction point, increasing with the increase of cell concentration up to 320 g L(-1) wet cell weight (WCW). The reduction of the methanol feeding rate for induction, and consequently of the oxygen uptake rate, have important consequences for optimizing product titers and quality and thus on the scale-up of this production process; hence one of the major limitations upon high cell density cultivation in bioreactors is keeping the high oxygen transfer rate required. From the results obtained, a scale-up strategy was developed based on the available oxygen transfer rates at larger scales, allowing the definition of the optimum biomass concentration for induction and methanol feeding strategy for maximization of product titer and quality.

Cell Division↗