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PubMed1995

Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities.

Lactate dehydrogenase M-subunit deficiency was first reported 1980 as an exertional myoglobinuria. Since then, 6 Japanese and 3 Caucasian families have been reported. Also, typical skin lesions were observed in 1 Japanese patient. Since then, 2 families, one Japanese and one Caucasian, have been found with this typical skin eruption. The metabolic background of exertional myoglobinuria was demonstrated as a result of the impaired reoxidation of NADH produced by glyceraldehyde-3-phosphate-dehydrogenase (G3PD) action. The excess NADH was partly reoxidized by the action of alpha-glycerophosphate dehydrogenase abundant in cytosolic fraction of skeletal muscle. This enzyme reoxidizes excess NADH simultaneously draining out triose phosphate from the glycolytic pathway. Abortive glycolysis results in impaired ATP production followed by rhabdomyolysis. Genomic analysis revealed the heterogeneities of the mutations of this disease.

Adolescent↗
PubMed1981

Characterization of potato (Solanum tuberosum)lactate dehydrogenase isoenzymes by affinity chromatography and hybridization.

The five isoenzymes of potato (Solanum tuberasum) lactate dehydrogenase have been resolved by affinity chromatography. Mixtures of isoenzymes LDH-1 and LDH-5 dissociate and reassociate during freezing and thawing to produce five isoenzymes. These results indicate that potato lactate dehydrogenase isoenzymes are primary isoenzymes of the vertebrate type, which are composed of two subunit types.

Chemical Phenomena↗
PubMed2001

Lipopeptide adjuvants: generation of lactate dehydrogenase isoenzyme-specific antibodies for immunochemical diagnosis.

Lactate dehydrogenase catalyzes the final step in glycolysis, the interconversion of pyruvate and lactate. The tetrameric enzyme is composed of one or two subunits (H and/or M) resulting in five isoenzyme forms: LDH-H4, -H3M1, -H2M2, -H1M3, and -M4. The relative distribution of the LDH isoenzymes is tissue dependent and a significant marker for the diagnosis of hepatoma of the liver, myocardial infarction, muscular dystrophy, and a wide variety of other acute and chronic diseases to be detected by alterations of the LDH isoenzyme pattern in serum. Immunochemical approaches to the routine determination of LDH depend on isoenzyme specific antibodies. Since the H- and M-subunits for human LDH are highly homologous, LDH isoenzyme specific antibodies for immunochemical monitoring are hard to generate. Here we present data on the generation and characterization of LDH isoenzyme-specific mono- and polyclonal antibodies in different species in the presence of lipopeptide adjuvants. Western-Blot and ELISA analysis showed that antisera and monoclonal antibodies recognize their homologous antigens with high specificity and are therefore suitable for immunochemical monitoring of the LDH isoenzymes H4 and M4. In addition, they can be used for the determination of LDH isoenzyme specific activity which is an essential prerequisite for online amperometric immunosensor monitoring.

Adjuvants, Immunologic↗
PubMed1980

Effect of lactate dehydrogenase virus on chemically induced mouse lung tumorigenesis.

Lactate dehydrogenase virus is the third in a series of viruses which have been examined for the capacity to alter chemically induced mouse lung tumorigenesis. This virus was given to strain A mice by i.p. injection either 4 weeks before, on the same days as, 4 weeks after, or 8 weeks after the s.c. injection of urethan (either 0.25 or 1.0 mg/g). The pulmonary adenoma response to urethan was suppressed in all of the lactate dehydrogenase-infected mice, with a maximum suppression of 30 to 40% when the virus was given simultaneously with or 4 weeks after urethan. As with murine sarcoma virus and reovirus, it is postulated that this suppression of chemically induced mouse lung tumorigenesis is due to virally induced alterations in the immune response of the mouse to chemically induced tumors.

Adenoma↗
PubMed1994

Allosteric activation in Bacillus stearothermophilus lactate dehydrogenase investigated by an X-ray crystallographic analysis of a mutant designed to prevent tetramerization of the enzyme.

The crystal structure of a mutant Bacillus stearothermophilus lactate dehydrogenase, into which an additional loop has been engineered in order to prevent tetramerization of the enzyme, has been solved and refined at 2.4 A. The minimal repeat unit in the crystal is a dimer and the tetramer cannot be generated by any of the crystallographic symmetry operations in P2(1). The loop protrudes out into the solvent, stabilized by a good hydrogen bonding arrangement, and clearly sterically hinders tetramer formation. This is the first structure of B. stearothermophilus lactate dehydrogenase (bsLDH) in which the allosteric activator fructose, 1,6-bisphosphate (FBP) is not present. To investigate the mechanism of allosteric activation in this enzyme we have compared the structure with a ternary complex of B. stearothermophilus lactate dehydrogenase. Many of our observations confirm those reported from a comparison of FBP-bound ternary bsLDH complex with an FBP free LDH from another bacterial source, Bifidobacterium longum. Our results suggest that quaternary structural alterations may have less influence on the mechanism than previously reported. The differences in the quaternary structural behaviour of these two enzymes is discussed.

Allosteric Regulation↗
PubMed1978

[Cytology, lactate dehydrogenase, and creatine kinase in CSF in mild head injuries (author's transl)].

Cytology, lactate dehydrogenase, and creatine kinase in cerebrospinal fluid were investigated 6-72h after mild head injuries in 59 patients aged 16-49 years. Significant differences were not found in creatine kinase. Lactate dehydrogenase, however, was significantly more elevated in mild cerebral contusions compared with concussions 24h after head injury. Monocytoid reaction in cerebrospinal fluid was significantly more distinct in mild contusions compared with concussions 24h after impact. Large phagocytes were rarely found in concussions and were not traceable 48h after impact. Large phagocytes, however, were found in 50-55% of the mild contusions 48-72h after head injury. Siderophages were found only in contusions (16.5-35%), 48-72h after impact). The optimal time for lumbar punction is 24h after head injury.

Adolescent↗
PubMed2000

Tumor induction by the c-Myc target genes rcl and lactate dehydrogenase A.

The characterization of c-Myc target genes, such as rcl and lactate dehydrogenase A (LDH-A), is critical for understanding the mechanisms of c-Myc-induced cell transformation and tumorigenesis. We have previously demonstrated that Rcl induces anchorage-independent growth in Ratla fibroblasts and that LDH-A is required for cell transformation by c-Myc. In this study, we report that Rcl and LDH-A act synergistically to induce anchorage-independent growth. Cells expressing both Rcl and LDH-A form tumors after s.c. injection into nude mice, although neither Rcl or LDH-A overexpression alone induces tumorigenesis. The inability of Rcl and LDH-A to fully recapitulate c-Myc activity, however, indicates that other c-Myc target genes participate in tumorigenesis. In addition, cells that coexpress Rcl and vascular endothelial growth factor are more comparable with c-Myc overexpressing cells in their ability to form tumors in nude mice. These findings confirm Rcl and LDH-A as critical components of the cell transformation program induced by c-Myc and suggest that Rcl is tumorigenic in cells that are provided with a permissive metabolic milieu.

Animals↗
PubMedDate not supplied

[Lactate dehydrogenase and glucose-6-phosphate dehydrogenase activity in the erythrocytes in diabetes mellitus].

In human erythrocytes activities of glucose-6-phosphate and lactate dehydrogenases were decreased approximately 2-fold in moderately severe and critical forms of diabetes mellitus, as compared with normal state. The lactate dehydrogenase activity was more distinctly decreased than the glucose-6-phosphate dehydrogenase activity. General medical treatment increased the activity of the enzymes (which catalyzed the ATP formation in erythrocytes) and normalized their relation.

Adolescent↗
PubMed1999

Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase.

Although the molecular mechanism by which chloroquine exerts its effects on the malarial parasite Plasmodium falciparum remains unclear, the drug has previously been found to interact specifically with the glycolytic enzyme lactate dehydrogenase from the parasite. In this study we have determined the crystal structure of the complex between chloroquine and P. falciparum lactate dehydrogenase. The bound chloroquine is clearly seen within the NADH binding pocket of the enzyme, occupying a position similar to that of the adenyl ring of the cofactor. Chloroquine hence competes with NADH for binding to the enzyme, acting as a competitive inhibitor for this critical glycolytic enzyme. Specific interactions between the drug and amino acids unique to the malarial form of the enzyme suggest this binding is selective. Inhibition studies confirm that chloroquine acts as a weak inhibitor of lactate dehydrogenase, with mild selectivity for the parasite enzyme. As chloroquine has been shown to accumulate to millimolar concentrations within the food vacuole in the gut of the parasite, even low levels of inhibition may contribute to the biological efficacy of the drug. The structure of this enzyme-inhibitor complex provides a template from which the quinoline moiety might be modified to develop more efficient inhibitors of the enzyme.

Animals↗
PubMed1977

Differential scanning calorimetry of the thermal denaturation of lactate dehydrogenase.

1. Differential scanning calorimetry has been used to study the thermal denaturation of lactate dehydrogenase. At pH 7.0 in 0.1 M potassium phosphate buffer, only one transition was observed. Both the enthalpy of denaturation and the melting temperature are linear function of heating rate. The enthalpy is 430 kcal/mol and the melting temperature 61 degrees C at 0 degrees C/min heating rate. The ratio of the calorimetric heat to the effective enthalpy indicated that the denaturation is highly cooperative. Subunit association does not appear to significantly contribute to the enthalpy of denaturation. 2. Both cofactor and sucrose addition stabilized the protein against thermal denaturation. Pyruvate addition produced no changes. Only a small time-dependent destabilization was observed at low concentrations of urea. Large effects were observed in concentrated NaCl solutions and with sulfhydryl-modified lactate dehydrogenase.

Animals↗
PubMed1969

Multiple forms of lactate dehydrogenase in Staphylococcus aureus.

Activities for nicotinamide adenine dinucleotide (NAD)-dependent and NAD-independent forms of lactate dehydrogenase (LDH) were measured in cell-free extracts of Staphylococcus aureus strain PS 6 for the d and l isomers of lactate. Data obtained for the NAD-dependent lactate dehydrogenases indicate that oxidation of both isomers of lactate is due to both an l-lactate-specific LDH and a lactate racemase. After acrylamide gel electrophoresis, two bands exhibiting LDH activity were detected in crude or in partially purified cell-free extracts. The fast band exhibited LDH activity that was not NAD-dependent for both isomers of lactate, whereas, the slow band had very high NAD-dependent LDH activity for the l isomer but just detectable activity or the d isomer. Both bands appeared when d-lactate was used as the substrate, but only the slow band was formed when l-lactate was the substrate. NAD-dependent LDH, in apparent association with a nonspecific tetrazolium-reducing protein, is responsible for the production of the slow band.

Cell-Free System↗
PubMed1984

Kinetic characterization of the lactate dehydrogenase (LDH-B4) allozymes of Fundulus heteroclitus.

In order to evaluate whether functional differences exist between allelic variants (allozymes) of the B-type lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 1.1.1.27) in the fish Fundulus heteroclitus, the kinetic properties were examined. Differences in product inhibition between allelic isozymes were observed. LDH-Bb4 was found to be inhibited by lower concentrations of both lactate and pyruvate than either LDH-Ba/Bb or LDH-Ba4. While the pH and temperature dependence for maximal catalysis (Vmax) in both the forward and reverse directions were indistinguishable among the allozymes, reaction velocities at low substrate concentrations (Vmax/Km) were significantly different. These differences could be explained by LDH-Bb4 having a greater substrate affinity than LDH-Ba4 at cold temperatures while the reverse was true at elevated temperatures. At a given pH, LDH-Bb4 showed a greater reaction rate at lower temperatures (e.g. 10 degrees C) than LDH-Ba4. The phenomenon was reversed at higher temperatures (e.g. greater than 35 degrees C). When reaction rates were compared at constant relative alkalinity, that is, a constant [OH-]/[H+] ratio, similar findings were obtained. The response for the heterozygous allozyme, LDH-Ba/Bb, was not the arithmetic average of the two homotetrameric allozymes. The biological significance of these allozymic differences is discussed.

Alleles↗
PubMed1991

Inactive and temperature-sensitive folding mutants generated by tryptophan substitutions in the membrane-bound d-lactate dehydrogenase of Escherichia coli.

A combination of site-specific mutagenesis and 19F nuclear magnetic resonance has been used to investigate the structural properties of D-lactate dehydrogenase, a membrane-associated enzyme of Escherichia coli. The protein (65,000 Da) has been labeled with 5-fluorotryptophan for 19F nuclear magnetic resonance studies. Tryptophan has been substituted for individual phenylalanine, tyrosine, isoleucine, and leucine residues at various positions throughout the enzyme molecule, and the fluorinated native and substituted tryptophan residues have been used as probes of the local environment. All 24 mutants thus generated are expressed in E. coli. Ten are fully active and purfiable following the usual procedure, while 14 either are inactive or produce low levels of activity. The amount of active enzyme produced from the low-yield mutants is dependent on the temperature at which synthesis is carried out, with more active enzyme produced at 18 degrees C than at 27, 35, or 42 degrees C. Cells grown at 27 degrees C and then incubated at 42 degrees C retain 90-100% of their activity. All of the expressed protein from the inactive mutants is Triton-insoluble, aggregated, and not readily purfiable; the inactive mutant protein appears to be improperly folded. Most of the expressed D-lactate dehydrogenase from the partially active mutants is also Triton-insoluble; a small fraction, however, is soluble in Triton and can be purified to yield active enzyme. All the purified enzymes from these low-yield mutants of D-lactate dehydrogenase have essentially normal VmaxS, and all but two have normal KmS. Once purified, the low-yield mutant enzymes are stable at 42 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane↗
PubMed1983

ATP, ADP and AMP on the regulation of lactate dehydrogenase activity of Phycomyces blakesleeanus.

1. The inhibition of ATP, ADP and AMP on lactate dehydrogenase activity from Phycomyces blakesleeanus was investigated kinetically at pH 6.0 and 7.5. 2. At pH 6.0 ATP was more effective as inhibitor than ADP and AMP. 3. All three nucleotides bind cooperatively to the enzyme, ATP and ADP decrease the positive homotropic interactions of NADH at pH 6.0. 4. The results obtained may contribute to explain the regulation of lactate dehydrogenase from Phycomyces blakesleeanus at acid pH values.

Adenosine Diphosphate↗
PubMedDate not supplied

[Regulation of enzyme activity in adsorptive enzyme systems. II. Influence of dextran sulfate on catalytic properties of lactate dehydrogenase (isozyme M4)].

It has been shown that the binding of pig skeletal muscle lactate dehydrogenase (isozyme M4) by dextran sulfate with weight-average molecular weight 500 000 is accompanied by a decrease of the rate of enzymatic reduction of pyruvate. The hyperbolic dependence of the enzymic reaction rate on NADH concentration observed for free lactate dehydrogenase is transformed in a sigmoidal curve in the case of adsorbed enzyme form (Hill's coefficient is equal to 2.1). The experimental data have been described quantitatively using the model of adsorptive enzyme system where the enzyme interacts reversibly with the support and co-operative interaction of substrate binding sites in the adsorbed enzyme molecule are realized. It is assumed that the value of microscopic dissociation constant for the complex of the substrate with adsorbed enzyme is being changed by a constant factor during saturation of the binding sites by the substrate in the enzyme molecule. The value of parameters of the model for the adsorptive enzyme system under study are determined.

Animals↗
PubMed1975

[Aging of rat liver lactate dehydrogenase and cell renewal].

We have shown the presence of a "Cross Reacting Material" for Lactate Dehydrogenase in liver of very old rats. Partial hepatectomy, followed by hepatic regeneration increases the specific activity of the enzyme, which becomes equal to that of Lactate Dehydrogenase of rat liver. Consequently, aging seems to be a cellular phenomenon and not a consequence of the accumulation of errors in transcription or translation.

Aging↗
PubMed1987

A strong carboxylate-arginine interaction is important in substrate orientation and recognition in lactate dehydrogenase.

Using site-directed mutagenesis, Arginine-171 at the substrate-binding site of Bacillus stearothermophilus, lactate dehydrogenase has been replaced by lysine. In the closely homologous eukaryotic lactate dehydrogenase, this residue binds the carboxylate group of the substrate by forming a planar bifurcated bond. The mutation diminishes the binding energy of pyruvate, alpha-ketobutyrate and alpha-ketovalerate (measured by kcat/Km) by the same amount (about 6 kcal/mol). For each additional methylene group on the substrate, there is a loss of about 1.5 kcal/mol of binding energy in both mutant and wild-type enzymes. From these parallel trends in the two forms of enzyme, we infer that the mode of productive substrate binding is identical in each, the only difference being the loss of a strong carboxylate-guanidinium interaction in the mutant. In contrast to this simple pattern in kcat/Km, the Km alone increases with substrate-size in the wild-type enzyme, but decreases in the mutant. These results can be most simply explained by the occurrence of relatively tight unproductive enzyme-substrate complexes in the mutant enzyme as the substrate alkyl chain is extended. This does not occur in the wild-type enzyme, because the strong orienting effect of Arg-171 maximizes the frequency of substrates binding in the correct alignment.

Arginine↗