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PubMed1980

Studies on the active center of D- and L-lactate dehydrogenases using oxamate-diaminohexyl-Sepharose affinity chromatography.

Vertebrate and invertebrate L-lactate dehydrogenases (L-lactate:NAD+ oxidoreductase, EC 1.1.1.27) are effectively bound to oxamate-diaminohexyl-Sepharose, whereas several D-lactate dehydrogenases (D-lactate:NAD+ oxidoreductase, EC 1.1.1.28) do not bind to the same Sepharose. One explanation for our findings is that the enzymes' substrate is oriented in a reversed manner in the active center of the D- and L-lactate dehydrogenases.

Animals↗
PubMed1990

Structure determination and refinement of Bacillus stearothermophilus lactate dehydrogenase.

Structures have been determined of Bacillus stearothermophilus "apo" and holo lactate dehydrogenase. The holo-enzyme had been co-crystallized with the activator fructose 1,6-bisphosphate. The "apo" lactate dehydrogenase structure was solved by use of the known apo-M4 dogfish lactate dehydrogenase molecule as a starting model. Phases were refined and extended from 4 A to 3 A resolution by means of the noncrystallographic molecular 222 symmetry. The R-factor was reduced to 28.7%, using 2.8 A resolution data, in a restrained least-squares refinement in which the molecular symmetry was imposed as a constraint. A low occupancy of coenzyme was found in each of the four subunits of the "apo"-enzyme. Further refinement proceeded with the isomorphous holo-enzyme from Bacillus stearothermophilus. After removing the noncrystallographic constraints, the R-factor dropped from 30.3% to a final value of 26.0% with a 0.019 A and 1.7 degrees r.m.s. deviation from idealized bond lengths and angles, respectively. Two sulfate ions per subunit were included in the final model of the "apo"-form--one at the substrate binding site and one close to the molecular P-axis near the location of the fructose 1,6-bisphosphate activator. The final model of the holo-enzyme incorporated two sulfate ions per subunit, one at the substrate binding site and another close to the R-axis. One nicotinamide adenine dinucleotide coenzyme molecule per subunit and two fructose 1,6-bisphosphate molecules per tetramer were also included. The phosphate positions of fructose 1,6-bisphosphate are close to the sulfate ion near the P-axis in the "apo" model. This structure represents the first reported refined model of an allosteric activated lactate dehydrogenase. The structure of the activated holo-enzyme showed far greater similarity to the ternary complex of dogfish M4 lactate dehydrogenase with nicotinamide adenine dinucleotide and oxamate than to apo-M4 dogfish lactate dehydrogenase. The conformations of nicotinamide adenine dinucleotide and fructose 1,6-bisphosphate were also analyzed.

Amino Acid Sequence↗
PubMed1966

D(-)-lactate dehydrogenase in lower fungi.

A lactate dehydrogenase, specific for nicotinamide-adenine dinucleotide and D(-)-lactate, has been detected in extracts from two fungi of the order Leptomitales (Oomycetes). Several fungi of this order carry out a lactic acid fermentation under conditions of reduced oxygen tension.

Chemical Phenomena↗
PubMed1984

Mechanism of platelet interference with measurement of lactate dehydrogenase activity in plasma.

Platelets reportedly inhibit lactate dehydrogenase activity in plasma under reaction conditions of low osmolality. We describe observations inconsistent with these reports, and we attribute this "inhibition" to optical interference by platelets during the course of a reaction. We conclude that when platelet lysis is prevented and the optical interference of platelets corrected, platelet-rich plasma, platelet-poor plasma, and serum show essentially the same lactate dehydrogenase activity. Furthermore, platelet contamination can cause unexpected problems when lactate dehydrogenase is assayed with centrifugal analyzers. Results can be high or low, depending on the volume of diluent pipetted with the sample, and extreme within-run variations in activity are possible. When plasma is used instead of serum for routine analyses, regular checks for platelet contamination should be performed as a quality-control procedure, especially by laboratories separating plasma with bench-top centrifuges. Platelets can also interfere optically with assay of other enzymes and metabolites.

Blood Platelets↗
PubMed1981

Stability of lactate dehydrogenases. I. Chemical modification of lysines.

The lysine residues of lactate dehydrogenase (L-lactate: NAD+ oxidoreductase, EC 1.1.1.27) can be amidinated by methyl-4-hydroxy-3-nitrobenzimidate to introduce nitrophenolate anions. This modification results in lowered thermal stability, as does acetylation. The conversion of these groups into uncharged aminophenol groups without further modification of the enzyme itself stabilizes the enzymes from pig heart and muscle and from chicken muscle, as does acetamidination, but the unusually stable enzyme from chicken heart reverts only to the stability of the native form. The results allow for the following conclusions. Destabilization is brought about at many points at the surface of lactate dehydrogenases by neutralization of positive charges. Stabilization, in contrast, is concluded to be due to modification of one lysine at position 241 of the sequence. This lysine must have been changed to arginine during the evolution of heart-type lactate dehydrogenases in going from lower to higher reptiles. This exchange has been conserved in the enzymes from the hearts of birds and therefore the enzyme from chicken heart is very stable and cannot further be stabilized by modification of lysines. From X-ray structure analysis, the stabilization by exchange of Arg for Lys at position 241 or by amidination is explained by the formation of additional ion pairs with aspartic acid57 of the Q-related subunits.

Animals↗
PubMed1980

Cerebrospinal fluid lactate dehydrogenase in infants with perinatal asphyxia.

Cerebrospinal fluid (CSF) lactate dehydrogenase was determined in 19 control infants without asphyxia (Group I), 24 infants with perinatal asphyxia (Group II), and 26 asphyxiated infants with seizures (Group III). Mean birthweights, gestational ages, CSF glucose, protein and red blood cells, and the ages at which the lumbar punctures were performed were not significantly different among the three groups. Mean CSF lactate dehydrogenase was significantly higher in Group III than in Groups I and II. Isoenzyme patterns indicated that the origin of the CSF lactate dehydrogenase was neuronal tissue, or a plasma transudate from increased permeability of the blood-brain barrier. There were 10 deaths due to anoxic encephalopathy in Group III, but none in Groups I or II. Follow-up of survivors at 10 to 30 months of age revealed neurological sequelae in three infants in Group I, two in Group II and five in Group III. Mean CSF lactate dehydrogenase in those with sequelae had not been significantly different from that of normal survivors; however, the mean was significantly higher in infants who died with anoxic encephalopathy compared with normal infants. These data indicate that CSF lactate dehydrogenase is significantly elevated in infants with fatal anoxic brain damage, and suggest that determinations may be of prognostic value in non-fatal cerebral hypoxia.

Asphyxia Neonatorum↗
PubMed1989

Inhibition of endogenous oxalate production: biochemical considerations of the roles of glycollate oxidase and lactate dehydrogenase.

1. Both the peroxisomal, flavin-linked glycollate oxidase [(S)-2-hydroxy-acid oxidase; EC 1.1.3.15] and the cytosolic, nicotinamide-adenine dinucleotide (NAD)-linked lactate dehydrogenase (L-lactate dehydrogenase; EC 1.1.1.27) are thought to contribute to the formation of oxalate from its immediate precursors, glycollate and glyoxylate, but the relative contributions of each enzyme to endogenous oxalate production is not known. 2. In rat liver homogenates, [14C]oxalate production from labelled glycollate is halved and that from labelled glyoxylate is increased fourfold by the addition of either NAD or NADH. 3. In isolated rat hepatocytes, the 3-hydroxy-1H-pyrrole-2,5-dione derivatives of glycollate, which are specific inhibitors of glycollate oxidase, have a greater effect on glycollate metabolism than on glyoxylate metabolism. 4. These findings are consistent with an important role for lactate dehydrogenase in oxalate formation from glyoxylate. 5. With human and rat liver homogenates and with purified human liver glycollate oxidase and rabbit muscle lactate dehydrogenase, DL-phenyl-lactate (2 mmol/l) completely inhibits glycollate oxidase but has not effect on lactate dehydrogenase. On the other hand, the reduced form of a chemically synthesized, NAD-pyruvate adduct (1 mmol/l) almost completely inhibited lactate dehydrogenase but had no effect on glycollate oxidase. 6. Either alone or in combination, DL-phenyl-lactate and reduced NAD-pyruvate adduct reduce oxalate production from glycollate and glyoxylate in isolated rat hepatocytes, but do not abolish it completely. 7. These findings support a role for another enzyme, probably glycollate dehydrogenase (EC 1.1.99.14), in oxalate production in integrated cell metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Oxidoreductases↗
PubMed1994

Population screening of lactate dehydrogenase deficiencies in Fukuoka Prefecture in Japan and molecular characterization of three independent mutations in the lactate dehydrogenase-B(H) gene.

Screening for lactate dehydrogenase (LDH) subunit deficiencies was performed on 2880 blood samples from healthy individuals in the Fukuoka Prefecture in Japan by means of electrophoresis. The frequencies of heterozygotes with either LDH-A or LDH-B deficiency were found to be 0.104% at each locus. These estimated frequencies of either LDH-A or LDH-B deficiencies were slightly lower than, but not significantly different from, those found previously in Shizuoka Prefecture. The genetic mutations in individuals heterozygous for LDH-B deficiency were analyzed by the polymerase chain reaction and DNA conformation polymorphism. Abnormal migration patterns were observed in individuals heterozygous for LDH-B deficiency. Subsequent sequence determination of the mutant alleles revealed three novel mutations: an eight-base duplication in exon 3, a four-base duplication in exon 4, and a one-base deletion in exon 7 of the LDH-B gene. These three mutations result in frame-shift translation and premature termination. In addition, the mutations resulting in the duplication of eight or four nucleotides appear to cause a decrease in the levels of LDH-B mRNA.

Amino Acid Sequence↗
PubMedDate not supplied

[Effect of ultraviolet irradiation on properties and physicochemical properties of lactate dehydrogenase].

Catalytic and some physicochemical properties of lactate dehydrogenase have been studied as affected by UV-irradiation. The degree of lactate dehydrogenase inactivation has been determined both at UV-irradiation of a free enzyme and of the enzyme in complex with NADH. It is shown that at pH 7.4 NADH makes a photosensitizing effect on the enzyme. Based on the analysis of changes in the absorption spectrum and molecular weight of lactate dehydrogenase caused by UV-irradiation it is supposed that this irradiation induces the process of unrolling-rolling up of the protein globule.

Animals↗
PubMed1979

Selective inactivation of lactate dehydrogenase of rat tissues by sodium deoxycholate.

Soluble lactate dehydrogenase (EC 1.1.1.27) extracted from brain, skeletal and cardiac muscle and liver of rats, and purified isoenzymes LDH-1 and LDH-5, were incubated with sodium deoxycholate. Deoxycholate almost totally inactivated isoenzyme LDH-5 (A4), whereas it left isoenzyme LDH-1 (B4) unaffected. Tissue lactate dehydrogenase was inactivated to different degrees depending on the origin of the enzyme. Electrophoretic isoenzyme studies of tissue lactate dehydrogenase showed the loss of activity to be quantitatively related to the overall percentage of subunit A distributed among the homotetramer LDH-5 and the heterotetramers LDH-2, LDH-3 and LDH-4. It was concluded that subunit A of lactate dehydrogenase interacts selectively with deoxycholate, irrespective of its association with subunit B. Distinct changes in electrophoretic mobilities of deoxycholate-treated isoenzymes strongly indicated an indiscriminate binding of deoxycholate by all LDH isoenzymes, probably through hydrophobic interactions. The results suggest that the inactivation of the enzyme is non-competitive, but the basis of the selectivity of deoxycholate towards subunit A is not known at present.

Animals↗
PubMed1987

Immunoglobulin A (lambda chains) conjugated with lactate dehydrogenase in serum.

An atypical pattern for lactate dehydrogenase (EC 1.1.1.27) isoenzymes in a patient with sclerosis of the bladder neck was ascribable to complexing between lactate dehydrogenase and IgA. This complex formation was also replicable "in vitro." We determined that the IgA bound to lactate dehydrogenase was of the lambda type, a very unusual occurrence.

Humans↗
PubMed1994

Effects of nitrate respiration on expression of the Arc-controlled operons encoding succinate dehydrogenase and flavin-linked L-lactate dehydrogenase.

Expression of sdhCDAB (encoding succinate dehydrogenase) and lctD (encoding the flavin-linked L-lactate dehydrogenase) is elevated aerobically and repressed anaerobically in Escherichia coli. The repression is initiated by autophosphorylation of the sensor protein ArcB, followed by phosphoryl group transfer to the regulator ArcA. ArcA-P, a global transcriptional regulator, then prevents sdh and lct expression. The stimulus for ArcB is not O2 deficiency per se. In vitro experiments showed that ArcB phosphorylation is enhanced by pyruvate, D-lactate, acetate, and NADH, the concentrations of which are likely to increase with the lack of an effective exogenous electron sink. In addition to their aerobic function, the two primary dehydrogenases also have roles in anaerobic nitrate respiration. Results presented here indicate that the increase of sdh and lct expression by nitrate depended on its chemical reduction, which in turn diminished the ArcA-P pool. Unexpectedly, a mutation in the fnr gene (encoding a global regulator involved in anaerobic metabolism) also alleviated the anaerobic repressions. Mutations in arcB or arcA were epistatic over that of fnr. Moreover, since this relief was counteracted by pyruvate in the growth medium, Fnr appears to affect formation of stimuli for ArcB. It is possible that Fnr also indirectly affects some of the other members of the arcA modulon, e.g., cyoABCDE (encoding the cytochrome o complex), cydAB (encoding the cytochrome d complex), and sodA (encoding the manganese-dependent superoxide dismutase).

Anaerobiosis↗
PubMed1970

Horseshoe crab lactate dehydrogenase: tissue distribution and molecular weight.

Lactate dehydrogenase from Xiphosura (Limulus) polyphemus i D(-)-lactate specific. It does not use L(+)-lactate, alpha-hydroxybutyrate, alpha-hydroxyvalerate, or alpha-hydroxyisocaproate as substrate. In most tissues lactate dehydrogenase is composed of five isozymes with a molecular weight of 140,000 for each, as judged by gel-filtration chromatography. This suggests that the isozyme, are tetramers comprised of varying amounts of two physicochemically distinc subunits.

Animals↗
PubMed1973

Affinity chromatography of lactate dehydrogenase on immobilized nucleotides.

The interaction of two isoenzymes of lactate dehydrogenase from pig heart muscle (H(4)) and rabbit skeletal muscle (M(4)), with immobilized nucleotides was examined: the effects of pH and temperature on the binding of lactate dehydrogenase were studied with immobilized NAD(+) matrices. The influence of substrate, product and sulphite on the binding of heart muscle lactate dehydrogenase to immobilized NAD(+) was investigated. The interaction of both lactate dehydrogenase isoenzymes with immobilized pyridine and adenine nucleotides and their derivatives were measured. The effects of these parameters on the interaction of lactate dehydrogenase with immobilized nucleotides were correlated with the known kinetic and molecular properties of the enzymes in free solution.

Adenine Nucleotides↗
PubMedDate not supplied

[Effective method of isolating M4-lactate dehydrogenase from rat liver].

Lactate dehydrogenase M4-isoform in the homogeneous state was isolated from the rat liver by successive application of sulphate-ammonium fractionation, phosphocellulose ion-exchange chromatography with high-affinity elution of 1 mM NADH and subsequent hydroxyl apatite fractionation. The method permits obtaining the preparation amounts of the enzymic protein with yield 37.5%, specific activity 386.8 units per 1 mg of protein. It is established that 1 mM NAD+, 10 mM pyruvate and 100 mM lactate are also effective as agents of the selective enzyme elution.

Animals↗
PubMed1984

The use of auramine O to study ligand binding and subunit cooperativity of lactate dehydrogenase.

The tetrameric molecule of pig skeletal muscle lactate dehydrogenase binds a cationic fluorescent probe, auramine O, at four equal non-interacting sites with a dissociation constant of (1.25 +/- 0.2) X 10(-4) M. Fluorescence of the dye/enzyme mixture is strongly pH-dependent, with a maximum at pH 6.3-6.8. Auramine O-binding sites are located outside the active center of the enzyme. The microenvironment of the bound dye changes upon interaction of lactate dehydrogenase with NAD+, NADH, ADP and pyruvate. The binding of specific ligands induces an increase in fluorescence of auramine O-enzyme complex. This effect was used to determine the dissociation constants of the complexes of lactate dehydrogenase with specific ligands. Pyruvate was demonstrated to bind to the apoenzyme-auramine O complex with a dissociation constant of 5.2 X 10(-4) M. With the use of auramine O, it became possible to reveal subunit interactions within the tetrameric molecule of lactate dehydrogenase. They are manifested in the changes of the microenvironment of a dye-binding site located on one of the subunits induced by the binding of ligands in the active center of a neighboring subunit.

Adenosine Diphosphate↗