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PubMed1982

In vitro synthesis of the membrane-bound D-lactate dehydrogenase of Escherichia coli.

Synthesis of the membrane-bound, flavin-linked D-lactate dehydrogenase of Escherichia coli has been studied by using a recombinant plasmid containing the dld gene [Young, I. G., Jaworowski, A., & Poulis, M. (1982) Biochemistry (following paper in this issue)]. Expression of the cloned dld gene was achieved either in vivo with transformed minicells or in vitro with a fractionated transcription/translation system. In both instances, a product is observed that is specifically immunoprecipitated by gamma-globulin prepared against the purified enzyme and comigrates with authentic D-lactate dehydrogenase on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Furthermore, the product is catalytically active and binds to membrane vesicles during or after synthesis. Thus, it seems likely that the protein is synthesized in mature form and binds to the membrane without a leader peptide sequence. Interestingly, addition of flavin adenine dinucleotide to the in vitro reaction mixtures causes a 2-fold increase in the synthesis of the enzyme, suggesting that the cofactor plays a regulatory role in the synthesis of the apoprotein. Finally, L factor, a protein involved in regulation of protein elongation, has an inhibitory effect on the expression of the dld gene and a stimulatory effect on the expression of the ndh gene (encoding NADH dehydrogenase).

DNA, Bacterial↗
PubMed1981

Depletion of myocardial creatine kinase, lactate dehydrogenase, myoglobin and K+ after coronary artery ligation in dogs.

In order to compare the time-course of disappearance of macromolecules and electrolytes from ischaemic myocardium, measurements of creatine kinase and lactate dehydrogenase activity and myoglobin, K+ and Na+ concentration were made on myocardial extracts from dogs which had left anterior descending coronary artery ligation for 3, 6, 12 and 24 h (4 groups of 6 dogs each). Intensity of ischaemia was assessed by myocardial blood flow measured with 15+/- 5 micrometers microspheres at 15 min after ligation. Creatine kinase and lactate dehydrogenase activities and K+/Na+ concentration ratios were at all times correlated with the magnitude of collateral blood flow in the ischaemic myocardium, while myoglobin concentration was correlated with blood flow only at 12 and 24h. Comparisons of the intensity of depletion at the various times after ligation showed that K+, K+/Na+ and creatine kinase had all reached a steady state at 12 h after ligation while lactate dehydrogenase and myoglobin had still to reach a steady state at 24 h. We conclude that these indices are mutually supportive markers of the intensity of ischaemia of 24 h duration, but K+ or K+/Na+ may be the most reliable indices for shorter periods of ischaemia of 3 to 6 h duration.

Animals↗
PubMed2001

Bone-specific alkaline phosphatase protein, total alkaline phosphatase activity and lactate dehydrogenase in sera of patients with sickle cell disease.

Serum bone-specific alkaline phosphatase protein (bAP) was evaluated as indicator of bone turnover by immunoradiometric assay (IRMA) in twenty patients with sickle cell disease and in twenty healthy control subjects. Serum bAP was also compared with serum total alkaline phosphatase activity and serum lactate dehydrogenase in the same group. The concentrations of serum bAP and serum lactate dehydrogenase were significantly higher in the study group than in the control group (p < 0.05, p < 0.01, respectively). The serum total alkaline phosphatase activity showed no significant difference with the control healthy subjects. There was no correlation between serum bAP and total alkaline phosphatase or lactate dehydrogenase levels in the patient group. In conclusion, serum bAP protein measured by IRMA can be considered a sensitive marker of bone turnover and could be especially useful as valuable non-invasive biochemical marker for identifying sickle cell patients with skeletal complications.

Adolescent↗
PubMed1978

Effect of pregnancy on the turnover of lactate dehydrogenase and its isoenzymes in mouse tissues.

The turnover characteristics of total protein and of lactate dehydrogenase and its isoenzymes have been determined in several tissues of the mouse during the later stages of pregnancy. Whereas most tissues showed markedly decreased rates of both synthesis and degradation of proteins, the incorporation rate in uterus increased. Significant differences in the extent of isotope distribution between total protein and lactate dehydrogenase and its isozymes were also noted. Overall the concept emerges of a pool of body protein which is responsive to the physiological stresses of pregnancy at the level of both tissue and cellular function.

Animals↗
PubMed1980

Lactate dehydrogenases of Atlantic hagfish: physiological and evolutionary implications of a primitive heart isozyme.

Isozymes of lactate dehydrogenase from heart and muscle of Atlantic hagfish show less functional divergence than those from other fishes and higher vertebrates. The enzyme from hagfish heart (B4) displays a higher Michaelis constant for pyruvate and lower substrate inhibition at moderate pyruvate concentrations than heart isozymes from other species. These properties support the hypothesis that the ancestral vertebrate lactate dehydrogenase was a muscle (A4)-type enzyme and also suggest a role for the B4 enzyme in the unusual physiology of hagfish cardiac tissue which functions under sustained hypoxic conditions.

Anaerobiosis↗
PubMed2002

Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer.

We applied a combined data mining and experimental validation Approach for the discovery of germ cell-specific genes aberrantly expressed in cancer. Six of 21 genes with confirmed germ cell specificity were detected in tumors, indicating that ectopic activation of testis-specific genes in cancer is a frequent phenomenon. Most surprisingly one of the genes represented lactate dehydrogenase C (LDHC), the germ cell-specific member of the lactate dehydrogenase family. LDHC escapes from transcriptional repression, resulting in significant expression levels in virtually all tumor types tested. Moreover, we discovered aberrant splicing of LDHC restricted to cancer cells, resulting in four novel tumor-specific variants displaying structural alterations of the catalytic domain. Expression of LDHC in tumors is neither mediated by gene promotor demethylation, as previously described for other germ cell-specific genes activated in cancer, nor induced by hypoxia as demonstrated for enzymes of the glycolytic pathway. LDHC represents the first lactate dehydrogenase isoform with restriction to tumor cells. In contrast to other LDH isoenzymes, LDHC has a preference for lactate as a substrate. Thus LDHC activation in cancer may provide a metabolic rescue pathway in tumor cells by exploiting lactate for ATP delivery.

Alternative Splicing↗
PubMed1977

Lactate dehydrogenase content related to cross-sectional area in muscle fibres.

Cross-sectional areas and lactate dehydrogenase activity were determined of separate muscle fibres of mouse rectus femoris muscle in both ventral and dorsal parts of the muscle. The lactate dehydrogenase activity was measured quantitatively by microscope photometry using a tetrazolium staining in absence or presence of either vitamin K3 or phenazine methosulfate. If the observations are restricted to a relatively small area of the muscle cross section, one can distinguish categorically narrow ("red") and broad ("white) fibres with average values for cross sectional area and LDH content that depend on the part of the muscle chosen (higher LDH and smaller area in ventral part). However, if these data from the different parts or from the whole muscle are added together, no categorical distinction between the fibre types is allowed. On the basis of the observations a categorical division of muscle fibres within relatively large muscle areas or in a whole muscle is rather dubious. A relation is suggested between the subjective impression of different muscle fibre types in a field of observation with the number of motorunits present in that field.

Animals↗
PubMed1988

Measurements of M-subunit lactate dehydrogenase before therapy as an aid to tumour typing in serous effusions.

The levels of lactate dehydrogenase (LDH) isoenzymes were assayed in serous effusions from 111 hospital patients under investigation for cancer. The levels of M-subunit LDH in effusions from patients proven to have cancer were significantly higher than in patients in whom cancer was not proven (p less than 0.001). Chemotherapeutic agents used to combat cancer such as 5-fluorouracil, vincristine and cyclophosphamide are known to affect lactate dehydrogenase. On excluding these effects by studying patients before therapy was instituted, levels of M-subunit LDH were found to be significantly different for certain tumour types found in serous effusions, such as mesothelioma, adenocarcinoma and dedifferentiated carcinoma (p less than 0.005).

Exudates and Transudates↗
PubMedDate not supplied

[Identification of multiple molecular forms of lactate dehydrogenase during isoelectric focusing with ampholines in polyacrylamide gel thin layer].

Multiple molecular forms of lactate dehydrogenase fractionated by isoelectric focusing with ampholines in the polyacrylamide gel thin layer were identified in the supernatant fluid of the myocardium and liver homogenate of the intact rats and rabbits. Differential detection of the enzyme fractions was based on differences in their substrate dependences and sensitivity to specific inhibitors. Simultaneously the analysis was made for the partially purified preparations of lactate dehydrogenase five isoenzymes from the same sources obtained by means of the preparative electrophoresis in polyacrylamide gel and ion-exchange adsorption on DEAE-Sephadex A-50. The isoelectric points of the identified fractions are determined. It is shown that redistribution of the enzyme multiple molecular forms within the pH gradient is subordinated to a certain strictly regularity: fractions from LDH1 to LDH5 occupy successively the sites in a weak-acid, neutral and weak-alkaline regions of the pH gradient.

Animals↗
PubMed1983

Creatine kinase and lactate dehydrogenase: stability of isoenzymes and their activity in stored human plasma and prostatic tissue extracts and effect of sample dilution.

We examined the effect of storing human plasma or extracts of prostate at -90 degrees C on the activity of creatine kinase and lactate dehydrogenase and isoenzyme distribution. Enzyme activities were unaltered during storage for as long as six weeks. If these preparations were thawed only once at 2 to 4 degrees C, they could be stored for as long as 165 days at -90 degrees C with no change in isoenzyme distribution. Inexplicably, apparent isoenzyme distribution of prostatic lactate dehydrogenase was sensitive to sample dilution, whereas the isoenzyme distribution of lactate dehydrogenase in plasma was not. Our observations emphasize the importance of validating details of analytical protocols that are to be used for quantification of new types of specimens.

Creatine Kinase↗
PubMed1984

Fluctuation of a cancer-associated lactate dehydrogenase during S phase of the cell cycle in HeLa cells.

An unusual isozyme of lactate dehydrogenase, originally detected in Kirsten sarcoma virus-infected cells and later shown to be induced in normal mammalian cells by anaerobic shock, has also been reported at elevated levels in several human carcinomas. This enzyme is subject to inhibition by guanosine triphosphate and by the dinucleosides 5',5"'-diadenosine tetraphosphate and 5',5"'-diguanosine tetraphosphate (4). Fluctuation of the activity of this enzyme in soluble extracts of synchronized HeLa cells suggests the enzyme may be linked to DNA synthesis. The lactate dehydrogenase K activity increased in early S phase and then decreased to nearly undetectable levels during the period of most active DNA synthesis. This was observed in cells synchronized by thymidine excess or by aphidicolin, an inhibitor of DNA polymerase alpha.

Aphidicolin↗
PubMed1967

The determination of lactate dehydrogenase isoenzymes in normal human muscle and other tissues.

1. A technique has been developed, based on preferential inhibition by urea, for determining the amounts and proportions of the M and H sub-units of lactate dehydrogenase (referred to as LDH-M and LDH-H respectively) in human tissues, including muscle. 2. There was good agreement between the results obtained with urea inhibition and those obtained with starch-gel electrophoresis. 3. With increasing age there was a significant decrease in the total amount of lactate dehydrogenase and the amount of LDH-M in skeletal muscle. This could not be accounted for by the replacement of functioning muscle tissue by fibrous connective tissue. 4. The proportion of LDH-M was less in certain muscles (e.g. soleus and extra-ocular) than in other muscles (e.g. gastrocnemius and rectus abdominis). 5. The proportions of LDH-M and LDH-H did not differ significantly in different superficial limb muscles and were not significantly affected by either age or sex. 6. Specimens of muscle from 86 different individuals (all Europeans) have been subjected to electrophoresis, but no variants of lactate dehydrogenase isoenzymes have been found.

Age Factors↗
PubMed1975

Purification, characterization, and regulation of a nicotinamide adenine dinucleotide-dependent lactate dehydrogenase from Actinomyces viscosus.

A nicotinamide adenine dinucleotide-specific L-(+)-lactate dehydrogenase (LDH) (EC 1.11.27) from Actinomyces viscosus T-6-1600 was purified approximately 110-fold by a combination of diethylaminoethyl-cellulose and 0.5 M Agarose A column chromatography. The ldh was stable at 26 C, but was quite labile at temperatures below 5 C. The enzyme had a molecular weight of 100,000 +/- 10,000 as determined by 0.5 M Agarose molecular exclusion chromatography and showed optimum activity between pH 5.5 and 6.2. The A. viscosus LDH exhibited homotropic interactions with its substrate, pyruvate, and its coenzyme, reduced nicotinamide adenine dinucleotide, indicating multiple binding sites on the enzyme for these ligands with some degree of cooperative interaction between them. The enzyme was under negative control by adenosine 5'-triphosphate, and its kinetic response to the negative effector was sigmoidal in nature. Inorganic phosphate reversed the inhibition exerted on the A. viscosus LDH by adenosine. The 5'-triphosphate thermal stability at 65 C of the LDH from A. viscosus was increased in the presence of its negative effector, adenosine 5'-triphosphate, but was markedly decreased in the presence of its coenzyme, reduced nicotinamide adenine dinucleotide. The glycolytic intermediate, fructose-1,6-diphosphate, had no effect on the catalytic activity of the A. viscosus LDH at saturating pyruvate concentrations. However, fructose-1,6-diphosphate was a potent positive effector at low substrate concentrations. Thus the A. viscosus LDH is under positive control by fructose-1,6-diphosphate and inorganic phosphate, but under negative control by adenosine 5'-triphosphate.

Actinomyces↗
PubMed1986

Chronic exercise training alters kinetic properties of rat skeletal muscle and myocardial lactate dehydrogenase.

10 weeks of treadmill running dramatically altered the kinetic properties of lactate dehydrogenase (EC 1.1.1.27) in skeletal muscle and myocardium in the rat. These changes, including Vmax, Km and optimal concentrations for pyruvate and lactate, indicate that exercise training induces the formation of H-isozyme in skeletal muscle and M-isozyme in the heart and represent metabolic adaptations of these tissues to chronic aerobic exercise.

Animals↗
PubMed2000

The crystal structure of D-lactate dehydrogenase, a peripheral membrane respiratory enzyme.

d-Lactate dehydrogenase (d-LDH) of Escherichia coli is a peripheral membrane respiratory enzyme involved in electron transfer, located on the cytoplasmic side of the inner membrane. d-LDH catalyzes the oxidation of d-lactate to pyruvate, which is coupled to transmembrane transport of amino acids and sugars. Here we describe the crystal structure at 1.9 A resolution of the three domains of d-LDH: the flavin adenine dinucleotide (FAD)-binding domain, the cap domain, and the membrane-binding domain. The FAD-binding domain contains the site of d-lactate reduction by a noncovalently bound FAD cofactor and has an overall fold similar to other members of a recently discovered FAD-containing family of proteins. This structural similarity extends to the cap domain as well. The most prominent difference between d-LDH and the other members of the FAD-containing family is the membrane-binding domain, which is either absent in some of these proteins or differs significantly. The d-LDH membrane-binding domain presents an electropositive surface with six Arg and five Lys residues, which presumably interacts with the negatively charged phospholipid head groups of the membrane. Thus, d-LDH appears to bind the membrane through electrostatic rather than hydrophobic forces.

Amino Acid Sequence↗
PubMed1988

Regional creatine kinase, adenylate kinase, and lactate dehydrogenase in normal canine brain.

Following acute stroke, creatine kinase and other enzymes are released into the cerebrospinal fluid and blood from injured brain tissue. To determine whether regional differences in brain enzyme activity might exist and therefore affect the amount of enzyme released, we quantified the levels of creatine kinase, adenylate kinase, and lactate dehydrogenase in 12 regions of normal canine brain (n = 4). Adenylate kinase activity varied the least among regions (49 +/- 7 units/g), followed by lactate dehydrogenase activity (122 +/- 28 units/g). The pattern for both adenylate kinase and lactate dehydrogenase was higher activity in predominantly gray matter areas, lower activity in white matter, and intermediate activity in mixed regions. The distribution of creatine kinase brain isoenzyme and mitochondrial creatine kinase in canine brain was less predictable, showing wider variations among regions (isoenzyme, 462 +/- 116 units/g; mitochondrial, 42 +/- 20 units/g). Even cerebral gray matter demonstrated substantial regional variations in creatine kinase brain isoenzyme, ranging from 606 units/g in the parietal cortex to 329 units/g in the temporal cortex. We conclude that the content of creatine kinase brain isoenzyme varies more than twofold among areas of brain. This regional variation may be important in the interpretation of creatine kinase brain isoenzyme measurements in cerebrospinal fluid and serum used to assess neurologic injury following stroke.

Adenylate Kinase↗
PubMed1987

Immunochemical evidence that the single lactate dehydrogenase of lampreys is more similar to LDHB4 than to LDHA4 of hagfish.

The tetrameric lactate dehydrogenases (LDH) of vertebrates contain several different subunits that arose by gene duplication. While the A and B subunits occur in all classes of gnathostomes, the enzymes of agnathans appear to represent two stages in the evolution of vertebrate LDH. Lampreys of the family Petromyzontidae have a single enzyme classified as LDHA4, while hagfish possess both A and B subunits which form only the two homopolymers LDHA4 and LDHB4. It is generally assumed that the original vertebrate LDH was an A4 type, that duplication to give the B subunit occurred prior to the divergence of lampreys and hagfish, and that modern lampreys subsequently lost expression of the B gene. Lactate dehydrogenases were purified from representatives of all three lamprey families, and it was confirmed that members of the Mordaciidae and Geotriidae also possess single tetrameric LDH enzymes containing one subunit type. The kinetic properties of the lamprey LDH enzymes were compared with the LDH homopolymers of hagfish, skate, and sardine. These properties did not allow the lamprey enzymes to be unequivocally identified as either LDHA4 or LDHB4. Immunochemical titration using antisera against lamprey and hagfish LDH homopolymers demonstrated that the lamprey LDH enzymes showed greater immunochemical similarity to LDHB4 than to LDHA4 of hagfish. It is concluded that there is little evidence for the claim that the original vertebrate LDH was an A4 rather than B4 type.

Animals↗