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Cancer Medicine Dec 2018Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A... (Review)
Review
Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio-characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.
Topics: Animals; Biomarkers; Carcinogenesis; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Neoplasms
PubMed: 30403008
DOI: 10.1002/cam4.1820 -
Proteins May 2001Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant interconversion of NADH and NAD(+). Although crystal structures of a variety of LDH have...
Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant interconversion of NADH and NAD(+). Although crystal structures of a variety of LDH have previously been described, a notable absence has been any of the three known human forms of this glycolytic enzyme. We have now determined the crystal structures of two isoforms of human LDH-the M form, predominantly found in muscle; and the H form, found mainly in cardiac muscle. Both structures have been crystallized as ternary complexes in the presence of the NADH cofactor and oxamate, a substrate-like inhibitor. Although each of these isoforms has different kinetic properties, the domain structure, subunit association, and active-site regions are indistinguishable between the two structures. The pK(a) that governs the K(M) for pyruvate for the two isozymes is found to differ by about 0.94 pH units, consistent with variation in pK(a) of the active-site histidine. The close similarity of these crystal structures suggests the distinctive activity of these enzyme isoforms is likely to result directly from variation of charged surface residues peripheral to the active site, a hypothesis supported by electrostatic calculations based on each structure. Proteins 2001;43:175-185.
Topics: Crystallization; Humans; Isoenzymes; Kinetics; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Models, Molecular; Static Electricity; Structure-Activity Relationship
PubMed: 11276087
DOI: 10.1002/1097-0134(20010501)43:2<175::aid-prot1029>3.0.co;2-# -
Cancer Letters Mar 2015A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the... (Review)
Review
A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main source of energy. Lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability of NAD(+) to maintain the continuity of glycolysis. It is therefore an important control point in the system of cellular energy release. Its upregulation is common in many malignant tumors. Inhibiting LDH-5 activity has an anti-proliferative effect on cancer cells. It may reverse their resistance to conventional chemo- and radiotherapy. Recent research has renewed interest in LDH-5 as an anticancer drug target. This review summarizes recent studies exploring the role of LDH-5 in cancer growth, its utility as a tumor marker, and developments made in identifying and designing anti-LDH-5 therapeutic agents.
Topics: Carcinogenesis; Citric Acid Cycle; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Molecular Targeted Therapy; Neoplasms
PubMed: 25528630
DOI: 10.1016/j.canlet.2014.12.035 -
Annals of Clinical and Laboratory... 1985Lactate dehydrogenase (LD: EC 1.1.1.27) is the most important clinically of several dehydrogenases occurring in human serum. Lactate dehydrogenase is cytoplasmic in its... (Review)
Review
Lactate dehydrogenase (LD: EC 1.1.1.27) is the most important clinically of several dehydrogenases occurring in human serum. Lactate dehydrogenase is cytoplasmic in its cellular location and in any one tissue is composed of one or two of five possible isoenzymes. While many of its clinical applications involve quantification of one or more specific serum isoenzymes, an estimate of total LD is required usually. Lactate dehydrogenase catalyzes the reversible reaction: L-lactate + NAD+ in equilibrium pyruvate + NADH. The bidirectional reaction is monitored spectrophotometrically by measuring either the increase in NADH at 340 nm produced in the lactate-to-pyruvate reaction (L----P) or by the decrease in NADH at 340 nm produced in the pyruvate-to-lactate (P----L) reaction. Kinetic assay systems for the measurement of the reaction system in both directions are comprehensively reviewed as well as the standardization efforts proposed to date.
Topics: Enzyme Activation; Enzyme Reactivators; Hemolysis; Humans; Kinetics; L-Lactate Dehydrogenase; NAD; Oxidoreductases; Pyruvates
PubMed: 3882046
DOI: No ID Found -
Cell Biochemistry and Function Jul 1984
Review
Topics: Amino Acid Sequence; Animals; Humans; Isoenzymes; Kinetics; L-Lactate Dehydrogenase; Macromolecular Substances
PubMed: 6383647
DOI: 10.1002/cbf.290020302 -
Bioelectrochemistry (Amsterdam,... Aug 2023Flavin-dependent L-lactate dehydrogenase (LDH) from baker's yeast (Saccharomyces cerevisiae) reversibly catalyzes the oxidation of L-lactate to L-pyruvate. In this...
Flavin-dependent L-lactate dehydrogenase (LDH) from baker's yeast (Saccharomyces cerevisiae) reversibly catalyzes the oxidation of L-lactate to L-pyruvate. In this study, four different enzymatic constructs were generated, and their catalytic and electrochemical properties were compared. Specifically, a truncated form of the native enzyme that includes only the catalytic domain, the native enzyme that includes an intrinsic electron-transferring cytochrome b2, a novel artificial enzyme containing a minimal cytochrome c and a version of the enzyme containing a fusion between two cytochromes were designed. All four variants were successfully expressed in Escherichia coli and presented properly matured heme domains. Assessing in vitro biocatalytic performance as reflected by lactate oxidation revealed the fusion-containing enzyme to be ∼ 12 times more active than the native enzyme. Electrochemical studies of electrode drop-casted enzyme variants also showed the superior performance of the dual-cytochrome construct, which displayed a lower average redox-potential for lactate oxidation, oxygen insensitivity in the lactate oxidation potential range and a wider dynamic range for lactate sensing, relative to the native enzyme. Moreover, product inhibition of this variant occurred at much higher lactate concentrations than with the native enzyme. In addition, when lower potentials were scanned using cyclic voltammetry, lactate-dependent oxygen reduction was measured for the dual-cytochrome fusion enzyme.
Topics: L-Lactate Dehydrogenase; Kinetics; Oxidation-Reduction; Saccharomyces cerevisiae; Pyruvic Acid; Lactic Acid; Cytochromes c; Oxygen
PubMed: 36931144
DOI: 10.1016/j.bioelechem.2023.108406 -
Brain Pathology (Zurich, Switzerland) Jan 2016There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and... (Review)
Review
There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.
Topics: Animals; Brain Neoplasms; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5
PubMed: 26269128
DOI: 10.1111/bpa.12299 -
Comparative Biochemistry and... Sep 2016Comparative enzymology explores the molecular mechanisms that alter the properties of enzymes to best fit and adapt them to the biotic demands and abiotic stresses that... (Comparative Study)
Comparative Study Review
Comparative enzymology explores the molecular mechanisms that alter the properties of enzymes to best fit and adapt them to the biotic demands and abiotic stresses that affect the cellular environment in which these protein catalysts function. For many years, comparative enzymology was primarily concerned with analyzing enzyme functional properties (e.g. substrate affinities, allosteric effectors, responses to temperature or pH, stabilizers, denaturants, etc.) in order to determine how enzyme properties were optimized to function under changing conditions. More recently it became apparent that posttranslational modifications of enzymes play a huge role in metabolic regulation. At first, such modifications appeared to target just crucial regulatory enzymes but recent work is showing that many dehydrogenases are also targets of posttranslational modification leading to substantial changes in enzyme properties. The present article focuses in particular on lactate dehydrogenase (LDH) showing that stress-induced changes in enzyme properties can be linked with reversible posttranslational modifications; e.g. changes in the phosphorylation state of LDH occur in response to dehydration stress in frogs and anoxia exposure of turtles and snails. Furthermore, these studies show that LDH is also a target of other posttranslational modifications including acetylation, methylation and ubiquitination that change in response to anoxia or dehydration stress. Selected new methods for exploring posttranslational modifications of dehydrogenases are discussed and new challenges for the future of comparative enzymology are presented that will help to achieve a deeper understanding of biochemical adaptation through enzyme regulation.
Topics: Animals; Enzyme Stability; Humans; L-Lactate Dehydrogenase; Phosphorylation; Protein Processing, Post-Translational
PubMed: 26688543
DOI: 10.1016/j.cbpb.2015.12.004 -
Cell Biochemistry and Function Jul 1984
Review
Topics: Exudates and Transudates; Hematologic Diseases; Humans; Isoenzymes; Kinetics; L-Lactate Dehydrogenase; Liver Diseases; Muscular Diseases; Myocardial Infarction; Neoplasms
PubMed: 6383649
DOI: 10.1002/cbf.290020304 -
Biochimica Et Biophysica Acta May 1989
Review
Topics: Animals; Cloning, Molecular; Escherichia coli; L-Lactate Dehydrogenase; Lipids; Magnetic Resonance Spectroscopy; Membrane Proteins; Molecular Structure; Mutation
PubMed: 2655708
DOI: 10.1016/0304-4157(89)90018-x