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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 -
Cold Spring Harbor Protocols Jun 2018A common method for determining cytotoxicity is based on measuring the activity of cytoplasmic enzymes released by damaged cells. Lactate dehydrogenase (LDH) is a stable...
A common method for determining cytotoxicity is based on measuring the activity of cytoplasmic enzymes released by damaged cells. Lactate dehydrogenase (LDH) is a stable cytoplasmic enzyme that is found in all cells. LDH is rapidly released into the cell culture supernatant when the plasma membrane is damaged, a key feature of cells undergoing apoptosis, necrosis, and other forms of cellular damage. LDH activity can be easily quantified by using the NADH produced during the conversion of lactate to pyruvate to reduce a second compound in a coupled reaction into a product with properties that are easily quantitated. This protocol measures the reduction of a yellow tetrazolium salt, INT, by NADH into a red, water-soluble formazan-class dye by absorbance at 492 nm. The amount of formazan is directly proportional to the amount of LDH in the culture, which is, in turn, directly proportional to the number of dead or damaged cells.
Topics: Cell Count; Cell Death; Cell Line; Cell Survival; Enzyme Assays; Humans; L-Lactate Dehydrogenase
PubMed: 29858337
DOI: 10.1101/pdb.prot095497 -
Seminars in Cancer Biology Dec 2022Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most... (Review)
Review
Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Glycolysis; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Neoplasms
PubMed: 36371026
DOI: 10.1016/j.semcancer.2022.11.007 -
Endocrine, Metabolic & Immune Disorders... 2020Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme,... (Review)
Review
BACKGROUND
Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These diverse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well.
OBJECTIVE
The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases.
METHODS
With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents.
DISCUSSION
LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have diversified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases.
CONCLUSION
LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.
Topics: Animals; Biomarkers; Diagnostic Techniques, Endocrine; Energy Metabolism; Humans; Isoenzymes; Kinetics; L-Lactate Dehydrogenase; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Pyruvic Acid
PubMed: 31886754
DOI: 10.2174/1871530320666191230141110 -
Nature Communications Feb 2023Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular...
Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.
Topics: Mice; Male; Female; Animals; Lactate Dehydrogenase 5; Astrocytes; Lactic Acid; L-Lactate Dehydrogenase; Proteomics; Carrier Proteins
PubMed: 36759610
DOI: 10.1038/s41467-023-36209-5 -
Nature Reviews. Clinical Oncology Dec 2022High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically... (Review)
Review
High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically improved outcomes in patients with melanoma over the past decade, provide only marginal benefit to those with high serum LDH levels. When viewed separately from the oncological, biochemical, biological and immunological perspectives, serum LDH is often interpreted in very different ways. Oncologists usually see high serum LDH only as a robust biomarker of a poor prognosis, and biochemists are aware of the complexity of the various LDH isoforms and of their key roles in cancer metabolism, whereas LDH is typically considered to be oncogenic and/or immunosuppressive by cancer biologists and immunologists. Integrating these various viewpoints shows that the regulation of the five LDH isoforms, and their enzymatic and non-enzymatic functions is closely related to key oncological processes. In this Review, we highlight that serum LDH is far more than a simple indicator of tumour burden; it is a complex biomarker associated with the activation of several oncogenic signalling pathways as well as with the metabolic activity, invasiveness and immunogenicity of many tumours, and constitutes an extremely attractive target for cancer therapy.
Topics: Humans; L-Lactate Dehydrogenase; Tumor Burden; Melanoma; Prognosis
PubMed: 36207413
DOI: 10.1038/s41571-022-00686-2 -
Biochemical and Biophysical Research... Jul 2022Osteoblast cells tend to metabolize glucose to lactate via aerobic glycolysis during osteogenic differentiation. However, the function of lactate in this process is...
Osteoblast cells tend to metabolize glucose to lactate via aerobic glycolysis during osteogenic differentiation. However, the function of lactate in this process is still elusive. As a newly discovered protein posttranslational modification, lactate-derived histone lactylation has been found to play important roles in gene regulation and have profound effects on diverse biological processes. Here, we found that the expression of lactate dehydrogenase A (LDHA), intracellular lactate, and histone lactylation levels were all gradually increased during osteogenic differentiation. Knockdown of LDHA impaired the formation of mineralized nodules and ALP activity. RNA-sequencing and subsequent validation experiments showed that JunB expression was decreased in LDHA knockdown cells. Mechanistically, knockdown of LDHA decreased histone lactylation mark enrichment on JunB promoter, and exogenous lactate treatment rescued this effect. Our study revealed a non-canonical function of lactate during osteogenic differentiation.
Topics: Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glycolysis; Histones; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Osteoblasts; Osteogenesis
PubMed: 35605402
DOI: 10.1016/j.bbrc.2022.05.028 -
International Journal of Molecular... Apr 2019Tumor cells possess a high metabolic plasticity, which drives them to switch on the anaerobic glycolysis and lactate production when challenged by hypoxia. Among the... (Review)
Review
Tumor cells possess a high metabolic plasticity, which drives them to switch on the anaerobic glycolysis and lactate production when challenged by hypoxia. Among the enzymes mediating this plasticity through bidirectional conversion of pyruvate and lactate, the lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), are indicated. LDHA has a higher affinity for pyruvate, preferentially converting pyruvate to lactate, and NADH to NAD in anaerobic conditions, whereas LDHB possess a higher affinity for lactate, preferentially converting lactate to pyruvate, and NAD to NADH, when oxygen is abundant. Apart from the undisputed role of LDHA and LDHB in tumor cell metabolism and adaptation to unfavorable environmental or cellular conditions, these enzymes participate in the regulation of cell death. This review presents the latest progress made in this area on the roles of LDHA and LDHB in apoptosis and autophagy of tumor cells. Several examples of how LDHA and LDHB impact on these processes, as well as possible molecular mechanisms, will be discussed in this article. The information included in this review points to the legitimacy of modulating LDHA and/or LDHB to target tumor cells in the context of human and veterinary medicine.
Topics: Animals; Apoptosis; Autophagy; Cell Line, Tumor; Energy Metabolism; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Neoplasms
PubMed: 31035592
DOI: 10.3390/ijms20092085 -
Current Protocols in Bioinformatics Jun 2016Comparative protein structure modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more...
Comparative protein structure modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and how to use the ModBase database of such models, and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described. © 2016 by John Wiley & Sons, Inc.
Topics: Amino Acid Sequence; Chemistry Techniques, Analytical; L-Lactate Dehydrogenase; Models, Molecular; Protein Conformation; Proteins; Sequence Alignment; Software; Trichomonas vaginalis
PubMed: 27322406
DOI: 10.1002/cpbi.3 -
Nature Cell Biology Sep 2017Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated...
Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.
Topics: Acrylates; Animals; Anion Transport Proteins; Cell Proliferation; Cellular Senescence; Female; Genotype; Glycolysis; Hair Follicle; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Phenotype; Proto-Oncogene Proteins c-myc; Signal Transduction; Stem Cells; Time Factors
PubMed: 28812580
DOI: 10.1038/ncb3575