-
Future Medicinal Chemistry Mar 2020Dysregulated metabolism is one of the hallmarks of cancer. Under normal physiological conditions, ATP is primarily generated by oxidative phosphorylation. Cancers...
Dysregulated metabolism is one of the hallmarks of cancer. Under normal physiological conditions, ATP is primarily generated by oxidative phosphorylation. Cancers commonly undergo a dramatic shift toward glycolysis, despite the presence of oxygen. This phenomenon is known as the Warburg effect, and requires the activity of LDHA. LDHA converts pyruvate to lactate in the final step of glycolysis and is often upregulated in cancer. LDHA inhibitors present a promising therapeutic option, as LDHA blockade leads to apoptosis in cancer cells. Despite this, existing LDHA inhibitors have shown limited clinical efficacy. Here, we review recent progress in LDHA structure, function and regulation as well as strategies to target this critical enzyme.
Topics: Apoptosis; Enzyme Inhibitors; Humans; L-Lactate Dehydrogenase; Neoplasms; Protein Conformation
PubMed: 32064930
DOI: 10.4155/fmc-2019-0287 -
Bioorganic & Medicinal Chemistry Letters Jun 2021Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the...
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
Topics: Aniline Compounds; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Ethers; Humans; L-Lactate Dehydrogenase
PubMed: 33771585
DOI: 10.1016/j.bmcl.2021.127974 -
The Journal of Veterinary Medical... Oct 2022Lactate dehydrogenase (LDH) in blood is measured using the Japanese Society of Clinical Chemistry (JSCC) method in Japan and the International Federation of Clinical...
Lactate dehydrogenase (LDH) in blood is measured using the Japanese Society of Clinical Chemistry (JSCC) method in Japan and the International Federation of Clinical Chemistry (IFCC) method in other countries. In human clinical practice, the IFCC method replaced the JSCC method due to international standardization. Moreover, veterinary LDH measurement will also eventually shift to the IFCC method. However, the relationship between the IFCC and JSCC methods for LDH in various animals and whether they can be equated or not have not yet been investigated. This study aimed to present the changes in measurements in canines and felines after switching to the IFCC method. The plasma LDH activity of canines (N=177) and felines (N=115), who visited a secondary care veterinary clinic, was measured using the JSCC and IFCC methods. The IFCC/JSCC ratio was <1.0 in 85% of canines and 88% of felines, indicating that the IFCC method tended to show lower values than the JSCC method, presumably because LDH5 is dominant among the LDH isozymes in canines and felines. The increase in the systematic errors of both assays was in the high value range, with some samples exceeding the error tolerance from near the upper end of the reference range. When switching to the IFCC method for LDH measurement in canines and felines, each institution should consider whether the reference range and clinical diagnostic values established by the JSCC method are appropriate for continued use.
Topics: Animals; Cat Diseases; Cats; Dog Diseases; Dogs; Humans; Isoenzymes; L-Lactate Dehydrogenase; Reference Standards
PubMed: 35934797
DOI: 10.1292/jvms.22-0278 -
Development (Cambridge, England) Sep 2019The dramatic growth that occurs during larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands...
The dramatic growth that occurs during larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (LDH) activity. The resulting metabolic program is ideally suited for synthesis of macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of LDH in promoting biosynthesis, we examined how mutations influence larval development. Our studies unexpectedly found that mutants grow at a normal rate, indicating that LDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both LDH and G3P dehydrogenase (GPDH1) exhibit growth defects, synthetic lethality and decreased glycolytic flux. Considering that human cells also generate G3P upon inhibition of lactate dehydrogenase A (LDHA), our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness to growing animal tissues.
Topics: Adenosine Triphosphate; Animals; Animals, Genetically Modified; Drosophila melanogaster; Female; Glycerolphosphate Dehydrogenase; Glycolysis; Homeostasis; L-Lactate Dehydrogenase; Lactic Acid; Larva; Male; Mutation; NAD; Oxidation-Reduction; Sugars
PubMed: 31399469
DOI: 10.1242/dev.175315 -
Current Opinion in Nephrology and... Jul 2020Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly... (Review)
Review
PURPOSE OF REVIEW
Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly primary hyperoxaluria type I and II, threatening renal function. Ethylene glycol poisoning may induce the precipitation of calcium oxalate crystals in renal tubules, leading to acute renal failure. In both cases, oxalate results from glyoxylate transformation to oxalate in the liver, by lactate dehydrogenase (LDH) enzymes, especially the LDH-5 isoenzyme. The purpose of the review is to highlight LDH as a potential therapeutic target according to recent publications.
RECENT FINDINGS
Genetic therapy targeting LDH metabolism decreases urine oxalate excretion in rodents. Stiripentol is an antiepileptic drug that has been shown recently to inhibit neuronal LDH-5 isoenzyme. Stiripentol was hypothesized to reduce hepatic oxalate production and urine oxalate excretion. In vitro, stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol oral administration decreases urine oxalate excretion in rats and protects renal function and renal tissue against ethylene glycol intoxication and chronic calcium oxalate crystalline nephropathy.
SUMMARY
The use of stiripentol in-vitro and in-vivo highlights that targeting hepatic LDH by pharmacological or genetic tools may decrease oxalate synthesis, deserving clinical studies.
Topics: Dioxolanes; Humans; Hyperoxaluria; Hyperoxaluria, Primary; L-Lactate Dehydrogenase; Oxalic Acid
PubMed: 32452916
DOI: 10.1097/MNH.0000000000000621 -
Acetylation of Lactate Dehydrogenase Negatively Regulates the Acidogenicity of Streptococcus mutans.MBio Oct 2022Lysine acetylation, a ubiquitous and dynamic regulatory posttranslational modification (PTM), affects hundreds of proteins across all domains of life. In bacteria,...
Lysine acetylation, a ubiquitous and dynamic regulatory posttranslational modification (PTM), affects hundreds of proteins across all domains of life. In bacteria, lysine acetylation can be found in many essential pathways, and it is also crucial for bacterial virulence. However, the biological significance of lysine acetylation events to bacterial virulence factors remains poorly characterized. In Streptococcus mutans, the acetylome profiles help identify several lysine acetylation sites of lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactic acid, causing the deterioration of teeth. We investigated the regulatory mechanism of LDH acetylation and characterized the effect of LDH acetylation on its function. We overexpressed the 15 Gcn5 -acetyltransferases (GNAT) family members in S. mutans and showed that the acetyltransferase ActA impaired its acidogenicity by acetylating LDH. Additionally, enzymatic acetyltransferase reactions demonstrated that purified ActA could acetylate LDH , and 10 potential lysine acetylation sites of LDH were identified by mass spectrometry, 70% of which were also detected . We further demonstrated that the lysine acetylation of LDH inhibited its enzymatic activity, and a subsequent rat caries model showed that ActA impaired the cariogenicity of S. mutans. Collectively, we demonstrated that ActA, the first identified and characterized acetyltransferase in S. mutans, acetylated the LDH enzymatically and inhibited its enzymatic activity, thereby providing a starting point for the further analysis of the biological significance of lysine acetylation in the virulence of S. mutans. Lysine acetylation, a dynamic regulatory posttranslational modification, remains poorly characterized in bacteria. Hundreds of proteins have been identified to be acetylated in bacteria, with advances made in acetylome analyses. However, the regulatory mechanisms and functional significance of the majority of these acetylated proteins remain unclear. We analyzed the acetylome profiles of Streptococcus mutans and found that lactate dehydrogenase (LDH) contains several lysine acetylation sites. We also demonstrated that the acetyltransferase ActA, a member of the Gcn5 -acetyltransferases (GNAT) family in S. mutans, acetylated LDH, inhibited its enzymatic ability to catalyze the conversion of pyruvate to lactic acid, and impaired its cariogenicity in a rat caries model. Therefore, LDH acetylation might be a potential target that can be exploited in the design of novel therapeutics to prevent dental caries.
Topics: Rats; Animals; Acetylation; Streptococcus mutans; Lysine; L-Lactate Dehydrogenase; Dental Caries; Protein Processing, Post-Translational; Virulence Factors; Acetyltransferases; Lactic Acid; Pyruvates
PubMed: 36043788
DOI: 10.1128/mbio.02013-22 -
NMR in Biomedicine Feb 2021Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can...
Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance.
Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed. One such functional biomarker could be the myocardium pH. Although tissue pH is already determinable via MR techniques, and has been since the early 1990s, it remains elusive to use practically. The objective of this study was to explore the possibility to evaluate cardiac pH noninvasively, using in-cell enzymatic rates of hyperpolarized [1- C]pyruvate metabolism (ie, moles of product produced per unit time) determined directly in real time using magnetic resonance spectroscopy in a perfused mouse heart model. As a gold standard for tissue pH we used P spectroscopy and the chemical shift of the inorganic phosphate (Pi) signal. The nonhomogenous pH distribution of the perfused heart was analyzed using a multi-parametric analysis of this signal, thus taking into account the heterogeneous nature of this characteristic. As opposed to the signal ratio of hyperpolarized [ C]bicarbonate to [ CO ], which has shown correlation to pH in other studies, we investigated here the ratio of two intracellular enzymatic rates: lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), by way of determining the production rates of [1- C]lactate and [ C]bicarbonate, respectively. The enzyme activities determined here are intracellular, while the pH determined using the Pi signal may contain an extracellular component, which could not be ruled out. Nevertheless, we report a strong correlation between the tissue pH and the LDH/PDH activities ratio. This work may pave the way for using the LDH/PDH activities ratio as an indicator of cardiac intracellular pH in vivo, in an MRI examination.
Topics: Animals; Carbon Isotopes; Heart; Hydrogen-Ion Concentration; Intracellular Fluid; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Myocardium; Perfusion; Phosphorus; Pyruvate Dehydrogenase Complex
PubMed: 33258527
DOI: 10.1002/nbm.4444 -
Biochemical and Biophysical Research... Jun 2022Plasma glucose levels are homeostatically regulated within strict boundaries and are maintained through a balance between peripheral glucose uptake and hepatic glucose...
Plasma glucose levels are homeostatically regulated within strict boundaries and are maintained through a balance between peripheral glucose uptake and hepatic glucose production. However, little is known about the regulatory mechanism of glucose uptake in adipocytes during fasting. Under fasting conditions, the expression levels of 8 glycolytic enzymes were significantly reduced in adipose tissue. Among them, we focused on lactate dehydrogenase A (LDHA), the last enzyme of the glycolytic pathway. Under fasting conditions, both LDHA and Glut1 protein levels tended to decrease in adipose tissue. To elucidate the significance of LDHA in adipocytes, we generated adipocyte-specific LDHA knockout mice (AdLDHAKO) for the first time. AdLDHAKO mice showed no apparent changes in body weight or tissue weight. Under fasting conditions, AdLDHAKO mice exhibited a significant reduction in Glut1 protein levels and glucose uptake in adipose tissues compared with control mice. Similarly, siRNA of LDHA in 3T3-L1 adipocytes reduced Glut1 protein levels and basal glucose uptake. Moreover, treatment with bafilomycin A1, an inhibitor of lysosomal protein degradation, restored Glut1 protein levels by siRNA of LDHA. These results indicate that LDHA regulates Glut1 expression and basal glucose uptake in adipocytes.
Topics: Adipocytes; Animals; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; Insulin; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Mice; RNA, Small Interfering
PubMed: 35366539
DOI: 10.1016/j.bbrc.2022.03.113 -
The Journal of Eukaryotic Microbiology May 2021An NAD-linked lactate dehydrogenase (LDH) in a crude mitochondrial fraction obtained from Tetrahymena homogenates was previously reported by this laboratory. This...
An NAD-linked lactate dehydrogenase (LDH) in a crude mitochondrial fraction obtained from Tetrahymena homogenates was previously reported by this laboratory. This fraction contains the NADH and succinate oxidase system as well as the mitochondrial cytochromes and carries out oxidative phosphorylation. The preparation catalyzes the oxidation of D- and L-lactate linked only to certain analogs of NAD; it has not been possible to demonstrate NAD-dependent D- or L-lactate oxidation nor is there any evidence that either of these enzymes is a flavoprotein as indicated by their inability to reduce directly certain artificial electron acceptors. A lactate racemase is not present.
Topics: L-Lactate Dehydrogenase; Lactate Dehydrogenases; Mitochondria; Nucleotides; Oxidation-Reduction; Pyridines; Tetrahymena
PubMed: 33749960
DOI: 10.1111/jeu.12851 -
Clinica Chimica Acta; International... Apr 2020Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of...
BACKGROUND
Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of LDH-C4 in breast cancer (BC) has not been characterized.
METHODS
We determined LDHC mRNA expression in serum and serum-derived exosomes of BC patients by quantitative RT-PCR. We also evaluated the protein expression of LDH-C4 in BC tissues using high-throughput tissue microarray analysis and immunohistochemistry.
RESULTS
Our results showed high mRNA expression level of LDHC in serum and serum-derived exosomes of BC patients. The LDHC level in serum and exosomes could distinguish BC cases from healthy individuals based on their AUCs of 0.9587 and 0.9464, respectively. Besides, the LDHC level in exosomes of BC patients associated with tumor size, and positively correlated with HER2 and Ki-67 expressions (all with P < 0.05). Serum and exosomal level of LDHC negatively correlated with medical treatment and positively with the recurrence of BC. Survival analysis showed that LDH-C4 expression negatively correlated with BC prognosis.
CONCLUSION
Serum and exosomal LDHC may be an effective indicator for the diagnosis, efficacy evaluation, and monitoring the recurrence of BC. LDH-C4 may act as a biomarker that predicts BC prognosis.
Topics: Adult; Area Under Curve; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Exosomes; Female; Humans; Isoenzymes; L-Lactate Dehydrogenase; Male; Middle Aged; Prognosis; RNA, Messenger; Recurrence; Survival Analysis; Treatment Outcome
PubMed: 31794764
DOI: 10.1016/j.cca.2019.11.032