Human Lactate Dehydrogenase Research Articles

Overcoming cross-reactivity of antibodies against human lactate dehydrogenase.

Lactate dehydrogenase subunit A (LD-A) plays an important role in cancer regulation and therapy. We attempted to develop an enzyme-linked immune-solvent assay (ELISA) for LD-A in human serum. However, commercial antibodies against LD-A exhibited cross-reactivity with an unknown protein. The unknown protein was purified and characterized by protein sequencing and Western blotting. In addition, we attempted to prepare a specific antibody for the ELISA using partially synthesized peptides of LD-A as immunogens. The epitope position in LD-A was carefully selected based on bioinformatics analysis. Peptide sequencer elucidated a ten amino acid sequence of the purified protein at the N-terminal. A BLAST search revealed that this sequence perfectly matched that at the N-terminus of the IgG heavy chain (H-chain). Furthermore, we demonstrated that twelve commercially available antibodies targeting LD-A or LD-B (subunit B) primarily cross-reacted with IgG or its H-chain, with only one specific antibody for each subunit. As the specific antibody against LD-A is no longer commercially accessible, we successfully produced two kinds of specific antibodies using partially synthesized LD-A peptides as immunogens. In conclusion, we have successfully produced specific antibodies against LD-A. Moreover, our findings underscore the utility of bioinformatics tools for determining the optimal positions of immunizing peptides.

(E)-N-(4-Methoxyphenyl)-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methanimine

The title compound (1) was obtained within a project aimed at synthesizing inhibitors of the human enzyme lactate dehydrogenase A (hLDHA). Compound 1 was synthesized by Suzuki cross-coupling of (E)-1-(4-bromophenyl)-N-(4-methoxyphenyl)methanimine (2a) or (E)-1-(4-iodophenyl)-N-(4-methoxyphenyl)methanimine (2b) with 4-(trifluoromethyl)phenylboronic acid (3) using Pd(PPh3)4 as a catalyst in 86% and 87% yields, respectively. Halo-imines 2a and 2b were previously obtained by condensation reaction between p-anisidine (4) and 4-bromo-benzaldehyde (5a) or 4-iodo-benzaldehyde (5b), respectively. The structure of compound 1 was established by 1D and 2D NMR spectroscopy, infrared and ultraviolet spectroscopies, and high-resolution mass spectrometry.

Synthesis and hLDHA Inhibitory Activity of New Stiripentol-Related Compounds of Potential Use in Primary Hyperoxaluria.

Human lactate dehydrogenase A (hLDHA) is a homotetrameric isozyme involved in the conversion of glyoxylate into oxalate in the cytosol of liver cells (hepatocytes) and partially responsible for the overproduction of oxalate in patients with the rare disease called primary hyperoxaluria (PH). Recently, hLDHA inhibition has been validated as a safe therapeutic method to try to control the PH disease. Stiripentol (STP) is an approved drug used in the treatment of seizures associated with Dravet's syndrome (a severe form of epilepsy in infancy) which, in addition, has been drawing interest in recent years also for potentially treating PH, due to its hLDHA inhibitory activity. In this work, several new STP-related compounds have been synthesized and their hLDHA inhibitory activity has been compared to that of STP. The synthesis of these analogues to STP was accomplished using crossed-aldol condensation guided by lithium enolate chemistry and a successive regioselective reduction of the resulting α,β-unsaturated ketones. The target molecules were obtained as racemates, which were separated into their enantiomers by chiral HPLC. The absolute configurations of pure enantiomers were determined by the modified Mosher's method and electronic circular dichroism (ECD) spectroscopy. For the inhibitory effect over the hLDHA catalytic activity, a kinetic spectrofluorometric assay was used. All the new synthesized compounds turned out to be more active at 500 μM (46-72% of inhibition percentage) than STP (10%), which opens a new line of study on the possible capacity of these analogues to reduce urinary oxalate levels in vivo more efficiently.

New tumor markers for testicular cancer - in the here and now and in the future

Germ cell tumors of the testis are the most common tumor entities in young men. Since the introduction of platinum-based chemotherapy in the 1970s, most patients can be cured despite the aggressiveness of germ cell tumors. Optimal serum tumor markers are required for diagnostics, therapy monitoring and aftercare, and these are subject to high requirements. The conventional testicular tumor markers human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) only meet these requirements with insufficient sensitivity (30-70%). The markers investigated in recent decades, such as PLAP, CEA and NSE, have not become established. Currently, miRNA-371 is being researched in particular. Reliable findings are available for initial staging with significantly better specificities of miRNA-371 compared to conventional tumor markers. Further prospective studies are being conducted for other possible clinical applications, such as follow-up care, therapy monitoring or residual tumors, in order to investigate the revolutionary potential of miRNA-371 in these areas as well. Research is also currently being conducted on circulating tumor cells (CTCs) and cell-free DNA (cfNA) in various areas of application. With regard to germ cell tumors of the testis, however, these analyses are still in their infancy, but it is hoped that this will provide a further sufficient opportunity to use serum tumor markers.

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors.

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 μM. Additionally, all compounds with IC50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 μM, and the other thirteen behaving as double inhibitors.

Testicular Germ Cell Tumours - features and prospects of the novel tumour marker microRNA-371a-3p (M371 test): a narrative review

Testicular germ cell tumours (GCTs) represent a paradigm for the usefulness of serum tumour markers in clinical management of diseases. However, the tumour markers currently in use, beta human chorionic gonadotropin (bHCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) are expressed in less than 50% of GCT cases. In 2011, microRNA-371a-3p (currently named M371) was suggested as a novel marker for the first time. Chemically, microRNAS represent small RNA molecules consisting of 18-24 base pairs. Physiologically, these microRNAs play a prominent role in the epigenetic control of protein biosynthesis. M371 can be measured in serum with PCR-techniques.There is high level evidence for a 90% sensitivity and >90% specificity for GCTs of the marker M371. That high diagnostic accuracy is true for both seminoma and nonseminoma but not for the histologic subgroup of teratoma. Testicular tumours of non-germ cell origin and malignant neoplasms of other organs do not express the marker. M371 involves a very short half-life of <24 hours.The test does likely involve the prospects of providing substantial aid in clinical decision-making with respect to instances where improvement of GCT management is still required. In particular, the following clinical scenarios will probably benefit from the employment of the M371 test: (1) diagnostic work-up of incidentally detected small testicular masses with decision-making in regard to testis sparing surgery or full orchiectomy (2) simplifying the follow-up of GCT patients with sparing of imaging procedures in a number of cases; (3) diagnostic evaluation of retroperitoneal lymphadenopathy upon clinical staging; (4) diagnostic evaluation of false-positive elevations of classical tumour markers (AFP, bHCG); (5) rapid appraisal of therapeutic success or failure by means of the very short half-life of M371; (6) diagnostic evaluation of postchemotherapy residual masses particularly those in seminoma patients.The discovery and development of the novel tumour marker M371 probably represents a milestone progress in the history of the clinical management of testicular GCTs.

Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay.

Lactate dehydrogenase A (LDHA) is highly expressed in many tumor cells and promotes the conversion of pyruvate to lactic acid in the glucose pathway, providing energy and synthetic precursors for rapid proliferation of tumor cells. Therefore, inhibition of LDHA has become a widely concerned tumor treatment strategy. However, the research and development of highly efficient and low toxic LDHA small molecule inhibitors still faces challenges. To discover potential inhibitors against LDHA, virtual screening based on molecular docking techniques was performed from Specs database of more than 260,000 compounds and Chemdiv-smart database of more than 1,000 compounds. Through molecular dynamics (MD) simulation studies, we identified 12 potential LDHA inhibitors, all of which can stably bind to human LDHA protein and form multiple interactions with its active central residues. In order to verify the inhibitory activities of these compounds, we established an enzyme activity assay system and measured their inhibitory effects on recombinant human LDHA. The results showed that Compound 6 could inhibit the catalytic effect of LDHA on pyruvate in a dose-dependent manner with an EC50 value of 14.54 ± 0.83 µM. Further in vitro experiments showed that Compound 6 could significantly inhibit the proliferation of various tumor cell lines such as pancreatic cancer cells and lung cancer cells, reduce intracellular lactic acid content and increase intracellular reactive oxygen species (ROS) level. In summary, through virtual screening and in vitro validation, we found that Compound 6 is a small molecule inhibitor for LDHA, providing a good lead compound for the research and development of LDHA related targeted anti-tumor drugs.

Synthesis and characterization of mesoporous silicas with dendritic and spongy-like structures: Potential supports for human lactate dehydrogenase-based microreactors aimed at anticancer inhibitor screening

Mesoporous silica are versatile materials with wide-ranging potential. Notably, they excel as enzyme supports. This work examines the influence of three distinct siliceous mesoporous materials used as supports for the enzyme human lactate dehydrogenase (hLDH-A). Drugs with inhibition effects have recently shown favorable effects on diminishing the proliferation of cancerous cells. The ultimate goal of this research is to produce a stable and effective biocatalyst suitable for being employed in a microreactor for the screening of hLDH-A inhibitors. The synthesized mesoporous silica exhibited distinctive structural features, including a quasi-mesocellular network, bent-channels structure, and a dendritic geometry with radial symmetry, as evidenced by FESEM and HR-TEM. These materials were functionalized with amino and aldehyde groups to covalently immobilize hLDH-A. Characterization of both pristine and functionalized materials involved a comprehensive examination of their physico-chemical properties. The CO dosing revealed Brønsted acidity characteristic of mesoporous silica, while FT-IR spectroscopy and N2 physisorption at 77 K confirmed their successful functionalization. Enzyme immobilization on the functionalized supports, performed with stabilizing agents such as PEG (0.05 mg mL−1) or trehalose (300 mM), produced promising results. The immobilization yield consistently exceeded 80 %, with retained activity reaching values as high as 15 %. The immobilization of the enzyme on mesoporous silica increased the stability of hLDH-A against alkaline and organic solutions. These findings hold significance for those exploring siliceous porous supports for enzyme immobilization, paving the way for the development of stable and active biocatalysts.

Computational Analysis and NGS for Human LDHC Complexed with NAD+ and Ethylamino Acetic Acid (Lung Cancer)

Abstract: This study presents a multidimensional exploration of the structural and functional characteristics of the human Lactate Dehydrogenase C (LDHC) complexed with NAD+ and ethylamino acetic acid (EAA), focusing on its implications in lung cancer. Leveraging data from the Protein Data Bank (PDB) and Molecular Modeling Database (MMDB), a comprehensive analysis was conducted using various computational tools and resources. Structural insights were gained through PDBsum and RasMol, elucidating molecular interactions and identifying potential drug-target sites. Sequence analysis via BLAST and Multiple Sequence Alignment provided further understanding of conserved sequences and structural motifs. Visualization and manipulation of molecular structures were facilitated by PyMOL, enabling the identification of active drug-target sites. Proteinligand docking studies using the CB-Dock2 server assessed the efficiency of LDHC complexation with NAD+. Structural validation through the SAVES server ensured the reliability of the complex structure. Additionally, biological network analysis using the STRING database revealed associations with gene ontology and structural classification of the protein, offering insights into targeted interventions in the ancestry of the protein. This comprehensive approach provides valuable insights into LDHC's role in cancer biology and offers promising avenues for therapeutic development in lung cancer.

Possible inhibitory effects of hoslundal, hoslundin and hoslunddiol on human lactate dehydrogenases: a bioinformatics proof

The development of anti-malarial drugs is of great importance due to the detrimental effects of this disease all around the world. In recent years, bioinformatics tools provide considerable contributions to develop new small molecules which have important bioactivities against many bio-targets. However, biases in the methodologies or aims of the studies in which in silico tools are used may reveal problematic cases. Hoslundal, hoslundin, and hoslunddiol were proposed by Shadrack et al. (2016) to inhibit Plasmodium falciparum lactate dehydrogenase (Pf-LDH) to fight malaria. But these molecules may have potential to inhibit mammalian LDHs. To investigate whether these molecules have inhibitions on mammalian LDHs or not, we studied a comprehensive and comparative molecular docking studies as described in the present paper. According to the results, the vina scores of hoslundal without NADH for Pf-LDH, HM-LDH, HH-LDH were found as -7.5, -7.6 and -8.2 kJ/mol, respectively. Moreover, multiple sequence alignment analysis reveals high similarities among sequences. In the light of molecular studies, hoslundal were found to be connected to Pf-LDH, HM-LDH, HH-LDH (31, 26, 34), (2, -7, 154), (11, 41, 54), respectively. In conclusion, novel small molecules which are developed via in silico tools could show excellent activities against bio-targets of the pathogenic microorganisms. However, it should not be forgotten that active site of the enzymes is conserved, therefore, after a possible proposal of small molecule, its molecular docking and also Swiss-ADME studies should be necessarily carried out.

Oxaloacetate as a Holy Grail Adjunctive Treatment in Gliomas: A Revisit to Metabolic Pathway.

India experiences a significant amount of morbidity and mortality due to gliomas particularly glioblastoma multiforme (GBM), which ranks among the worst cancers. Oxaloacetate (OAA) is a human keto acid that is central to cellular metabolism; it has been recognized by the US FDA for use in GBM patients, triggering a review to revisit the cellular mechanism of its therapeutic action.Various cellular and molecular studies have proposed that instead of fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), gliomas prefer to use glycolysis (the Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis. A study found that oxaloacetate (OAA) inhibits human lactate dehydrogenase A (LDHA) in cancer cells, reversing the Warburg effect. Studies revealed that OAA supplementation reduced Warburg glycolysis, improved neuronal cell bioenergetics, and triggered brain mitochondrial biogenesis, thereby enhancing the efficacy of standard treatment. Similarly, OAA has been found in preclinical investigations to be able to decrease tumor development and survival rates by blocking the conversion of glutamine to alpha-ketoglutarate (alpha-KG) in the TCA cycle and lowering nicotinamide adenine dinucleotide phosphate (NADPH) levels. OAAis a safe adjuvant that has the potential to be an effective therapy in gliomas when combined with temozolomide (TMZ) chemotherapy and routine surgery.

A Review Concerning the Use of Etravirine and Darunavir in Translational Medicine

This comprehensive review explores two antiretroviral drugs, Etravirine (ETV) and Darunavir (DRV), a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor, that are commonly used in human immunodeficiency virus (HIV) infection treatment, often in combination with each other. The pharmacokinetic properties of these drugs are covered as well as the clinical trials of these two drugs combined. This paper also delves into the possible repurposing of these two drugs for other diseases, with drug repurposing being a significant factor in addressing global health challenges. DRV was extensively studied for treating COVID-19, as well as other infections, such as candidiasis and cryptococcosis, while ETV proved to be efficient in hampering Zika virus brain infection. The focus on cancer repurposing is also explored, with the results revealing that ETV has a particular inhibitory effect on ovarian cancer in vitro and on cancer molecules, such as anterior gradient protein 2 homolog (AGR2) and casein kinase 1 (CK1ε), and that DRV has an in silico inhibitory effect on human lactate dehydrogenase A (LDHA) and induces the in vitro and in vivo inhibition of pepsin, consequent laryngopharyngeal reflux, and possible laryngeal and hypopharyngeal carcinomas. The significance of fresh methods of drug development is emphasized in this work, as is the enormous potential for new therapeutic uses of the antiretroviral drugs ETV and DRV in viral and non-viral disorders.

Preparation of a Mesoporous Biosensor for Human Lactate Dehydrogenase for Potential Anticancer Inhibitor Screening.

Cancer is the second leading cause of death worldwide, with a dramatic impact due to the acquired resistance of cancers to used chemotherapeutic drugs and treatments. The enzyme lactate dehydrogenase (LDH-A) is responsible for cancer cell proliferation. Recently the development of selective LDH-A inhibitors as drugs for cancer treatment has been reported to be an efficient strategy aiming to decrease cancer cell proliferation and increase the sensitivity to traditional chemotherapeutics. This study aims to obtain a stable and active biocatalyst that can be utilized for such drug screening purposes. It is conceived by adopting human LDH-A enzyme (hLDH-A) and investigating different immobilization techniques on porous supports to achieve a stable and reproducible biosensor for anticancer drugs. The hLDH-A enzyme is covalently immobilized on mesoporous silica (MCM-41) functionalized with amino and aldehyde groups following two different methods. The mesoporous support is characterized by complementary techniques to evaluate the surface chemistry and the porous structure. Fluorescence microscopy analysis confirms the presence of the enzyme on the support surface. The tested immobilizations achieve yields of ≥80%, and the best retained activity of the enzyme is as high as 24.2%. The optimal pH and temperature of the best immobilized hLDH-A are pH 5 and 45 °C for the reduction of pyruvate into lactate, while those for the free enzyme are pH 8 and 45 °C. The stability test carried out at 45 °C on the immobilized enzyme shows a residual activity close to 40% for an extended time. The inhibition caused by NHI-2 is similar for free and immobilized hLDH-A, 48% and 47%, respectively. These findings are significant for those interested in immobilizing enzymes through covalent attachment on inorganic porous supports and pave the way to develop stable and active biocatalyst-based sensors for drug screenings that are useful to propose drug-based cancer treatments.

Synthesis and hLDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold.

Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. hLDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new hLDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (42-70) by reaction between flavylium salts (27-35) and several nucleophiles (36-41). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC50 values lower than 10 µM against hLDHA and better activity than our previously reported compound 2. In order to know the selectivity of the synthesized compounds against hLDHA, their hLDHB inhibitory activities were also measured. In particular, compounds 58, 62a, 65b, and 68a have shown the lowest IC50 values against hLDHA (3.6-12.0 µM) and the highest selectivity rate (>25). Structure-activity relationships have been deduced. Kinetic studies using a Lineweaver-Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on hLDHA enzyme.

Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme.

A new series of thiazole central scaffold-based small molecules of hLDHA inhibitors were designed using an in silico approach. Molecular docking analysis of designed molecules with hLDHA (PDB ID: 1I10) demonstrates that Ala 29, Val 30, Arg 98, Gln 99, Gly 96, and Thr 94 possessed strong interaction with the compounds. Compounds 8a, 8b, and 8d showed good binding affinity (-8.1 to -8.8 kcal/mol), whereas an additional interaction of NO2 at the ortho position in compounds 8c with Gln 99 through hydrogen bonding enhanced the affinity to -9.8 kcal/mol. Selected high-scored compounds were synthesized and screened for hLDHA inhibitory activities and in vitro anticancer activity in six cancer cell lines. Biochemical enzyme inhibition assays showed the highest hLDHA inhibitory activity observed with compounds 8b, 8c, and 8l. Compounds 8b, 8c, 8j, 8l, and 8m depicted significant anticancer activities, exhibiting IC50 values in the range of 1.65-8.60 μM in HeLa and SiHa cervical cancer cell lines. Compounds 8j and 8m exhibited notable anticancer activity with IC50 values of 7.90 and 5.15 μM, respectively, in liver cancer cells (HepG2). Interestingly, compounds 8j and 8m did not induce noticeable toxicity in the human embryonic kidney cells (HEK293). Insilico absorption, distribution, metabolism, and excretion profiling demonstrates that the compounds possess drug-likeness, and results may pave the way for the development of novel thiazole-based biologically active small molecules for therapeutics.

Proanthocyanidins in Pruning Wood Extracts of Four European Plum (Prunus domestica L.) Cultivars and Their hLDHA Inhibitory Activity

European plum tree (Prunus domestica L.) is cultivated in many countries for its delicious and nutritive fruit and, accordingly, certain amounts of wood (from pruning works) are generated every year. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from four European plum cultivars was investigated, and the human lactate dehydrogenase A (hLDHA) inhibitory activity of plum wood extracts and pure proanthocyanidins present in those extracts was measured. For the chemical characterization, total phenolic content and DPPH radical-scavenging assays and HPLC-DAD/ESI-MS analyses were performed, the procyanidin (-)-ent-epicatechin-(2α→O→7,4α→8)-catechin (4), the phenolic glucoside (-)-annphenone (3) and the flavan-3-ol catechin (1) being the major components of the wood extracts. Some quantitative and qualitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.51 (cv. 'Claudia de Tolosa') to 8.51 (cv. 'De la Rosa') mg g-1 of dry wood. For the hLDHA inhibitory activity, six wood extracts and six proanthocyanidins were evaluated by a UV spectrophotometric assay, compound 4 showing the highest inhibitory activity (IC50 3.2 μM) of this enzyme involved on the excessive production of oxalate in the liver of patients affected by the rare disease Primary Hyperoxaluria.

Human lactate dehydrogenase and malate dehydrogenase possess the catalytic properties to produce aromatic α-hydroxy acid

Lactate dehydrogenase and malate dehydrogenase are the two main alpha-hydroxy acid dehydrogenases in the human body. We investigated the catalytic properties of human lactate dehydrogenase LDHC, LDHL6A and malate dehydrogenase MDH1 on aromatic α-keto acids phenylpyruvic acid, p-hydroxyphenylpyruvic acid and 3,4-dihydroxyphenylpyruvic acid. The optimum temperatures for LDHC, LDHL6A, and MDH1 are 37 °C, 35 °C, and 45 °C, respectively; and the optimum pH is 6.5, 6.5, and 5.5, respectively. The Km of LDHC for phenylpyruvic acid and 3,4-dihydroxyphenylpyruvic acid were 0.90 mM and 0.92 mM, respectively. LDHL6A has a high affinity for phenylpyruvic acid and 3,4-dihydroxyphenylpyruvic acid with Km of 0.77 mM and 0.80 mM, respectively; MDH1 has an extremely high affinity (Km = 0.46 mM) and catalytic efficiency (kcat/Km = 23.87 s−1·mM−1) for p-hydroxyphenylpyruvic acid. It also has a high affinity for 3,4-dihydroxyphenylpyruvic acid with a Km of 0.90 mM, but with a low affinity for phenylpyruvic acid (Km = 3.76 mM). The catalytic properties of human LDHC, LDHL6A, and MDH1 for the abovementioned aromatic α-keto acids may be one of the sources of L-phenyllactic acid, L-p-hydroxyphenyllactic acid, and L-3,4-dihydroxyphenyllactic acid in humans.

Exploring the possibility of drug repurposing for cancer therapy targeting human lactate dehydrogenase A: a computational approach

Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials. Communicated by Ramaswamy H. Sarma

Prepubertal-Type Testicular Tumors in Postpubertal Patients: Epidermoid Cyst and Well-Differentiated Neuroendocrine Tumor

A man in his late 30s presented with testicular pain. On further evaluation, he was found to have a testicular mass, and serum tumor markers that are frequently elevated in germ cell tumors (beta subunit of human chorionic gonadotropin, lactate dehydrogenase, and alpha-fetoprotein) were within normal limits. He underwent radical orchiectomy, which revealed a 4.0 cm cystic mass.

Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review.

Reprogramming cancer metabolism has become the hallmark of cancer progression. As the key enzyme catalyzing the conversion of pyruvate to lactate in aerobic glycolysis of cancer cells, human lactate dehydrogenase (LDH) has been a promising target in the discovery of anticancer agents. Natural products are important sources of new drugs. Up to now, some natural compounds have been reported with the activity to target LDH. To give more information on the development of LDH inhibitors and application of natural products, herein, we reviewed the natural compounds with inhibition of LDH from diverse structures and discussed the future direction of the discovery of natural LDH inhibitors for cancer therapy.