Disease relevance of LDHA

• Further, these analyses identify two syntenic clusters of muscle-associated genes on the short arm of human chromosome 11, one in the region of rhabdomyosarcoma locus that includes IGF2 and TH and the second the tightly linked MYOD1 and LDHA loci, which have been evolutionarily conserved in homologous regions of both the mouse and the rat genomes [1].
• Activation in transcription from the LDHA promoter increased by desferrioxamine treatment or hypoxia was further enhanced when PLAGL2 was expressed [2].
• Electrophoretic variant of a lactate dehydrogenase isoenzyme and selective promoter methylation of the LDHA gene in a human retinoblastoma cell line [3].
• Recurrent rhabdomyolysis due to decreased glycolysis occurred during strenuous exercise in patients with lactate dehydrogenase-A-subunit (LDH-A; muscle) deficiency [4].
• Hormonal regulation of lactate dehydrogenase-A through activation of protein kinase C pathways in MCF-7 breast cancer cells [5].

Psychiatry related information on LDHA

• Association of an exonic LDHA polymorphism with altered respiratory response in probands at high risk for panic disorder [6].
• Total LDH and isoenzyme LDH-1 were significantly higher, whereas the fractions of LDH-2 and LDH-3 were significantly lower in CJD patients [7].

High impact information on LDHA

• Here we report the observation of reactions of individual molecules of lactate dehydrogenase (LDH-1), which produces NADH from lactate and nicotinamide adenine dinucleotide (NAD+) [8].
• Therefore, new CK-MB or LDH1 elevations associated with arrhythmias must result from myocardial damage to DC cardioversion [9].
• To determine whether DC cardioversion affects these serum enzyme levels, we recorded total CK, total LDH, CK-MB, and LDH1 levels serially during 24 hours following elective DC cardioversion in 18 patients without cardiac ischemia [9].
• Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked [10].
• The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene [10].

Chemical compound and disease context of LDHA

• Using a transcription system from nuclear extracts of rat C6 glioma cells we have investigated the mechanism by which transcription from the lactate dehydrogenase A subunit (LDH) promoter is regulated via the cAMP-activated pathway [11].
• Increases in Ldh1 mRNA and LDH activity were not correlated with lactic acid production, which was maximal at the onset of anoxia in unacclimated roots and then declined [12].
• Serum malondialdehyde-like material (MDA-LM), as an index of lipid peroxidation, and the serum enzymes CK, CK-MB, LDH, LDH1 and, alpha-HBDH were evaluated in a group of 26 patients with acute myocardial infarction (AMI), seven with angina pectoris (AP), and in a normal control group of 94 subjects [13].
• Total lactate dehydrogenase and LDH-1 are supplemental to creatine kinase (CK) and CK-MB, while aspartate aminotransferase may be omitted in the diagnosis of myocardial infarction [14].
• Jaundice with increased indirect bilirubin, anemia with reticulocytosis, elevated plasma hemoglobin concentration and predominance of LDH1 were indicative of hemolysis [15].

Biological context of LDHA

• PCR analysis of sodium bisulfite-treated genomic DNA revealed that the CpG island in the promoter region around exon a of the LDHA gene was completely methylated [3].
• The structural gene LDHA has been previously assigned to human chromosome 11, while LDHB maps to chromosome 12 [16].
• However, the data presented in this paper show conclusively that LDHC is syntenic with LDHA on human chromosome 11 [16].
• Chromosomes 1, 2, 4, 9, and 10 appear to contain LDHA gene-related sequences, whereas the X chromosome and chromosome 13 possess LDHB gene-related sequences [17].
• But, comparison of LDHA exon 5 genotypes in PD probands (n = 25) to that of random newborn controls (n = 182) did not demonstrate any significant differences [6].

Anatomical context of LDHA

• The pattern of bands with LDHC hybridization is easily distinguished from the pattern detected by LDHA hybridization, and the LDHC probe is specific for testis mRNA [16].
• In situ hybridization data and analysis of mouse/human somatic cell hybrids carrying deletions of human chromosome 11 suggest that the gene is localized at p15.3-p15.5 close to the LDHA gene [18].
• In contrast, LDH-A and LDH-B were ubiquitously expressed in normal and tumor tissues, with LDH-B levels considerably lower and heterogeneous in normal samples compared to those expressed in tumor cell lines [19].
• All genotypes were consistent with their biochemical phenotypes as evaluated by the ratio of LDH-B to LDH-A subunits in erythrocytes [20].
• Eight cDNA clones for lactate dehydrogenase-A isozyme (LDH-A) were isolated from a human fibroblast cDNA library, characterized, and no sequence heterogeneity was found [21].

Associations of LDHA with chemical compounds

• Locus determining the human sperm-specific lactate dehydrogenase, LDHC, is syntenic with LDHA [16].
• The following loci could not be localized with full confidence: LDHA, NP, PEPD, ITP, and PGK [22].
• For the oxidation of glyoxylate, K(M) values were 0.18 mM and 0.26 mM for LDHA and LDHB respectively with NAD+ as cofactor [23].
• Neither LDHA nor LDHB utilised glycolate as substrate and NADPH was a poor cofactor with a relative activity less than 3% that of NADH [23].
• A combination of different indicators, such as opposite changes in LDH and alpha-glycerophosphate dehydrogenase activity, coupled with elevated proportions of LDH-M, may be used to diagnose neoplasia most reliably [24].

Physical interactions of LDHA

• The possible biochemical role of the tyrosylphosphorylated LDH-A complexed with ras p21 in cell transformation and progression of human ovarian cancer is worthy of further investigation [25].
• Herein we review current findings indicating that the c-Myc oncogenic transcription factor and hypoxia-inducible factor 1 (HIF-1) are able to bind the lactate dehydrogenase A promoter cis acting elements, which resemble the core carbohydrate response element (ChoRE), CACGTG [26].

Regulatory relationships of LDHA

• CONCLUSIONS: The somatic LDHA in R51 cells is transcriptionally silenced by promoter hypermethylation around exon a, leaving only LDHB to be expressed normally and a testis-specific variant transcript of LDHA containing exon 0 [3].
• In patients after administration of chemotherapy, TNF-alpha in a dose of 100 U/ml induced a significant increase ( p<0.05) of LDH-M isotype activity, but not of LDH-H [27].

Other interactions of LDHA

• Conserved canonical E boxes in ENO1, HK2, and LDHA occur in 31- to 111-bp islands with high interspecies sequence identity (>65%) [28].
• LD2ex possibly results from tetramerization of three wild-type LDHB molecules and one variant LDHA product [3].
• The difficulties observed for LDHA and VIL1 are probably due to the fact that these genes belong to large gene families and therefore suggest that they may not be the most appropriate markers for a standardisation effort [29].
• The Km values and specificity constants (Kcat/K(M)) of purified recombinant human LDHA, LDHB and GRHPR were determined for the reduction of glyoxylate and hydroxypyruvate [23].
• Southern and protein analysis of LDHA and ALB provided identical segregation data [30].

Analytical, diagnostic and therapeutic context of LDHA

• RESULTS: Northern blot analysis revealed that R51 cells expressed no wild-type/somatic LDHA mRNA, but did express a small amount of LDHA-related mRNA with a slightly higher molecular mass [3].
• Immunofluorescence staining showed the presence of LDH-A protein within the cytoplasm [4].
• The amplified fragment was examined by direct agarose gel electrophoresis, and a deletion of 20 base pairs (bp) in exon 6 of the LDH-A gene was found [20].
• We used polyacrylamide gradient gel and silver staining procedures for DCP analysis and observed abnormal migration patterns in individuals heterozygous for LDH-A deficiency [31].
• For GAPDH and LDH A higher protein levels in the tumors also were determined by Western blot analysis [32].

References