Lactate dehydrogenase A explained

Lactate dehydrogenase A (LDHA) is an enzyme which in humans is encoded by the LDHA gene.^[1] It is a monomer of Lactate dehydrogenase, which exists as a tetramer. The other main subunit is lactate dehydrogenase B (LDHB).

Function

Lactate dehydrogenase A catalyzes the inter-conversion of pyruvate and L-lactate with concomitant inter-conversion of NADH and NAD⁺. LDHA is found in most somatic tissues, though predominantly in muscle tissue and tumors, and belongs to the lactate dehydrogenase family. It has long been known that many human cancers have higher LDHA levels compared to normal tissues. It has also been shown that LDHA plays an important role in the development, invasion and metastasis of malignancies. Mutations in LDHA have been linked to exertional myoglobinuria.^[2]

LDHA Inhibitors

The following compounds have been demonstrated to inhibit the LDHA enzyme:

• Oxamate^[3]
• Epigallocatechin gallate^[4]
• Quinoline 3-sulfonamide^[5]

Further reading

• Miyajima H, Shimizu T, Kaneko E . [Gene expression in lactate dehydrogenase-A subunit deficiency] . Rinsho Shinkeigaku . 32 . 10 . 1087–92 . October 1992 . 1297552 .
• Sudo K, Maekawa M, Shioya M, Ikeda K, Takahashi N, Isogai Y, Li SS, Kanno T, Machida K, Toriumi J . Molecular analysis of genetic mutation in electrophoretic variant of human lactate dehydrogenase-A(M) subunit . Biochemistry International . 27 . 6 . 1051–7 . September 1992 . 1445373 .
• Maekawa M, Sudo K, Li SS, Kanno T . Analysis of genetic mutations in human lactate dehydrogenase-A(M) deficiency using DNA conformation polymorphism in combination with polyacrylamide gradient gel and silver staining . Biochemical and Biophysical Research Communications . 180 . 2 . 1083–90 . October 1991 . 1953713 . 10.1016/S0006-291X(05)81177-5 .
• Maekawa M, Sudo K, Li SS, Kanno T . Genotypic analysis of families with lactate dehydrogenase A (M) deficiency by selective DNA amplification . Human Genetics . 88 . 1 . 34–8 . November 1991 . 1959923 . 10.1007/BF00204925 . 19321774 .
• Scrable HJ, Johnson DK, Rinchik EM, Cavenee WK . Rhabdomyosarcoma-associated locus and MYOD1 are syntenic but separate loci on the short arm of human chromosome 11 . Proceedings of the National Academy of Sciences of the United States of America . 87 . 6 . 2182–6 . March 1990 . 2315312 . 53650 . 10.1073/pnas.87.6.2182 . 1990PNAS...87.2182S . free .
• Maekawa M, Sudo K, Kanno T, Li SS . Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency . Biochemical and Biophysical Research Communications . 168 . 2 . 677–82 . April 1990 . 2334430 . 10.1016/0006-291X(90)92374-9 . Submitted manuscript .
• Gosti F, Marty MC, Courvalin JC, Maunoury R, Bornens M . Centrosomal proteins and lactate dehydrogenase possess a common epitope in human cell lines . Proceedings of the National Academy of Sciences of the United States of America . 84 . 4 . 1000–4 . February 1987 . 2434947 . 304349 . 10.1073/pnas.84.4.1000 . 1987PNAS...84.1000G . free .
• Chung FZ, Tsujibo H, Bhattacharyya U, Sharief FS, Li SS . Genomic organization of human lactate dehydrogenase-A gene . Biochemical Journal . 231 . 3 . 537–41 . November 1985 . 3000353 . 1152784 . 10.1042/bj2310537.
• Tsujibo H, Tiano HF, Li SS . Nucleotide sequences of the cDNA and an intronless pseudogene for human lactate dehydrogenase-A isozyme . European Journal of Biochemistry . 147 . 1 . 9–15 . February 1985 . 3838278 . 10.1111/j.1432-1033.1985.tb08711.x . free .
• Glass RD, Doyle D . Genetic control of lactate dehydrogenase expression in mammalian tissues . Science . 176 . 4031 . 180–1 . April 1972 . 5014440 . 10.1126/science.176.4031.180 . 1972Sci...176..180G . 20224553 .
• Maekawa M, Sudo K, Kobayashi A, Sugiyama E, Li SS, Kanno T . Fast-type electrophoretic variant of lactate dehydrogenase M(A) and comparison with other missense mutations in lactate dehydrogenase M(A) and H(B) genes . Clinical Chemistry . 40 . 4 . 665–8 . April 1994 . 7908613 . 10.1093/clinchem/40.4.665. free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Miyajima H, Takahashi Y, Suzuki M, Shimizu T, Kaneko E . Molecular characterization of gene expression in human lactate dehydrogenase-A deficiency . Neurology . 43 . 7 . 1414–9 . July 1993 . 8327147 . 10.1212/wnl.43.7.1414 . 41011165 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ . Antigens recognized by autologous antibody in patients with renal-cell carcinoma . International Journal of Cancer . 83 . 4 . 456–64 . November 1999 . 10508479 . 10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5 . free .
• Vilà MR, Nicolás A, Morote J, de I, Meseguer A . Increased glyceraldehyde-3-phosphate dehydrogenase expression in renal cell carcinoma identified by RNA-based, arbitrarily primed polymerase chain reaction . Cancer . 89 . 1 . 152–64 . July 2000 . 10897012 . 10.1002/1097-0142(20000701)89:1<152::AID-CNCR20>3.0.CO;2-T . 44477008 .
• Boutet A, Altmeyer R, Héry C, Tardieu M . Direct role of plasma membrane-expressed gp120/41 in toxicity to human astrocytes induced by HIV-1-infected macrophages . AIDS . 14 . 17 . 2687–97 . December 2000 . 11125887 . 10.1097/00002030-200012010-00008 . 12747999 . free .
• Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL . Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase . Proteins . 43 . 2 . 175–85 . May 2001 . 11276087 . 10.1002/1097-0134(20010501)43:2<175::AID-PROT1029>3.0.CO;2-# . 196599144 .
• Sung JH, Shin SA, Park HK, Montelaro RC, Chong YH . Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells . Journal of NeuroVirology . 7 . 5 . 454–65 . October 2001 . 11582518 . 10.1080/135502801753170318 . 12958486 .
• Pioli PA, Hamilton BJ, Connolly JE, Brewer G, Rigby WF . Lactate dehydrogenase is an AU-rich element-binding protein that directly interacts with AUF1 . Journal of Biological Chemistry . 277 . 38 . 35738–45 . September 2002 . 12107167 . 10.1074/jbc.M204002200 . free .

Notes and References

1. Chung FZ, Tsujibo H, Bhattacharyya U, Sharief FS, Li SS . Genomic organization of human lactate dehydrogenase-A gene . Biochemical Journal . 231 . 3 . 537–41 . November 1985 . 3000353 . 1152784 . 10.1042/bj2310537.
2. Web site: Entrez Gene: LDHA lactate dehydrogenase A .
3. Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS, Choi JY . Synergistic anti-cancer effect of phenformin and oxamate . PLOS ONE . 9 . 1 . e85576 . 2014 . 24465604 . 3897486 . 10.1371/journal.pone.0085576 . 2014PLoSO...985576M . free .
4. Lu QY, Zhang L, Yee JK, Go VW, Lee WN . Metabolic Consequences of LDHA inhibition by Epigallocatechin Gallate and Oxamate in MIA PaCa-2 Pancreatic Cancer Cells . Metabolomics . 11 . 1 . 71–80 . February 2015 . 26246802 . 4523095 . 10.1007/s11306-014-0672-8 .
5. Billiard J, Dennison JB, Briand J, Annan RS, Chai D, Colón M, Dodson CS, Gilbert SA, Greshock J, Jing J, Lu H, McSurdy-Freed JE, Orband-Miller LA, Mills GB, Quinn CJ, Schneck JL, Scott GF, Shaw AN, Waitt GM, Wooster RF, Duffy KJ . Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells . Cancer & Metabolism . 1 . 1 . 19 . September 2013 . 24280423 . 4178217 . 10.1186/2049-3002-1-19 . free .