Lactate dehydrogenase A
Lactate dehydrogenase A (LDHA) is an enzyme which in humans is encoded by the LDHA gene.[5] It is a monomer of Lactate dehydrogenase b, 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.[6]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
Glycolysis and Gluconeogenesis edit
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Model organisms
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Abnormal |
| Recessive lethal study | Abnormal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Abnormal[7] |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Abnormal[8] |
| Plasma immunoglobulins | Normal |
| Haematology | Abnormal[9] |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Tail epidermis wholemount | Normal |
| Skin Histopathology | Normal |
| Brain histopathology | Normal |
| Salmonella infection | Normal[10] |
| Citrobacter infection | Normal[11] |
| All tests and analysis from[12][13] |
Model organisms have been used in the study of LDHA function. A conditional knockout mouse line, called Ldhatm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty seven tests were carried out on mutant mice and five significant abnormalities were observed.[12] Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Animals of both sex had abnormal plasma chemistry, males also had improved glucose tolerance and increased red blood cell distribution width.[12]
LDHA Inhibitors
The following compounds have been demonstrated to inhibit the LDHA enzyme:
- Oxamate[20]
- Epigallocatechin gallate[21]
- Quinoline 3-sulfonamide[22]
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References
- ENSG00000288299 GRCh38: Ensembl release 89: ENSG00000134333, ENSG00000288299 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000063229 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Chung FZ, Tsujibo H, Bhattacharyya U, Sharief FS, Li SS (November 1985). "Genomic organization of human lactate dehydrogenase-A gene". Biochemical Journal. 231 (3): 537–41. doi:10.1042/bj2310537. PMC 1152784. PMID 3000353.
- "Entrez Gene: LDHA lactate dehydrogenase A".
- "Glucose tolerance test data for Ldha". Wellcome Trust Sanger Institute.
- "Clinical chemistry data for Ldha". Wellcome Trust Sanger Institute.
- "Haematology data for Ldha". Wellcome Trust Sanger Institute.
- "Salmonella infection data for Ldha". Wellcome Trust Sanger Institute.
- "Citrobacter infection data for Ldha". Wellcome Trust Sanger Institute.
- Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- Mouse Resources Portal, Wellcome Trust Sanger Institute.
- "International Knockout Mouse Consortium".
- "Mouse Genome Informatics".
- Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
- Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS, Choi JY (2014). "Synergistic anti-cancer effect of phenformin and oxamate". PLoS One. 9 (1): e85576. Bibcode:2014PLoSO...985576M. doi:10.1371/journal.pone.0085576. PMC 3897486. PMID 24465604.
- Lu QY, Zhang L, Yee JK, Go VW, Lee WN (February 2015). "Metabolic Consequences of LDHA inhibition by Epigallocatechin Gallate and Oxamate in MIA PaCa-2 Pancreatic Cancer Cells". Metabolomics. 11 (1): 71–80. doi:10.1007/s11306-014-0672-8. PMC 4523095. PMID 26246802.
- 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 (September 2013). "Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells". Cancer & Metabolism. 1 (1): 19. doi:10.1186/2049-3002-1-19. PMC 4178217. PMID 24280423.
Further reading
- Miyajima H, Shimizu T, Kaneko E (October 1992). "[Gene expression in lactate dehydrogenase-A subunit deficiency]". Rinsho Shinkeigaku. 32 (10): 1087–92. PMID 1297552.
- Sudo K, Maekawa M, Shioya M, Ikeda K, Takahashi N, Isogai Y, Li SS, Kanno T, Machida K, Toriumi J (September 1992). "Molecular analysis of genetic mutation in electrophoretic variant of human lactate dehydrogenase-A(M) subunit". Biochemistry International. 27 (6): 1051–7. PMID 1445373.
- Maekawa M, Sudo K, Li SS, Kanno T (October 1991). "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. doi:10.1016/S0006-291X(05)81177-5. PMID 1953713.
- Maekawa M, Sudo K, Li SS, Kanno T (November 1991). "Genotypic analysis of families with lactate dehydrogenase A (M) deficiency by selective DNA amplification". Human Genetics. 88 (1): 34–8. doi:10.1007/BF00204925. PMID 1959923.
- Scrable HJ, Johnson DK, Rinchik EM, Cavenee WK (March 1990). "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. Bibcode:1990PNAS...87.2182S. doi:10.1073/pnas.87.6.2182. PMC 53650. PMID 2315312.
- Maekawa M, Sudo K, Kanno T, Li SS (April 1990). "Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency". Biochemical and Biophysical Research Communications (Submitted manuscript). 168 (2): 677–82. doi:10.1016/0006-291X(90)92374-9. PMID 2334430.
- Gosti F, Marty MC, Courvalin JC, Maunoury R, Bornens M (February 1987). "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. Bibcode:1987PNAS...84.1000G. doi:10.1073/pnas.84.4.1000. PMC 304349. PMID 2434947.
- Chung FZ, Tsujibo H, Bhattacharyya U, Sharief FS, Li SS (November 1985). "Genomic organization of human lactate dehydrogenase-A gene". Biochemical Journal. 231 (3): 537–41. doi:10.1042/bj2310537. PMC 1152784. PMID 3000353.
- Tsujibo H, Tiano HF, Li SS (February 1985). "Nucleotide sequences of the cDNA and an intronless pseudogene for human lactate dehydrogenase-A isozyme". European Journal of Biochemistry. 147 (1): 9–15. doi:10.1111/j.1432-1033.1985.tb08711.x. PMID 3838278.
- Glass RD, Doyle D (April 1972). "Genetic control of lactate dehydrogenase expression in mammalian tissues". Science. 176 (4031): 180–1. Bibcode:1972Sci...176..180G. doi:10.1126/science.176.4031.180. PMID 5014440.
- Maekawa M, Sudo K, Kobayashi A, Sugiyama E, Li SS, Kanno T (April 1994). "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. doi:10.1093/clinchem/40.4.665. PMID 7908613.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Miyajima H, Takahashi Y, Suzuki M, Shimizu T, Kaneko E (July 1993). "Molecular characterization of gene expression in human lactate dehydrogenase-A deficiency". Neurology. 43 (7): 1414–9. doi:10.1212/wnl.43.7.1414. PMID 8327147.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ (November 1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". International Journal of Cancer. 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479.
- Vilà MR, Nicolás A, Morote J, de I, Meseguer A (July 2000). "Increased glyceraldehyde-3-phosphate dehydrogenase expression in renal cell carcinoma identified by RNA-based, arbitrarily primed polymerase chain reaction". Cancer. 89 (1): 152–64. doi:10.1002/1097-0142(20000701)89:1<152::AID-CNCR20>3.0.CO;2-T. PMID 10897012.
- Boutet A, Altmeyer R, Héry C, Tardieu M (December 2000). "Direct role of plasma membrane-expressed gp120/41 in toxicity to human astrocytes induced by HIV-1-infected macrophages". AIDS. 14 (17): 2687–97. doi:10.1097/00002030-200012010-00008. PMID 11125887.
- Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL (May 2001). "Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase". Proteins. 43 (2): 175–85. doi:10.1002/1097-0134(20010501)43:2<175::AID-PROT1029>3.0.CO;2-#. PMID 11276087.
- Sung JH, Shin SA, Park HK, Montelaro RC, Chong YH (October 2001). "Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells". Journal of NeuroVirology. 7 (5): 454–65. doi:10.1080/135502801753170318. PMID 11582518.
- Pioli PA, Hamilton BJ, Connolly JE, Brewer G, Rigby WF (September 2002). "Lactate dehydrogenase is an AU-rich element-binding protein that directly interacts with AUF1". Journal of Biological Chemistry. 277 (38): 35738–45. doi:10.1074/jbc.M204002200. PMID 12107167.
External links
- Overview of all the structural information available in the PDB for UniProt: P00338 (Human L-lactate dehydrogenase A chain) at the PDBe-KB.
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