Open Access Open Access  Restricted Access Subscription Access

Cellular Level, Molecular Level, Function, Mechanism, Patho Physiology and Clinical Significance of Lactate Dehydrogenase

Muralinath E., Guruprasad M., Madhavi Latha C., Sheethal U., Rajitha V., Manohar U., Srinadh G., Rohitha K.

Abstract


One crucial component of the anaerobic metabolic process is lactate dehydrogenase (LDH). It belongs to the class of oxidoreductases and has the EC 1.1.1.27 enzyme commission number. The enzyme's role is to catalyze the reduction of NAD+ to NADH and the reversible conversion of lactate to pyruvate. Numerous creatures, including plants and animals, have enzymes. It is seen in all tissues in a ubiquitous manner.and acts as an important checkpoint of gluconeogenesis and DNA metabolism. A species-wide examination of LDH reveals that its structure is largely intact and that the amino acid sequence varies very little between species. The structural similarity along with slight amino acid changes arranges a logical platform for designing functional molecules to modulate the catalytic potential as well as expression of the enzyme. The LDH enzyme's biochemical role, testing procedures, and clinical significance will all be covered in this article.

 


Full Text:

PDF

References


Schumann, G., Bonora, R., Ceriotti, F., Clerc-Renaud, P., Ferrero, C. A., Férard, G., Franck, P. F., Gella, F. J., Hölzel, W., Jørgensen, P. J., Kanno, T., Kessner, A., Klauke, R., Kristiansen, N., Lessinger, J. M., Linsinger, T. P., Misaki, H., Panteghini, M., Pauwels, J., Schimmel, H. G., Vialle, A., Weidemann, G., & Siekmann, L. (2002). IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 °C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase. Clinical Chemistry and Laboratory Medicine, 40(6), 643–648.

Holmes, R. S., & Goldberg, E. (2009). Computational analyses of mammalian lactate dehydrogenases: Human, mouse, opossum and platypus LDHs. Computational Biology and Chemistry, 33(5), 379–385.

Drent, M., Cobben, N. A., Henderson, R. F., Wouters, E. F., & van Dieijen-Visser, M. (1996). Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. European Respiratory Journal, 9(8), 1736–1742.

Read, J. A., Winter, V. J., Eszes, C. M., Sessions, R. B., & Brady, R. L. (2001). Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins: Structure, Function, and Bioinformatics, 43(2), 175–185.

Khan, A. A., Allemailem, K. S., Alhumaydhi, F. A., Gowder, S. J. T., & Rahmani, A. H. (2020). The biochemical and clinical perspectives of lactate dehydrogenase: An enzyme of active metabolism. Endocrine, Metabolic & Immune Disorders – Drug Targets, 20(6), 855–868.

Passarella, S., & Schurr, A. (2018). L-lactate transport and metabolism in mitochondria of Hep G2 cells: The Cori cycle revisited. Frontiers in Oncology, 8, Article 120.

Liang, X., Liu, L., Fu, T., Zhou, Q., Zhou, D., Xiao, L., Liu, J., Kong, Y., Xie, H., Yi, F., Lai, L., Vega, R. B., Kelly, D. P., Smith, S. R., & Gan, Z. (2016). Exercise-inducible lactate dehydrogenase B regulates mitochondrial function in skeletal muscle. Journal of Biological Chemistry, 291(49), 25306–25318.

de Bari, L., & Atlante, A. (2018). Including the mitochondrial metabolism of L-lactate in cancer metabolic reprogramming. Cellular and Molecular Life Sciences, 75(15), 2763–2776.

Laughton, J. D., Charnay, Y., Belloir, B., Pellerin, L., Magistretti, P. J., & Bouras, C. (2000). Differential messenger RNA distribution of lactate dehydrogenase LDH-1 and LDH-5 isoforms in the rat brain. Neuroscience, 96(3), 619–625.

Markert, C. L., Shaklee, J. B., & Whitt, G. S. (1975). Evolution of a gene: Multiple genes for LDH isozymes provide a model of the evolution of gene structure, function, and regulation. Science, 189(4197), 102–114.

Schueren, F., Lingner, T., George, R., Hofhuis, J., Dickel, C., Gärtner, J., & Thoms, S. (2014). Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals. eLife, 3, e03640.

Auerbach, G., Ostendorp, R., Prade, L., Korndörfer, I., Dams, T., Huber, R., & Jaenicke, R. (1998). Lactate dehydrogenase from the hyperthermophilic bacterium Thermotoga maritima: Crystal structure at 2.1 Å resolution reveals strategies for intrinsic protein stabilization. Structure, 6(6), 769–781.

Eventoff, W., Rossmann, M. G., Taylor, S. S., Torff, H. J., Meyer, H., Keil, W., & Kiltz, H. H. (1977). Structural adaptations of lactate dehydrogenase isozymes. Proceedings of the National Academy of Sciences of the United States of America, 74(7), 2677–2681.

Adeva-Andany, M., López-Ojén, M., Funcasta-Calderón, R., Ameneiros-Rodríguez, E., Donapetry-García, C., Vila-Altesor, M., & Rodríguez-Seijas, J. (2014). Comprehensive review on lactate metabolism in human health. Mitochondrion, 17, 76–100.

Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P., Evans, K. A., Nielsen, H. B., & Secher, N. H. (2012). Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB Journal, 26(7), 3012–3020.

Liberti, M. V., & Locasale, J. W. (2016). The Warburg effect: How does it benefit cancer cells? Trends in Biochemical Sciences, 41(3), 211–218.

Al Bawab, A. Q., Zihlif, M., Jarrar, Y., & Sharab, A. (2021). Continuous hypoxia and glucose metabolism: Effects on gene expression in the MCF-7 breast cancer cell line. Endocrine, Metabolic & Immune Disorders – Drug Targets, 21(3), 511–519.

Shi, Y., & Pinto, B. M. (2014). Human lactate dehydrogenase A inhibitors: A molecular dynamics investigation. PLOS ONE, 9(1), e86365.

Spriet, L. L., Howlett, R. A., & Heigenhauser, G. J. (2000). An enzymatic approach to lactate production in human skeletal muscle during exercise. Medicine & Science in Sports & Exercise, 32(4), 756–763.

Valvona, C. J., Fillmore, H. L., Nunn, P. B., & Pilkington, G. J. (2016). The regulation and function of lactate dehydrogenase A: Therapeutic potential in brain tumor. Brain Pathology, 26(1), 3–17.

Tokinoya, K., Ishikura, K., Yoshida, Y., Ra, S. G., Sugasawa, T., Aoyagi, A., Nabekura, Y., Takekoshi, K., & Ohmori, H. (2020). LDH isoenzyme 5 as an index of early onset muscle soreness during prolonged running. Journal of Sports Medicine and Physical Fitness, 60(7), 1020–1026.

Feng, Y., Xiong, Y., Qiao, T., Li, X., Jia, L., & Han, Y. (2018). Lactate dehydrogenase A: A key player in carcinogenesis and a potential target in cancer therapy. Cancer Medicine, 7(12), 6124–6136.

Mercer, R. M., Corcoran, J. P., Porcel, J. M., Rahman, N. M., & Psallidas, I. (2019). Interpreting pleural fluid results. Clinical Medicine, 19(3), 213–217.

Jurisic, V., Radenkovic, S., & Konjevic, G. (2015). The actual role of LDH as tumor marker: Biochemical and clinical aspects. Advances in Experimental Medicine and Biology, 867, 115–124.

Mishra, D., & Banerjee, D. (2019). Lactate dehydrogenases as metabolic links between tumor and stroma in the tumor microenvironment. Cancers, 11(6), Article 750.

Gallo, M., Sapio, L., Spina, A., Naviglio, D., Calogero, A., & Naviglio, S. (2015). Lactic dehydrogenase and cancer: An overview. Frontiers in Bioscience (Landmark Edition), 20(8), 1234–1249.

Liu, J., Chen, G., Liu, Z., Liu, S., Cai, Z., You, P., Ke, Y., Lai, L., Huang, Y., Gao, H., Zhao, L., Pelicano, H., Huang, P., McKeehan, W. L., Wu, C. L., Wang, C., Zhong, W., & Wang, F. (2018). Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer. Cancer Research, 78(16), 4459–4470.

Granchi, C., Bertini, S., Macchia, M., & Minutolo, F. (2010). Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Current Medicinal Chemistry, 17(7), 672–697.

Di Bussolo, V., Calvaresi, E. C., Granchi, C., Del Bino, L., Frau, I., Lang, M. C., Tuccinardi, T., Macchia, M., Martinelli, A., Hergenrother, P. J., & Minutolo, F. (2015). Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroxyindole class LDH inhibitors as anticancer agents. RSC Advances, 5(26), 19944–19954.

Urbańska, K., & Orzechowski, A. (2019). Unappreciated role of LDHA and LDHB in controlling apoptosis and autophagy in tumor cells. International Journal of Molecular Sciences, 20(9), Article 2085.

Augoff, K., Hryniewicz-Jankowska, A., & Tabola, R. (2015). Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer. Cancer Letters, 358(1), 1–7.

Martens, A., Wistuba-Hamprecht, K., Geukes Foppen, M., Yuan, J., Postow, M. A., Wong, P., Romano, E., Khammari, A., Dréno, B., Capone, M., Ascierto, P. A., Di Giacomo, A. M., Maio, M., Schilling, B., Sucker, A., Schadendorf, D., Hassel, J. C., Eigentler, T. K., Martus, P., Wolchok, J. D., Blank, C., Pawelec, G., Garbe, C., & Weide, B. (2016). Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clinical Cancer Research, 22(12), 2908–2918.

Weide, B., Martens, A., Hassel, J. C., Berking, C., Postow, M. A., Bisschop, K., Simeone, E., Mangana, J., Schilling, B., Di Giacomo, A. M., Brenner, N., Kähler, K., Heinzerling, L., Gutzmer, R., Bender, A., Gebhardt, C., Romano, E., Meier, F., Martus, P., Maio, M., Blank, C., Schadendorf, D., Dummer, R., Ascierto, P. A., Hospers, G., Garbe, C., & Wolchok, J. D. (2016). Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clinical Cancer Research, 22(22), 5487–5496.

Bedikian, A. Y., Millward, M., Pehamberger, H., Conry, R., Gore, M., Trefzer, U., Pavlick, A. C., DeConti, R., Hersh, E. M., Hersey, P., Kirkwood, J. M., Haluska, F. G., & Oblimersen Melanoma Study Group. (2006). Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma. Journal of Clinical Oncology, 24(29), 4738–4745.

Smylie, M. G. (2020). Use of immuno-oncology in melanoma. Current Oncology, 27(Suppl 2), S51–S58.


Refbacks

  • There are currently no refbacks.