There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.
LACTATE DEHYDROGENASELactate dehydrogenase (LDH) is a tetrameric enzyme, belonging to the 2-hydroxy acid oxidoreductase family, which increases the rate of the simultaneous inter-conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD + by 14 orders of magnitude (10) (Figure 1). The reaction involves the transfer of a hydride ion from NADH to the C2 carbon of pyruvate (99) and is commonly used by cells for anaerobic respiration. There are four LDH genes: LDHA, LDHB, LDHC and LDHD (Figure 2). LDHA, LDHB and LDHC are L isomers, whereas LDHD is a D isomer. The L isomers use or produce L-lactate, which is the major enantiomer found in vertebrates.The human LDHA gene is located on chromosome 11p15.4, the transcribed protein has 332 amino acids, a predicted molecular weight of 37 kDa and 24 splice variants; the human genome also contains several non-transcribed LDHA pseudogenes (32, 126). Evolutionarily, LDHA and LDHB are thought to have arisen from the duplication of a single LDHA-like LDH gene (82). LDHC, a testes-specific gene, is also thought to have evolved in mammals from the duplication of the LDHA gene after the A-B duplication (82).LDHA is also known as the M subunit as it is predominantly found in skeletal muscle, and LDHB is also known as the H subunit as it is predominantly found in the heart. Unlike the other LDH genes, which can form only homotetramers, LDHA and LDHB can form homo-or heterotetramers. There are five isoenzymes of LDH that can be made from the M and H subunits: LDH-1 (4H), LDH-2 (3H, 1M), LDH-3 (2H, 2M), LDH-4 (1H, 3M), and LDH-5 (5M) (Figure 2). LDH-1 and LDH-5 have identical active site regions and only differ in 81 out of 332 amino acid positions, mo...
