Question

1. An important paper published by Granchi et al. summarizes therapeutic potential of lactate dehydrogenase inhibitors (Curr Med Chem. 2010;17(7):672-97). Part of the abstract from this paper is shown below: Abstract: "In many different species, lactate dehydrogenase (LDH) constitutes a major checkpoint of anaerobic glycolysis, by catalyzing the reduction of pyruvate into lactate. This enzyme has recently received a great deal of attention since it may constitute a valid therapeutic target for diseases so different as malaria and cancer. In fact, the isoform expressed by Plasmodium falciparum (ELDH) is a key enzyme for energy generation of malarial parasites. These species mostly depend on anaerobic glycolysis for energy production, since they lack a citric acid cycle for ATP formation. Therefore, several small organic molecules have been recently designed and developed with the aim of blocking this new potential antimalarial chemotherapeutic target. Moreover, most invasive tumor phenotypes show a metabolic switch (Warburg effect) from oxidative phosphorylation to an increased anaerobic glycolysis, by promoting an upregulation of the human isoform-5 of lactate dehydrogenase (hLDH-5 or LDH-A), which is normally present in muscles and in the liver. Hence, inhibition of hLDH-5 may constitute an efficient way to interfere with tumor growth and invasiveness." a. Why is conversion of pyruvate to lactate necessary for glycolysis under anaerobic conditions? Why there is no conversion of pyruvate to lactate under aerobic conditions? Explain your answer. (12pt) b. Which glycolytic step would be affected by lactate dehydrogenase inhibitors? What glycolytic intermediate(s) would accumulate in the presence of lactate dehydrogenase inhibitors? Explain your answer. (7pt) c. Explain why the presence of lactate dehydrogenase inhibitors may cause mortality of P. falciparum and interfere with tumor growth and invasiveness? (2pt)

Answer 1

Solution :

a) Under anaerobic condition(oxygen is unavailable), fermentation will takes place in animal cells. This fermentation will results in the production of lactic acid. During exercise, oxygen will become acarce in mammalian skeletal muscle cells. So there is no oxygen available for further oxidising the pyruvate produced during glycolysis. Due to this reason muscle cells convert pyruvate in to lactic acid through a reduction reaction. Once it reaches the blood, some of the lactic acid passes through the liver, where it gets reoxidized to pyruvate and then to CO2 aerobically or back to glucose. Under aerobic condition, enough oxygen is available for further oxidising the pyruvate to acetyl coA to enter TCA cycle for the generation of high energy co enzymes such as NADH, FADH2 etc.

b) The conversion of pyruvic acid to lactic acid would be affected by the action of lactate dehydrogenase inhibitors. By the action of lactate dehydrogenase inhibitors, pyruvic acid and NADH gets accumulated in the cell.

c) Plasmodium falciparum is the causative organism for deadly disease malaria. The Lactate dehydrogenase in Plasmodium falciparum, also called as Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) is considered as a potential target for PfLDH inhibitors. It includes several antimalarial drugs. By inhibiting the lactate dehydogenase these inhibitors or drugs prevent the production of energy molecules such as ATP in Plasmodium falciparum cells which eventually leads to the death of the organism.