**1. Introduction**

164 Dehydrogenases

2012; 499: 250-255.

Biology 2004; 342; 943–952.

[252] Geissler W, Davis D, Wu L, Bradshaw K, Patel S, Mendonca B, Elliston K, Wilson J, Russell D. Andersson S. Male pseudohermaphroditism caused by mutations of

[254] Neocleous V, Sismani C, Shammas C, Efstathiou E, Alexandrou A, Ioannides M, Argyrou M, Patsalis PC, Phylactou LA, Skordis N. Duplication of exons 3-10 of the HSD17B3 gene: A novel type of genetic defect underlying 17β-HSD-3 deficiency. Gene

[255] Faienza MF, Giordani L, Delvecchio M, Cavallo L. Clinical, endocrine, and molecular findings in 17beta-hydroxysteroid dehydrogenase type 3 deficiency. Journal of

[256] Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reductases and

[257] Kissinger CR, Rejto PA, Pelletier LA, Thomson JA, Showalter RE, Abreo MA, Agree CS, Margosiak S, Meng JJ, Aust RM, Vanderpool D, Li B, Tempczyk-Russell A, Villafranca JE. Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics. Journal of Molecular

[258] Du Yan S, Zhu Y, Stern ED, Hwang YC, Hori O, Ogawa S, Frosch MP, Connolly ES Jr., Taggert RMc, Pinsky DJ, Clarke S, Stern DM, Ramasamy R. Amyloid beta-peptidebinding alcohol dehydrogenase is a component of the cellular response to nutritional

cancer. Annals of New York Academy of Sciences 2009; 1155: 33–42.

stress. Journal of Biological Chemistry 2000; 275: 27100–27109.

testicular 17β hydroxysteroid dehydrogenase 3. Nature Genetic 1994; 7: 34–39. [253] Day MJ, Tutill HJ, Foster PA, Bailey HV, Heaton WB, Sharland CM, Vicker N, Potter BV, Purohit A, Reed MJ. Development of hormonedependent prostate cancer models for the evaluation of inhibitors of 17beta-hydroxysteroid dehydrogenase type 3,

Molecular & Cellular Endocrinology 2009; 301: 251–258.

Endocrinological Investigations 2008; 31: 85-91.

Dehydrogenases are a group of biological catalysts (enzymes) that mediate in biochemical reactions removing hydrogen atoms [H] instead of oxygen [O] in its oxido-reduction reactions. It is a versatile enzyme in the respiratory chain pathway or the electron transfer chain. T. Turnberg discovered this group of enzymes between1900-1922. Several dehydrogenases are present in tissues of humans, plants and micro-organisms having enormous biochemical interests. As a result of the polymorphic nature of this enzyme, it is pertinent therefore to limit our interest on the different functions of Lactate dehydrogenase in the diagnosis and treatment of malaria. Lactate dehydrogenase, an oxidoreductase [EC 1.1.1.27] exists in different forms in different tissues possessing different subunits as a multienzyme complex called isoenzyme. It is the last enzyme of the glycolytic sequence or pathway essential for ATP generation. The enzyme, 17β-Hydroxysteroid dehydrogenase exists in at least fourteen isoforms in tissues involved in the biosynthesis of estrogenic and androgenic steroids. Lactate dehydrogenase is a tetrameric enzyme, but only two distinct subunits have been found; those designated H for heart (myocardium) and M for muscle. These two subunits are combined in five different ways. The lactate dehydrogenase isoenzymes, subunit compositions and major locations are shown below.

Following myocardial infarction (MI), the serum levels of LDH rise within 24-28 hrs, reaching a peak by 2-3 days and return to normal in 5-10 days. Especially diagnostic is a comparison of the LDH1/LDH2 ratio. Normally, the ratio is less than 1. A reversal of the ratio is referred to as "flipped LDH". Following an acute myocardial infarction, the flipped ratio will appear in 12-24 hours and it is definitely present by 48 hours in over 80% of cases. Also important, is the fact that, persons suffering from chest pain due to angina only, will not likely have LDH altered levels.

© 2012 Nwazue, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Functions of Dehydrogenases in Health and Disease 167

A correlation between levels of parasitemia and the activity of parasite LDH from patients with malaria is worthwhile. The serum assay for PLDH is followed up to monitor the level of PLDH in a patient with cerebral malaria prior to antimalarial therapy and also during recovery period. It is evident that measurement of pLDH has a strong correlation with malarial parasitemia and can follow a method that can be developed into a simple test for the detection of *Plasmodium falciparum* as an assessment of plasmodium parasitemia. In malarial falciparum parasitemia, LDH does not persist in blood, but clears about the time as the parasite, following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. LDH for

*P.vivax*, *P.ovale*, and *P. malariae* exhibit 90-92% identity to pLDH *from P. falciparum.*

**potential antimalarial agents** 

**3. Functions of inhibitors of parasite lactate dehydrogenase (pLDH) as** 

The *plasmodium falciparum* lactate dehydrogenase enzyme (Pf LDH), has been considered a potential molecular target to antimalarials due to this parasite dependence on glycolysis for energy production by catalyzing the reduction of pyruvate to lactate. It has been a routine activity among drug designers for malarial infestation to embark on the screening of analogs to NADH(an essential cofactor) to pLDH.The continued search for new molecular targets for drug design is an endless search, since the introduction of the quinolones in malaria therapy. Chloroquine interacts specifically with PfLDH in the NADH binding pocket, occupying a position similar to that of the adenyl ring cofactor, hence acting as a competitive inhibitor for this critical glycolytic enzyme [5,6,7,8]. Analogs of NADH have been identified as new potential inhibitors to PfLDH[9]. Computational studies have been undertaken to recognize the potential binding of selected compounds to the pLDH active site. This was analyzed using Motegro Virtual Docker Software. The researchers selected fifty (50) compounds based on their similarity to NADH. The compounds with the best bonding energies included: itraconazole, atorvastatin and posaconazole. These were tested against P. falciparum , chloroquine resistant blood parasites. All these compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to pfLDH or a histidine rich protein 2 (HRP 2). The IC 50 values for each drug in both tests are similar; values were lowest for posaconazole (< 5µM) and were 40-and 100-fold less active than chloroquine. The compounds so tested reduced *P. berghi* parasitemia in treated mice, in comparison to untreated control. The drug itraconazole is the least active compound. Posaconazole is an inhibitor of ergosterol biosynthesis [10]. In this study, it was the most active drug against *P. falciparum*. It is also, the most effective compound against murine malaria caused by *P. berghei* and was the most promising agent in vitro and in vivo. Itraconazole is normally acquired as a tablet, causes a strong inhibition of P. falciparum growth in vitro and is partially active against *P. berghei*. The results of these trials according to the authors proved that molecular docking studies are important in the strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology. The parasite enzyme, lactate dehydrogenase has recently received a great deal of attention, since it may constitute a valid therapeutic target for diseases such as malaria

**Table 1.** Subunit compositions and major locations of Lactate Dehydrogease Isoforms
