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Current Therapeutics, Their Problems, and Sulfur-Containing CLINICAL MICROBIOLOGY REVIEWS, Jan. 2007, p. 164–187 Vol. 20, No. 1 0893-8512/07/$08.00ϩ0 doi:10.1128/CMR.00019-06 Copyright © 2007, American Society for Microbiology. All Rights Reserved. Current Therapeutics, Their Problems, and Sulfur-Containing-Amino-Acid Metabolism as a Novel Target against Infections by “Amitochondriate” Protozoan Parasites Vahab Ali and Tomoyoshi Nozaki* Department of Parasitology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan INTRODUCTION .......................................................................................................................................................164 EPIDEMIOLOGY, BIOLOGY, AND DISEASE.....................................................................................................165 Entamoeba histolytica...............................................................................................................................................165 Giardia intestinalis ...................................................................................................................................................166 Trichomonas vaginalis..............................................................................................................................................166 ENERGY METABOLISM OF “AMITOCHONDRIATE” PARASITES..............................................................167 Divergence of Mitochondrion-Related Organelles .............................................................................................167 Diversity in the Conversion of Phosphoenolpyruvate to Acetyl Coenzyme A via Pyruvate..........................167 Predominant End Products of Energy Metabolism ...........................................................................................169 Three Major Iron-Sulfur Proteins That Play an Essential Role in Energy Metabolism .............................170 Downloaded from Pyruvate:ferredoxin oxidoreductase .................................................................................................................170 Ferredoxin............................................................................................................................................................170 Hydrogenase ........................................................................................................................................................171 CURRENT CHEMOTHERAPEUTICS....................................................................................................................171 Current Chemotherapeutics for E. histolytica Infection ....................................................................................171 Current Chemotherapeutics for G. intestinalis Infection...................................................................................172 cmr.asm.org Current Chemotherapeutics for T. vaginalis Infection ......................................................................................172 DRUG TARGETS AND MECHANISMS OF RESISTANCE ...............................................................................173 Mechanism of Action of 5-Nitroimidazole and Benzimidazoles...........................................................................173 Drug Resistance in E. histolytica...........................................................................................................................174 Drug Resistance in G. intestinalis .........................................................................................................................174 by on January 31, 2008 Drug Resistance in Trichomonas...........................................................................................................................174 SULFUR-CONTAINING-AMINO-ACID METABOLISM AS A NOVEL DRUG TARGET.............................175 Metabolic Pathways in Protozoan Parasites under Investigation To Explore as Targets for Drug Development ........................................................................................................................................................175 Physiological Importance of Cysteine and Fe-S Cluster Biosynthesis ............................................................176 Heterogeneity of Fe-S Cluster Biosynthesis ........................................................................................................176 Unique Aspects of Sulfur-Containing-Amino-Acid Metabolism.......................................................................176 Degradation of Sulfur-Containing Amino Acids ................................................................................................177 Structural Differences between Protozoan MGL and Mammalian CGL........................................................178 Drug Development Targeting Methionine ␥-Lyase............................................................................................178 Sulfur-Assimilatory De Novo Cysteine Biosynthesis..........................................................................................179 Cysteine Synthase as a Drug Target....................................................................................................................180 CONCLUSIONS .........................................................................................................................................................180 REFERENCES ............................................................................................................................................................180 INTRODUCTION reduced ability for the de novo synthesis of essential building blocks of DNA and proteins, including nucleic acid precursors Three protozoan parasites of humans, Entamoeba histolytica, (7, 10, 322) and amino acids (7, 233, 247). As a consequence, Giardia intestinalis, and Trichomonas vaginalis, share various biological and biochemical characteristics, including anaerobic certain metabolic pathways either are missing in these organ- carbohydrate metabolism and the lack of typical mitochondria isms or are divergent from those of mitochondriate organisms. (“amitochondriate”). The ATP generation in these parasites Sulfur-containing-amino-acid metabolism represents one such occurs exclusively through substrate-level phosphorylation, de- divergent metabolic pathway in these three “amitochondriate” spite differences in their life cycles and pathogenic properties protists. Sulfur-containing amino acids are essential for a va- (216, 217). As obligatory parasites, these organisms have a riety of biological activities, including protein synthesis, meth- ylation, polyamine synthesis, coenzyme A production, cyste- amine production, taurine production, iron-sulfur cluster * Corresponding author. Mailing address: Department of Parasi- (ISC) biosynthesis, and antioxidative stress defense (233). Be- tology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Phone: 81-27-220- sides the general importance of sulfur-containing amino acids, 8020. Fax: 81-27-220-8025. E-mail: [email protected]. it was previously shown that a high concentration of extracel- 164 VOL. 20, 2007 THERAPEUTICS AGAINST AMITOCHONDRIATE PROTOZOA 165 lular cysteine is required for the growth, attachment, and sur- hosts. Infection of the host occurs upon ingestion of water or vival of E. histolytica, T. vaginalis, and G. intestinalis under food contaminated with cysts. E. histolytica cysts are round, oxidative stress (2, 36, 106–110, 298). usually 10 to 15 ␮m in diameter, and surrounded by a refrac- Recent molecular and biochemical characterization of the tive wall containing chitin. After ingestion, the cyst excysts in sulfur-containing-amino-acid metabolism in these organisms the small intestine and forms the amoeboid trophozoite, which revealed that metabolic pathways for sulfur-containing amino then colonizes the large intestine of the host. Colonization by acids in E. histolytica, G. intestinalis, and T. vaginalis are distinct E. histolytica trophozoites often results in an asymptomatic from those of their mammalian hosts in several ways. First, intestinal infection similar to that resulting from E. dispar (67). they lack part of both the forward and reverse transsulfuration Unlike the inert cysts, E. histolytica trophozoites are highly pathways and thus are unable to complete transsulfuration motile, with polymorphic shapes and sizes varying from 10 to sequences in either direction between methionine and cys- 50 ␮m in diameter. Trophozoites reproduce by binary fission, teine. Second, they lack the enzymes responsible for cysteine ingest bacteria and food particles, and adhere to and destroy and homocysteine degradation in mammals. Instead, E. histo- epithelial cells in the bowel. The destruction of the epithelial lytica and T. vaginalis possess a unique enzyme for the degra- tissue causes disease and symptoms. After penetration into the dation of methionine, homocysteine, and cysteine called blood vessels, trophozoites are occasionally transported to ex- methionine ␥-lyase. Third, E. histolytica and T. vaginalis are traintestinal organs, including the liver, lung, brain, and skin, capable of sulfur-assimilatory de novo cysteine biosynthesis. and produce abscesses, often with lethal outcomes. Trophozo- Since aspects of sulfur-containing-amino-acid metabolism dif- ites transform into dormant and infectious cysts which are fer significantly between parasites and their mammalian hosts, excreted
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