Sulfur-Containing Amino Acid Metabolism in Parasitic Protozoa

Nozaki, Tomoyoshi; Ali, Vahab; Tokoro, Masaharu

doi:10.1016/s0065-308x(05)60001-2

Cited by 100 publications

(84 citation statements)

References 343 publications

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“…SAAs play critical roles in a variety of biological processes including protein synthesis, methylation, biosynthesis of vitamins, polyamines, and antioxidants. SAAs are ubiquitously distributed, but their metabolic pathways diverged among organisms, and are modulated in the life cycle and upon stresses and changes in environmental conditions (1).…”

Section: Introductionmentioning

confidence: 99%

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Sato

Nozaki

2009

IUBMB Life

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SummarySulfur-containing amino acids (SAAs) are essential components in many biological processes and ubiquitously distributed to all organisms. Both biosynthetic and catabolic pathways of SAAs are heterogeneous among organisms and between developmental stages, and regulated by the environmental changes. Limited lineage of organisms ranging from archaea to plants, but not human, possess a unique enzyme methionine gammalyase (MGL, EC 4.4.1.11) to directly degrade SAA to a-keto acids, ammonia, and volatile thiols. The reaction mechanisms and the physiological roles of this enzyme are partially demonstrated by the enzymological analyzes, structure determination, isotopic labeling of the intermediate metabolites, and functional analyzes of deficient mutants. MGL has been exploited as a drug target for the infectious diseases caused by parasitic protozoa and anaerobic periodontal bacteria. In addition, MGL has been utilized to develop therapeutic interventions of various cancers, by introducing recombinant proteins to deplete methionine essential for the growth of cancer cells. In this review, we discuss the current understanding of enzymological properties, putative physiological roles, and therapeutic applications of MGL.

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Section: Introductionmentioning

confidence: 99%

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Sato

Nozaki

2009

IUBMB Life

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“…A particularity of Trichomonas is constituted by the lack of mitochondria, which renders energy metabolism anaerobic [26]. Trichomonas compensates the less efficient metabolic processes by salvage pathways, demonstrated by a takeover of amino acids [6,27], nucleotide precursors [28] and lipids [6]. Hydrogenosomes partially substitute mitochondria by representing a compartmentalized machinery for part of the energy metabolism [29].…”

Section: Metabolic Peculiarities As Potential Drug Targetsmentioning

confidence: 99%

“…A further peculiarity of the parasite, and thereby presenting an additional drug target, is the biosynthesis of Fe-S-cluster proteins, with the necessity of cysteine as critical building block [36,37]. Unlike the human host, Trichomonas can synthesize cysteine de novo by assimilation of sulphur from the environment followed by catalysis via cysteine synthase, a protein absent in mammals [27,38]. However, Trichomonas offers no sulfur-containingamino acid metabolism, and additionally, it lacks the transsulfuration pathway to transform cysteine to methionine, or vice versa [39].…”

Section: Metabolic Peculiarities As Potential Drug Targetsmentioning

confidence: 99%

“…However, Trichomonas offers no sulfur-containingamino acid metabolism, and additionally, it lacks the transsulfuration pathway to transform cysteine to methionine, or vice versa [39]. To compensate, the parasite possesses a unique enzyme for sulfur-containing amino acid degradation, methionine gamma-lyase (MGL) [27]. This protein has revealed a potency for drug development, since the compound L-trifluoromethionine (TFM), which is activated by MGL, was shown to be an efficient growth inhibitor in vitro against T. vaginalis [40] and E. histolytica [41], another human protozoan parasite sharing various biological and biochemical characteristics.…”

Section: Metabolic Peculiarities As Potential Drug Targetsmentioning

confidence: 99%

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Development of Drug Resistance in Trichomonas vaginalis and its Overcoming with Natural Products

Gehrig¹,

Efferth²

2009

TOBCJ

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Abstract:Trichomoniasis is an infectious disease afflicting women worldwide. The protozoan parasite Trichomonas vaginalis is the causative agent of this sexually-transmitted disease, including also men in its infection cycle. The disease is usually not life-threatening, but has been associated with the development of cervical cancer and increased susceptibility to HIV. Approved drugs are 5-nitroimidazoles, with metronidazole being the drug of first choice. These drugs act via induction of oxidative stress and DNA-damage, leading to cell death in the parasite. Nevertheless, with the development of resistant T. vaginalis strains the treatment of the disease becomes exceedingly difficult. Mechanisms of drug resistance are characterized by reduced expression or even loss of proteins necessary for drug activation and a decreased reductive nature in the parasite. A promising strategy for research into new drugs and moreover, to overcome drug resistance, are compounds derived from natural sources. The present study provides a summary of all so far investigated small molecules with antitrichomonal activity; promisingly, some also show efficacy against resistant strains. Whereas the list of chemically characterized compounds derived from plants is rather short, literature provides immense applications of crude plant extracts tested against T. vaginalis. This demonstrates the absence of studies in this field aimed to identify and isolate single natural products exhibiting antitrichomonal features. Likewise, elucidating their mode of action on a molecular basis is of paramount importance.

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“…[2][3][4] The inhibition of enzymes involved in the metabolism of parasitic protozoa has been recognized as a promising strategy for the chemotherapy of tropical diseases. 5,6 Trypanothione, structurally characterized as N1,N8-bis(glutathionyl)spermidine, is a polyamine derivative used by trypanosomatids as a defense against reactive oxygen species during their infective cycle. The metabolism of trypanothione is a potential target for drug development against trypanosomiases and leishmanioses.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of a linker for primary amines used in the solid phase organic synthesis of spermidine

Silva¹,

Gil²,

Caldarelli³

et al. 2011

J. Braz. Chem. Soc.

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Neste trabalho é descrita a preparação de uma resina modificada, empregada como linker para a preparação de espermidina funcionalizada, em bom rendimento, assim como sua caracterização por infravermelho (IV), ressonância magnética nuclear de 13 C no estado sólido com polarização cruzada e rotação no ângulo mágico (RMN-CPMAS de 13 C) e ressonância magnética nuclear de 1 H de alta resolução com rotação no ângulo mágico (RMN-MAS de 1 H de alta resolução). O linker foi regenerado após clivagem da espermidina e reutilizado sem perda de eficiência.A linker resin for the synthesis of functionalized spermidine in good yield is described, along with its characterization by infrared (IR), 13 C solid-state nuclear magnetic resonance with cross polarization and magic angle spinning ( 13 C CPMAS NMR) and 1 H high resolution magic angle spinning nuclear magnetic resonance ( 1 H HRMAS NMR. This linker has been regenerated after cleavage of spermidine and re-used without loss of efficiency.

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Sulfur-Containing Amino Acid Metabolism in Parasitic Protozoa

Cited by 100 publications

References 343 publications

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Development of Drug Resistance in Trichomonas vaginalis and its Overcoming with Natural Products

Synthesis and characterization of a linker for primary amines used in the solid phase organic synthesis of spermidine

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