Trypanothione

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Trypanothione
Trypanothione(red).svg
Trypanothione(ox).svg
Reduced form (top) and oxidized form (bottom)
Names
Other names
N1,N8-Bis(glutathionyl)spermidine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
  • InChI=1S/C27H47N9O10S2/c28-16(26(43)44)4-6-20(37)35-18-14-47-48-15-19(36-21(38)7-5-17(29)27(45)46)25(42)34-13-23(40)32-11-3-9-30-8-1-2-10-31-22(39)12-33-24(18)41/h16-19,30H,1-15,28-29H2,(H,31,39)(H,32,40)(H,33,41)(H,34,42)(H,35,37)(H,36,38)(H,43,44)(H,45,46)/t16-,17-,18-,19-/m0/s1 Yes check.svgY
    Key: LZMSXDHGHZKXJD-VJANTYMQSA-N Yes check.svgY
  • InChI=1/C27H47N9O10S2/c28-16(26(43)44)4-6-20(37)35-18-14-47-48-15-19(36-21(38)7-5-17(29)27(45)46)25(42)34-13-23(40)32-11-3-9-30-8-1-2-10-31-22(39)12-33-24(18)41/h16-19,30H,1-15,28-29H2,(H,31,39)(H,32,40)(H,33,41)(H,34,42)(H,35,37)(H,36,38)(H,43,44)(H,45,46)/t16-,17-,18-,19-/m0/s1
    Key: LZMSXDHGHZKXJD-VJANTYMQBI
  • O=C(O)[C@@H](N)CCC(=O)N[C@@H]1C(=O)NCC(=O)NCCCNCCCCNC(=O)CNC(=O)[C@@H](NC(=O)CC[C@@H](C(=O)O)N)CSSC1
Properties
C27H47N9O10S2 (oxidized)
C27H49N9O10S2 (reduced)
Molar mass 721.84 g/mol (oxidized)
723.86 g/mol (reduced)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Trypanothione is an unusual form of glutathione containing two molecules of glutathione joined by a spermidine (polyamine) linker. It is found in parasitic protozoa such as leishmania and trypanosomes. [1] These protozoal parasites are the cause of leishmaniasis, sleeping sickness and Chagas' disease. Trypanothione was discovered by Alan Fairlamb. Its structure was proven by chemical synthesis. [2] It is present mainly in the Kinetoplastida but can be found in other parasitic protozoa such as Entamoeba histolytica . [3] Since this thiol is absent from humans and is essential for the survival of the parasites, the enzymes that make and use this molecule are targets for the development of new drugs to treat these diseases. [4]

Trypanothione-dependent enzymes include reductases, peroxidases, glyoxalases and transferases. Trypanothione-disulfide reductase (TryR) was the first trypanothione-dependent enzyme to be discovered (EC 1.8.1.12). It is an NADPH-dependent flavoenzyme that reduces trypanothione disulfide. TryR is essential for survival of these parasites both in vitro and in the human host. [5] [6]

A major function of trypanothione is in the defence against oxidative stress. [7] Here, trypanothione-dependent enzymes such as tryparedoxin peroxidase (TryP) reduce peroxides using electrons donated either directly from trypanothione, or via the redox intermediate tryparedoxin (TryX). Trypanothione-dependent hydrogen peroxide metabolism is particularly important in these organisms because they lack catalase. Since the trypanosomatids also lack an equivalent of thioredoxin reductase, trypanothione reductase is the sole path that electrons can take from NADPH to these antioxidant enzymes.

TryP cycle.png

Related Research Articles

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

<span class="mw-page-title-main">Peroxidase</span> Peroxide-decomposing enzyme

Peroxidases or peroxide reductases are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides, and should not be confused with other enzymes that produce peroxide, which are often oxidases.

<span class="mw-page-title-main">Trypanosomatida</span> Group of single-celled parasitic organisms

Trypanosomatida is a group of kinetoplastid unicellular organisms distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Some trypanosomatida are intracellular parasites, with the important exception of Trypanosoma brucei.

<span class="mw-page-title-main">Kinetoplastida</span> Flagellated protists belonging to the phylum Euglenozoa

Kinetoplastida is a group of flagellated protists belonging to the phylum Euglenozoa, and characterised by the presence of a distinctive organelle called the kinetoplast, a granule containing a large mass of DNA. The group includes a number of parasites responsible for serious diseases in humans and other animals, as well as various forms found in soil and aquatic environments. The organisms are commonly referred to as "kinetoplastids" or "kinetoplasts".

<i>Entamoeba coli</i> Species of parasitic amoeba

Entamoeba coli is a non-pathogenic species of Entamoeba that frequently exists as a commensal parasite in the human gastrointestinal tract. E. coli is important in medicine because it can be confused during microscopic examination of stained stool specimens with the pathogenic Entamoeba histolytica. This amoeba does not move much by the use of its pseudopod, and creates a "sur place (non-progressive) movement" inside the large intestine. Usually, the amoeba is immobile, and keeps its round shape. This amoeba, in its trophozoite stage, is only visible in fresh, unfixed stool specimens. Sometimes the Entamoeba coli have parasites as well. One is the fungus Sphaerita spp. This fungus lives in the cytoplasm of the E. coli. While this differentiation is typically done by visual examination of the parasitic cysts via light microscopy, new methods using molecular biology techniques have been developed. The scientific name of the amoeba, E. coli, is often mistaken for the bacterium, Escherichia coli. Unlike the bacterium, the amoeba is mostly harmless, and does not cause as many intestinal problems as some strains of the E. coli bacterium. To make the naming of these organisms less confusing, "alternate contractions" are used to name the species for the purpose making the naming easier; for example, using Esch. coli and Ent. coli for the bacterium and amoeba, instead of using E. coli for both.

<span class="mw-page-title-main">PFP (enzyme)</span> Class of enzymes

Diphosphate—fructose-6-phosphate 1-phosphotransferase also known as PFP is an enzyme of carbohydrate metabolism in plants and some bacteria. The enzyme catalyses the reversible interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate using inorganic pyrophosphate as the phosphoryl donor:

<span class="mw-page-title-main">Melarsoprol</span> Medication used to treat sleeping sickness

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness. It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred. It is effective in about 95% of people. It is given by injection into a vein.

<span class="mw-page-title-main">Pentose phosphate pathway</span> Series of interconnected biochemical reactions

The pentose phosphate pathway is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by Bernard Horecker and co-workers.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

<span class="mw-page-title-main">Glycosome</span> Organelle containing glycolytic enzymes in some protists

The glycosome is a membrane-enclosed organelle that contains the glycolytic enzymes. The term was first used by Scott and Still in 1968 after they realized that the glycogen in the cell was not static but rather a dynamic molecule. It is found in a few species of protozoa including the Kinetoplastida which include the suborders Trypanosomatida and Bodonina, most notably in the human pathogenic trypanosomes, which can cause sleeping sickness, Chagas's disease, and leishmaniasis. The organelle is bounded by a single membrane and contains a dense proteinaceous matrix. It is believed to have evolved from the peroxisome. This has been verified by work done on Leishmania genetics.

<span class="mw-page-title-main">Alan Fairlamb</span> British biochemist

Alan Hutchinson Fairlamb, CBE, FRSE, FLS, FMedSci, FRSB is a Wellcome Trust Principal Research Fellow and Professor of Biochemistry in the Division of Biological Chemistry and Drug Discovery at the School of Life Sciences, University of Dundee, Scotland. From 2006-2011 he was a member of the Scientific and Technical Advisory Committee of the Special Programme for Research and Training in Tropical Diseases (TDR) -- an independent global programme of scientific collaboration co-sponsored by UNICEF, UNDP, the World Bank and WHO. Currently he is a member of the governing board of the Tres Cantos Open Lab Foundation, whose aim is to accelerate the discovery and development of medicines to tackle diseases of the developing world in an open collaborative manner.

<span class="mw-page-title-main">Carbonyl reductase (NADPH)</span> Class of enzymes

In enzymology, a carbonyl reductase (NADPH) (EC 1.1.1.184) is an enzyme that catalyzes the chemical reaction

In enzymology, a CoA-glutathione reductase (EC 1.8.1.10) is an enzyme that catalyzes the chemical reaction

In enzymology, a pteridine reductase (EC 1.5.1.33) is an enzyme that catalyzes the chemical reaction

In enzymology, a trypanothione-disulfide reductase (EC 1.8.1.12) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Methionine gamma-lyase</span>

The enzyme methionine γ-lyase (EC 4.4.1.11, MGL) is in the γ-family of PLP-dependent enzymes. It degrades sulfur-containing amino acids to α-keto acids, ammonia, and thiols:

In enzymology, a glutathionylspermidine synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Trypanothione synthase</span> Class of enzymes

In enzymology, a trypanothione synthase (EC 6.3.1.9) is an enzyme that catalyzes the chemical reaction

The ascorbate-glutathione cycle, sometimes Foyer-Halliwell-Asada pathway, is a metabolic pathway that detoxifies hydrogen peroxide (H2O2), a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites: ascorbate, glutathione and NADPH and the enzymes linking these metabolites.

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

References

  1. Fairlamb AH, Cerami A (1992). "Metabolism and functions of trypanothione in the Kinetoplastida". Annu. Rev. Microbiol. 46: 695–729. doi:10.1146/annurev.mi.46.100192.003403. PMID   1444271.
  2. Fairlamb, A. H.; Blackburn, P.; Ulrich, P.; Chait, B. T.; Cerami, A. (Mar 1985). "Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids". Science. 227 (4693): 1485–1487. Bibcode:1985Sci...227.1485F. doi:10.1126/science.3883489. ISSN   0036-8075. PMID   3883489.
  3. Ondarza, Raul (2005). "Identification of trypanothione from the human pathogen Entamoeba histolytica by mass spectrometry and chemical analysis". Biotechnol. Appl. Biochem. 42 (Pt 2): 175–181. doi:10.1042/BA20050023. PMID   15801913. S2CID   23482542.
  4. Schmidt A, Krauth-Siegel RL (November 2002). "Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development". Curr Top Med Chem. 2 (11): 1239–59. doi:10.2174/1568026023393048. PMID   12171583. Archived from the original on July 21, 2012.{{cite journal}}: CS1 maint: unfit URL (link)
  5. Tovar J, Wilkinson S, Mottram JC, Fairlamb AH (July 1998). "Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus". Mol. Microbiol. 29 (2): 653–60. doi: 10.1046/j.1365-2958.1998.00968.x . PMID   9720880.
  6. Krieger S, Schwarz W, Ariyanayagam MR, Fairlamb AH, Krauth-Siegel RL, Clayton C (February 2000). "Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress". Mol. Microbiol. 35 (3): 542–52. doi: 10.1046/j.1365-2958.2000.01721.x . PMID   10672177.
  7. Krauth-Siegel RL, Meiering SK, Schmidt H (April 2003). "The parasite-specific trypanothione metabolism of trypanosoma and leishmania". Biol. Chem. 384 (4): 539–49. doi:10.1515/BC.2003.062. PMID   12751784. S2CID   46158890.