Trypanothione-disulfide reductase

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trypanothione-disulfide reductase
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EC no. 1.8.1.12
CAS no. 102210-35-5
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In enzymology, a trypanothione-disulfide reductase (EC 1.8.1.12) is an enzyme that catalyzes the chemical reaction

trypanothione + NADP+ trypanothione disulfide + NADPH + H+

Thus, the two substrates of this enzyme are trypanothione and NADP+, whereas its 3 products are trypanothione disulfide, NADPH, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is trypanothione:NADP+ oxidoreductase. Other names in common use include trypanothione reductase, and NADPH2:trypanothione oxidoreductase. It employs one cofactor, FAD.

The X-ray crystal structures of trypanothione reductase enzymes from several trypanosomatids species have been solved, including those from Crithidia fasciculata, Leishmania infantum, Trypanosoma brucei and Trypanosoma cruzi. The structures reveal that trypanothione reductase forms homodimers in solution with each of the two individual subunits comprising an FAD-binding domain, an NADPH-binding domain and an interface domain. [1] [2] Examples of trypanothione reductase inhibitors include 5-Nitro-Imidazole, [3] Febrifugine, [4] Imipramine [5] and Benzoxaborole. [6]

Related Research Articles

<span class="mw-page-title-main">Trypanothione</span> Chemical compound

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. 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. It is present mainly in the Kinetoplastida but can be found in other parasitic protozoa such as Entamoeba histolytica. 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.

<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">L-xylulose reductase</span> Enzyme

Dicarbonyl/L-xylulose reductase, also known as carbonyl reductase II, is an enzyme that in human is encoded by the DCXR gene located on chromosome 17.

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

GMP reductase EC 1.7.1.7 is an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of GMP into IMP.

<span class="mw-page-title-main">Shikimate dehydrogenase</span> Enzyme involved in amino acid biosynthesis

In enzymology, a shikimate dehydrogenase (EC 1.1.1.25) is an enzyme that catalyzes the chemical reaction

In enzymology, a gluconate 5-dehydrogenase (EC 1.1.1.69) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA reductase (NADPH)</span>

In enzymology, a hydroxymethylglutaryl-CoA reductase (NADPH) (EC 1.1.1.34) is an enzyme that catalyzes the chemical reaction

(R)-4-hydroxyphenyllactate dehydrogenase (EC 1.1.1.222) is an enzyme that catalyzes a chemical reaction

<span class="mw-page-title-main">3-oxoacyl-(acyl-carrier-protein) reductase</span> Enzyme

In enzymology, a 3-oxoacyl-[acyl-carrier-protein] reductase (EC 1.1.1.100) is an enzyme that catalyzes the chemical reaction

In enzymology, a ferredoxin-NADP+ reductase (EC 1.18.1.2) abbreviated FNR, is an enzyme that catalyzes the chemical reaction

In enzymology, a leucoanthocyanidin reductase (EC 1.17.1.3) (LAR, aka leucocyanidin reductase or LCR) is an enzyme that catalyzes the chemical reaction

In enzymology, a CoA-disulfide reductase (EC 1.8.1.14) 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 protein-disulfide reductase (EC 1.8.1.8) 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

<span class="mw-page-title-main">Lactoylglutathione lyase</span> Protein-coding gene in the species Homo sapiens

The enzyme lactoylglutathione lyase (EC 4.4.1.5, also known as glyoxalase I) catalyzes the isomerization of hemithioacetal adducts, which are formed in a spontaneous reaction between a glutathionyl group and aldehydes such as methylglyoxal.

<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

5β-Reductase, or Δ4-3-oxosteroid 5β-reductase (EC 1.3.1.3, 3-oxo-Δ4-steroid 5β-reductase, androstenedione 5β-reductase, cholestenone 5β-reductase, cortisone 5β-reductase, cortisone Δ4-5β-reductase, steroid 5β-reductase, testosterone 5β-reductase, Δ4-3-ketosteroid 5β-reductase, Δ4-5β-reductase, Δ4-hydrogenase, 4,5β-dihydrocortisone:NADP+ Δ4-oxidoreductase, 3-oxo-5β-steroid:NADP+ Δ4-oxidoreductase) is an enzyme with systematic name 5β-cholestan-3-one:NADP+ 4,5-oxidoreductase. This enzyme catalyses the following chemical reaction

Adrenodoxin-NADP+ reductase (EC 1.18.1.6, adrenodoxin reductase, nicotinamide adenine dinucleotide phosphate-adrenodoxin reductase, ADR, NADPH:adrenal ferredoxin oxidoreductase) is an enzyme with systematic name adrendoxin:NADP+ oxidoreductase. This enzyme catalyses the following chemical reaction

In enzymology, a prostaglandin-F synthase (PGFS; EC 1.1.1.188) is an enzyme that catalyzes the chemical reaction:

References

  1. ↑ Bond, Charles S; Zhang, Yihong; Berriman, Matthew; Cunningham, Mark L; Fairlamb, Alan H; Hunter, William N (1999). "Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors". Structure. 7 (1): 81–89. doi: 10.1016/s0969-2126(99)80011-2 . PMID   10368274.
  2. ↑ Jones, Deuan C.; Ariza, Antonio; Chow, Wing-Huen A.; Oza, Sandra L.; Fairlamb, Alan H. (2010-01-01). "Comparative structural, kinetic and inhibitor studies of Trypanosoma brucei trypanothione reductase with T. cruzi". Molecular and Biochemical Parasitology. 169 (1): 12–19. doi:10.1016/j.molbiopara.2009.09.002. PMC   2789240 . PMID   19747949.
  3. ↑ Pandey RK, Sharma D, Bhatt TK, Sundar S, Prajapati VK (2015). "Developing imidazole analogues as potential inhibitor for Leishmania donovani trypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach". Journal of Biomolecular Structure and Dynamics. 33 (12): 2541–53. doi:10.1080/07391102.2015.1085904. PMID   26305585. S2CID   205576053.
  4. ↑ Pandey RK, Kumbhar BV, Srivastava S, Malik R, Sundar S, Kunwar A, Prajapati VK (2017). "Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation". Journal of Biomolecular Structure and Dynamics. 35 (1): 141–158. doi:10.1080/07391102.2015.1135298. PMID   27043972. S2CID   3121806.
  5. ↑ Pandey RK, Verma P, Sharma D, Bhatt TK, Sundar S, Prajapati VK (2016). "High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania". Biomedicine & Pharmacotherapy. 83: 141–152. doi:10.1016/j.biopha.2016.06.010. PMID   27470561.
  6. ↑ Pandey RK, Kumbhar BV, Sundar S, Kunwar A, Prajapati VK (2017). "Structure-based virtual screening, molecular docking, ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase". Journal of Receptors and Signal Transduction. 37 (1): 60–70. doi:10.3109/10799893.2016.1171344. PMID   27147242. S2CID   36383056.


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