Trypanothione-disulfide reductase explained

trypanothione-disulfide reductase
Ec Number:	1.8.1.12
Cas Number:	102210-35-5
Go Code:	0015042

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

trypanothione + NADP⁺

\rightleftharpoons 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]

References

• Shames SL, Fairlamb AH, Cerami A, Walsh CT . 1986 . Purification and characterization of trypanothione reductase from Crithidia fasciculata, a newly discovered member of the family of disulfide-containing flavoprotein reductases . Biochemistry . 25 . 3519 - 26 . 3718941 . 10.1021/bi00360a007 . 12 .
• Marsh IR, Bradley M . 1997 . Substrate specificity of trypanothione reductase . Eur. J. Biochem. . 243 . 690 - 4 . 9057833 . 10.1111/j.1432-1033.1997.00690.x . 3 . free .
• Cunningham ML, Fairlamb AH . 1995 . Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials . Eur. J. Biochem. . 230 . 460 - 8 . 7607216 . 10.1111/j.1432-1033.1995.tb20583.x . 2 .
• Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F . 2007 . Betraying the Parasites Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties . ChemMedChem . 2 . 1708 - 12 . 17918760 . 10.1002/cmdc.200700172 . 12 . 31754415 .

Notes and References

1. Bond. Charles S. Zhang. Yihong. Berriman. Matthew. Cunningham. Mark L. Fairlamb. Alan H. Hunter. William N. 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. 10.1016/s0969-2126(99)80011-2. 1999. 10368274 . free.
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. 10.1016/j.molbiopara.2009.09.002. 2789240. 19747949.
3. Pandey RK, Sharma D, Bhatt TK, Sundar S, Prajapati VK . 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 . 2015 . 26305585 . 10.1080/07391102.2015.1085904 . 205576053 .
4. Pandey RK, Kumbhar BV, Srivastava S, Malik R, Sundar S, Kunwar A, Prajapati VK . 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 . 2017 . 27043972 . 10.1080/07391102.2015.1135298 . 3121806 .
5. Pandey RK, Verma P, Sharma D, Bhatt TK, Sundar S, Prajapati VK . High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania . Biomedicine & Pharmacotherapy. 83. 141–152. 2016 . 27470561. 10.1016/j.biopha.2016.06.010 .
6. Pandey RK, Kumbhar BV, Sundar S, Kunwar A, Prajapati VK . 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. 2017 . 27147242. 10.3109/10799893.2016.1171344 . 36383056 .