| trypanothione synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 | |||||||||
| Identifiers | |||||||||
| EC no. | 6.3.1.9 | ||||||||
| CAS no. | 130246-69-4 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
In enzymology, a trypanothione synthase (EC 6.3.1.9) is an enzyme that catalyzes the chemical reaction
- glutathione + glutathionylspermidine + ATP N1,N8-bis(glutathionyl)spermidine + ADP + phosphate
The 3 substrates of this enzyme are glutathione, glutathionylspermidine, and ATP, whereas its 3 products are N1,N8-bis(glutathionyl)spermidine, ADP, and phosphate[1].
This reaction is especially important for protozoa in the order kinetoplastida as the molecule of N1,N8-bis(glutathionyl)spermidine, also known as trypanothione, is homologous to the function of glutathione in most other prokaryotic and eukaryotic cells. This means that it is a key intermediate in maintaining thiol redox within the cell and defending against harmful oxidative effects in such protozoa.[2]
This enzyme belongs to the family of ligases, specifically those forming carbon-nitrogen bonds as acid-D-ammonia (or amine) ligases (amide synthases). The systematic name of this enzyme class is glutathionylspermidine:glutathione ligase (ADP-forming).
Structure
editThe active bifunctional enzyme of trypanothione synthase is found as a monomer consisting of 653 residues with two catalytic domains.[3] Its C-terminal domain is a synthetase and has an ATP-grasp family fold that is usually found in carbon-nitrogen ligases. The N-terminal domain is a cysteine, histidine-dependent aminohydrolase amidase.
It is currently known that the synthetase active site is shaped in the fashion of a triangular cavity that binds the three substrates such that the end of each molecule is nestled in a vertex of the triangle.[3] The particular residues of Arg-553 and Arg-613 have been found to key for synthetic function, however further research into the structure of trypanothione synthase must be done in order to fully understand the enzyme's active sites.[4]
Function
edit
The main function of trypanothione synthase is to use the free energy generated from ATP hydrolysis to conjugate glutathione and spermidine to form the intermediate of glutathionylspermidine and then the final product of trypanothione.[4] It also catalyzes the reverse reaction as well, albeit at a much lower rate. Under conditions found to be the optimum for both the forward and backwards reactions, trypanothione synthase from trypanosoma cruzi was found to have an amidase activity that was only about 1% of the forwards synthetase activity.[5]
Regulation
editClinical Significance
editReferences
edit- ^ Smith K, Nadeau K, Bradley M, Walsh C, Fairlamb AH (1992). "Purification of glutathionylspermidine and trypanothione synthetases from Crithidia fasciculata". Protein. Sci. 1 (7): 874–83. doi:10.1002/pro.5560010705. PMC 2142158. PMID 1304372.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Tetaud E, Manai F, Barrett MP, Nadeau K, Walsh CT, Fairlamb AH (July 1998). "Cloning and characterization of the two enzymes responsible for trypanothione biosynthesis in Crithidia fasciculata". J. Biol. Chem. 273 (31): 19383–90. doi:10.1074/jbc.273.31.19383. PMID 9677355.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ a b Fyfe PK, Oza SL, Fairlamb AH, Hunter WN (June 2008). "Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities". J. Biol. Chem. 283 (25): 17672–80. doi:10.1074/jbc.M801850200. PMC 2427367. PMID 18420578.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ a b Oza SL, Wyllie S, Fairlamb AH (September 2006). "Mapping the functional synthetase domain of trypanothione synthetase from Leishmania major". Mol. Biochem. Parasitol. 149 (1): 117–20. doi:10.1016/j.molbiopara.2006.05.001. PMID 16765464.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Oza SL, Tetaud E, Ariyanayagam MR, Warnon SS, Fairlamb AH (September 2002). "A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi". J. Biol. Chem. 277 (39): 35853–61. doi:10.1074/jbc.M204403200. PMID 12121990.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
Category:EC 6.3.1 Category:Enzymes of unknown structure Category:Article Feedback 5