TY - JOUR
T1 - Reassessment of the reaction mechanism in the heme dioxygenases
AU - Chauhan, Nishma
AU - Thackray, Sarah J.
AU - Rafice, Sara A.
AU - Eaton, Graham
AU - Lee, Michael
AU - Efimov, Igor
AU - Basran, Jaswir
AU - Jenkins, Paul R.
AU - Mowat, Christopher G.
AU - Chapman, Stephen K.
AU - Raven, Emma Lloyd
PY - 2009/4/1
Y1 - 2009/4/1
N2 - Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme enzymes that catalyze the O2-dependent oxidation of L-tryptophan to N-formyl-kynurenine. Previous proposals for the mechanism of this reaction have suggested that deprotonation of the indole NH group, either by an active-site base or by oxygen bound to the heme iron, as the initial step. In this work, we have examined the activity of 1-Me-L-Trp with three different heme dioxygenases and their site-directed variants. We find, in contrast to previous work, that 1-Me-L-Trp is a substrate for the heme dioxygenase enzymes. These observations suggest that deprotonation of the indole N1 is not essential for catalysis, and an alternative reaction mechanism, based on the known chemistry of indoles, is presented.
AB - Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme enzymes that catalyze the O2-dependent oxidation of L-tryptophan to N-formyl-kynurenine. Previous proposals for the mechanism of this reaction have suggested that deprotonation of the indole NH group, either by an active-site base or by oxygen bound to the heme iron, as the initial step. In this work, we have examined the activity of 1-Me-L-Trp with three different heme dioxygenases and their site-directed variants. We find, in contrast to previous work, that 1-Me-L-Trp is a substrate for the heme dioxygenase enzymes. These observations suggest that deprotonation of the indole N1 is not essential for catalysis, and an alternative reaction mechanism, based on the known chemistry of indoles, is presented.
UR - http://www.scopus.com/inward/record.url?scp=67849124704&partnerID=8YFLogxK
U2 - 10.1021/ja808326g
DO - 10.1021/ja808326g
M3 - Article (Academic Journal)
C2 - 19275153
AN - SCOPUS:67849124704
SN - 0002-7863
VL - 131
SP - 4186
EP - 4187
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 12
ER -