PMID- 28650043
OWN - NLM
STAT- MEDLINE
DCOM- 20180523
LR  - 20180913
IS  - 1756-591X (Electronic)
IS  - 1756-5901 (Linking)
VI  - 9
IP  - 9
DP  - 2017 Sep 20
TI  - Heme-containing enzymes and inhibitors for tryptophan metabolism.
PG  - 1230-1240
LID - 10.1039/c7mt00105c [doi]
AB  - Iron-containing enzymes such as heme enzymes play crucial roles in biological 
      systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 
      2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 
      2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of 
      l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression 
      of these enzymes causes depletion of tryptophan and the accumulation of metabolic 
      products, which contributes to tumor immune tolerance and immune dysregulation in 
      a variety of disease pathologies. In the past few decades, IDO1 has garnered the 
      most attention as a therapeutic target with great potential in cancer 
      immunotherapy. Many potential inhibitors of IDO1 have been designed, synthesized 
      and evaluated, among which indoximod (d-1-MT), INCB024360, GDC-0919 (formerly 
      NLG-919), and an IDO1 peptide-based vaccine have advanced to the clinical trial 
      stage. However, recently, the roles of TDO and IDO2 have been elucidated in 
      immune suppression. In this review, the current drug discovery landscape for 
      targeting TDO, IDO1 and IDO2 is highlighted, with particular attention to the 
      recent use of drugs in clinical trials. Moreover, the crystal structures of these 
      enzymes, in complex with inhibitors, and the mechanisms of Trp catabolism in the 
      first step, are summarized to provide information for facilitating the discovery 
      of new enzyme inhibitors.
FAU - Yan, Daojing
AU  - Yan D
AD  - Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, 
      Shanghai 200433, China. xstan@fudan.edu.cn.
FAU - Lin, Ying-Wu
AU  - Lin YW
FAU - Tan, Xiangshi
AU  - Tan X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - Metallomics
JT  - Metallomics : integrated biometal science
JID - 101478346
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Enzymes)
RN  - 0 (Hemeproteins)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 8DUH1N11BX (Tryptophan)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
SB  - IM
MH  - Animals
MH  - Enzyme Inhibitors/chemistry/*pharmacology
MH  - Enzymes/chemistry/*metabolism
MH  - Hemeproteins/*antagonists & inhibitors/chemistry/*metabolism
MH  - Humans
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & 
      inhibitors/chemistry/metabolism
MH  - Molecular Structure
MH  - Protein Conformation
MH  - Tryptophan/chemistry/*metabolism
MH  - Tryptophan Oxygenase/antagonists & inhibitors/chemistry/metabolism
EDAT- 2017/06/27 06:00
MHDA- 2018/05/24 06:00
CRDT- 2017/06/27 06:00
PHST- 2017/06/27 06:00 [pubmed]
PHST- 2018/05/24 06:00 [medline]
PHST- 2017/06/27 06:00 [entrez]
AID - 10.1039/c7mt00105c [doi]
PST - ppublish
SO  - Metallomics. 2017 Sep 20;9(9):1230-1240. doi: 10.1039/c7mt00105c.