Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.1.1.148 (
Thy1
)
1,210
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and
ThyX
, only
ThyX
is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against
ThyX
. We exploited the NADPH oxidation to
NADP
+
step, catalyzed by
ThyX
, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z'=0.77) and identification of selective
ThyX
inhibitors. The most potent compound is a tight-binding inhibitor with an IC
50
of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of
ThyX
mechanism and substrate and cofactor binding order.
...
PMID:Discovery of a new Mycobacterium tuberculosis thymidylate synthase X inhibitor with a unique inhibition profile. 2835 6
