Abstract：
:Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and has been exploited as the target for therapy against proliferative and parasitic diseases. In this study, we report the crystal structures of DHODH from Leishmania major, the species of Leishmania associated with zoonotic cutaneous leishmaniasis, in its apo form and in complex with orotate and fumarate molecules. Both orotate and fumarate were found to bind to the same active site and exploit similar interactions, consistent with a ping-pong mechanism described for class 1A DHODHs. Analysis of LmDHODH structures reveals that rearrangements in the conformation of the catalytic loop have direct influence on the dimeric interface. This is the first structural evidence of a relationship between the dimeric form and the catalytic mechanism. According to our analysis, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to validate DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping sickness and Chagas' diseases.
journal_name
Biochimiejournal_title
Biochimieauthors
Cordeiro AT,Feliciano PR,Pinheiro MP,Nonato MCdoi
10.1016/j.biochi.2012.04.003subject
Has Abstractpub_date
2012-08-01 00:00:00pages
1739-48issue
8eissn
0300-9084issn
1638-6183pii
S0300-9084(12)00137-Xjournal_volume
94pub_type
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