Chorismate synthase: an attractive target for drug development against orphan diseases.
The increase in incidence of infectious diseases worldwide, particularly in developing countries, is worrying. Each year, 14 million people are killed by infectious diseases, mainly HIV/AIDS, respiratory infections, malaria and tuberculosis.. Despite the great burden in the poor countries, drug discovery to treat tropical diseases has come to a standstill. There is no interest by the pharmaceutical industry in drug development against the major diseases of the poor countries, since the financial return cannot be guaranteed. This has created an urgent need for new therapeutics to neglected diseases. A possible approach has been the exploitation of the inhibition of unique targets, vital to the pathogen such as the shikimate pathway enzymes, which are present in bacteria, fungi and apicomplexan parasites but are absent in mammals. The chorismate synthase (CS) catalyses the seventh step in this pathway, the conversion of 5-enolpyruvylshikimate-3-phosphate to chorismate. The strict requirement for a reduced flavin mononucleotide and the anti 1,4 elimination are both unusual aspects which make CS reaction unique among flavin-dependent enzymes, representing an important target for the chemotherapeutic agents development. In this review we present the main biochemical features of CS from bacterial and fungal sources and their difference from the apicomplexan CS. The CS mechanisms proposed are discussed and compared with structural data. The CS structures of some organisms are compared and their distinct features analyzed. Some known CS inhibitors are presented and the main characteristics are discussed. The structural and kinetics data reviewed here can be useful for the design of inhibitors.
Dias
Marcio V B
MV
Programa de Pós-Graduação em Biofísica Molecular, Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brasil.
Ely
Fernanda
F
Palma
Mário S
MS
de Azevedo
Walter F
WF
Basso
Luiz A
LA
Santos
Diógenes S
DS
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D009965:Orphan Drug Production / Q000379:methods; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D035583:Rare Diseases / Q000188:drug therapy / Q000201:enzymology*
D004791:Enzyme Inhibitors; C019895:chorismate synthase; D019761:Phosphorus-Oxygen Lyases