Competitive inhibitors of type B ribose 5-phosphate isomerases: design, synthesis and kinetic evaluation of new D-allose and D-allulose 6-phosphate derivatives

Competitive inhibitors of type B ribose 5-phosphate isomerases : design, synthesis and kinetic evaluation of new D-allose and D-allulose 6-phosphate derivatives

This study reports syntheses Of D-allose 6-phosphate (All6P), D-allulose (or D-psicose) 6-phosphate (Allu6P), and seven D-ribose 5-phosphate isomerase (Rpi) inhibitors. The inhibitors were designed as analogues of the 6-carbon high-energy intermediate postulated for the All6P to Allu6P isomerization reaction (Allpi activity) catalyzed by type B Rpi from Escherichia coli (EcRpiB). 5-PhosphO-D-ribonate, easily obtained through oxidative cleavage of either All6P or Allu6P, led to the original synthon 5-dihydrogenopliospho-D-ribono-1,4-lactone from which the other inhibitors could be synthesized through nucleophilic addition in one step. Kinetic evaluation on Allpi activity of EcRpiB shows that two of these compounds. 5phospho-D-ribonohydroxamic acid and N-(5-phospho-D-ribonoyl)-methylamine, indeed behave as new efficient inhibitors of EcRpiB; further, 5-phospho-D-ribonohydroxamic acid was demonstrated to have competitive inhibition. Kinetic evaluation on Rpi activity of both EcRpiB and RpiB from Mycobacterium tuberculosis (MtRpiB) shows that several of the designed 6-carbon high-energy intermediate analogues are new competitive inhibitors of both RpiBs. One of them, 5-phospho-D-ribonate, not only appears as the strongest competitive inhibitor of a Rpi ever reported in the literature, with a K-i value of 9 mu M for MtRpiB, but also displays specific inhibition of MtRpiB versus EcRpiB.

Roos, Annette K.Uppsala universitet,Institutionen för cell- och molekylärbiologi (författare)
Mowbray, Sherry L.Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology(Swepub:slu)51420 (författare)
Salmon, Laurent (författare)
Uppsala universitetInstitutionen för cell- och molekylärbiologi (creator_code:org_t)
Sveriges lantbruksuniversitet

Av författaren/redakt...: Mariano, Sandrin ...; Roos, Annette K.; Mowbray, Sherry ...; Salmon, Laurent

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