Sammanfattning

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. (C) 2009 Elsevier Ltd. Ail rights reserved.

Nyckelord

Sugar phosphates; Enzyme inhibitor; Hydroxamic acids; Ribose 5-phosphate isomerase; Allose 6-phosphate isomerase; Mycobacterium tuberculosis

Publicerad i

Carbohydrate Research
2009, Volym: 344, nummer: 7, sidor: 869-880
Utgivare: ELSEVIER SCI LTD

SLU författare

• Mowbray, Sherry

  • Institutionen för molekylärbiologi, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Biokemi och molekylärbiologi
Organisk kemi


Publikationens identifierare

DOI: https://doi.org/10.1016/j.carres.2009.02.024

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/49915