- Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate
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C-1 carriers are essential cofactors in all domains of life, and in Archaea, these can be derivatives of tetrahydromethanopterin (H4-MPT) or tetrahydrofolate (H4-folate). Their synthesis requires 6-hydroxymethyl-7,8-dihydropterin dip
- De Crecy-Lagard, Valerie,Phillips, Gabriela,Grochowski, Laura L.,Yacoubi, Basma El,Jenney, Francis,Adams, Michael W. W.,Murzin, Alexey G.,White, Robert H.
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- Chemoenzymatic Assembly of Isotopically Labeled Folates
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Pterin-containing natural products have diverse functions in life, but an efficient and easy scheme for their in vitro synthesis is not available. Here we report a chemoenzymatic 14-step, one-pot synthesis that can be used to generate 13C- and 15N-labeled dihydrofolates (H2F) from glucose, guanine, and p-aminobenzoyl-l-glutamic acid. This synthesis stands out from previous approaches to produce H2F in that the average yield of each step is >91% and it requires only a single purification step. The use of a one-pot reaction allowed us to overcome potential problems with individual steps during the synthesis. The availability of labeled dihydrofolates allowed the measurement of heavy-atom isotope effects for the reaction catalyzed by the drug target dihydrofolate reductase and established that protonation at N5 of H2F and hydride transfer to C6 occur in a stepwise mechanism. This chemoenzymatic pterin synthesis can be applied to the efficient production of other folates and a range of other natural compounds with applications in nutritional, medical, and cell-biological research.
- Angelastro, Antonio,Dawson, William M.,Luk, Louis Y. P.,Loveridge, E. Joel,Allemann, Rudolf K.
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supporting information
p. 13047 - 13054
(2017/09/26)
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- Structure-based design and development of functionalized mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from staphylococcus aureus
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on ou
- Dennis, Matthew L.,Chhabra, Sandeep,Wang, Zhong-Chang,Debono, Aaron,Dolezal, Olan,Newman, Janet,Pitcher, Noel P.,Rahmani, Raphael,Cleary, Ben,Barlow, Nicholas,Hattarki, Meghan,Graham, Bim,Peat, Thomas S.,Baell, Jonathan B.,Swarbrick, James D.
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p. 9612 - 9626
(2015/02/02)
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