Incorporation of [²H₁]-(1R,2R)- and [²H₁]-(1S,2R)-glycerols into the antibiotic nucleocidin in Streptomyces calvus

Abstract

Deuterium incorporations from [H]-(1R,2R) and [H]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5' site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5' of nucleocidin after a feeding experiment with [H]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic.

An Fe2+‐ and α‐Ketoglutarate‐Dependent Halogenase Acts on Nucleotide Substrates

“…Halogenated nucleosides represent an important class of synthetic drugs used in anticancer and antiviral treatments, including Cladribine ( 1 , anti‐leukaemia), Clofarabine ( 2 , anti‐leukaemia), Fludaradine ( 3 , anti‐leukaemia), Fluorouracil ( 4 , antitumor), Gemcitabine ( 5 , anticancer), and Sofosbuvir ( 6 , anti‐Hepatitis C; Figure A). In contrast, there are relatively few known halogenated nucleoside natural products, with nucleocidin ( 7 a , fluorinated at C4′ of ribose), AT‐265 ( 7 b , dealanylascamycin, chlorinated at C2 of adenosine), and adechlorin ( 8 , chlorinated at C2′ of ribose; Figure B) being rare examples. Adechlorin is the 2′‐chloro derivative of pentostatin ( 9 ), a competitive inhibitor of adenosine deaminase that is approved as a drug for leukaemia treatment .…”

Chemical Aspects of Human and Environmental Overload with Fluorine

“…Deuterium labels of the pro-S CH 2 OH group of glycerol, in turn, are lost, and the secondary carbon of glycerol becomes the C4′ of nucleocidin (Scheme 11). 52,53 This shows that the pro-R CH 2 OH carbon is not oxidized as glycerol, and it is progressed along the pentose phosphate pathway, incorporating into the ribose moiety of nucleocidin. 52 Note that the enzyme responsible for fluorine incorporation is still unknown.…”

Enzyme-catalyzed C–F bond formation and cleavage

“…In 2015, Zechel's group reported that complementation of S. calvus ATCC13382 with a functional bldAencoded Leu-tRNA UUA molecule restores the production of nucleocidin 1 and identified the genes encoding the biosynthesis of the 5′-O-sulfamate group of the nucleocidin 1 (Zhu et al 2015). In the next year, O'Hagan's group provided the first biosynthetic data on nucleocidin 1 assembly from isotope labeling studies (Bartholomé et al 2016;Feng et al 2017). However, there was still no illumination for the mechanism of fluorination involved in this biosynthetic pathway.…”