Radical-mediated enzymatic carbon chain fragmentation-recombination.
The radical S-adenosylmethionine (S-AdoMet) superfamily contains thousands of proteins that catalyze highly diverse conversions, most of which are poorly understood, owing to a lack of information regarding chemical products and radical-dependent transformations. We here report that NosL, involved in forming the indole side ring of the thiopeptide nosiheptide (NOS), is a radical S-AdoMet 3-methyl-2-indolic acid (MIA) synthase. NosL catalyzed an unprecedented carbon chain reconstitution of L-tryptophan to give MIA, showing removal of the Cα-N unit and shift of the carboxylate to the indole ring. Dissection of the enzymatic process upon the identification of products and a putative glycyl intermediate uncovered a radical-mediated, unusual fragmentation-recombination reaction. This finding unveiled a key step in radical S-AdoMet enzyme-catalyzed structural rearrangements during complex biotransformations. Additionally, NosL tolerated fluorinated L-tryptophan as the substrate, allowing for production of a regiospecifically halogenated thiopeptide that has not been found among the more than 80 members of the naturally occurring thiopeptide family.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Qi
Q
Zhang
Yuxue
Y
Li
Dandan
D
Chen
Yi
Y
Yu
Lian
L
Duan
Ben
B
Shen
Wen
W
Liu
D001665:Binding Sites; D002244:Carbon / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism
D005609:Free Radicals; D007211:Indoles; D010455:Peptides; D013844:Thiazoles; D002244:Carbon; D012436:S-Adenosylmethionine; D014364:Tryptophan; C014134:nosiheptide
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