Radical-mediated enzymatic carbon chain fragmentation-recombination

Area of Science:

• Biochemistry
• Enzymology
• Organic Chemistry

Background:

• The radical S-adenosylmethionine (S-AdoMet) enzyme superfamily catalyzes diverse biochemical transformations.
• Understanding the chemical products and radical-dependent mechanisms of these enzymes remains a challenge.

Purpose of the Study:

• To elucidate the function and mechanism of NosL, an S-AdoMet enzyme involved in nosiheptide biosynthesis.
• To characterize the enzymatic conversion of L-tryptophan to 3-methyl-2-indolic acid (MIA).

Main Methods:

• Enzyme assays using NosL and L-tryptophan as substrate.
• Product identification and structural elucidation.
• Investigation of reaction intermediates and mechanism.

Main Results:

• NosL functions as a radical S-AdoMet 3-methyl-2-indolic acid (MIA) synthase.
• NosL catalyzes an unprecedented fragmentation-recombination reaction of L-tryptophan, forming MIA.
• A putative glycyl intermediate and radical-mediated mechanism were identified.
• NosL accepted fluorinated L-tryptophan, yielding halogenated thiopeptides.

Conclusions:

• This study reveals a novel radical-mediated fragmentation-recombination mechanism in S-AdoMet enzymes.
• NosL represents a key enzyme in thiopeptide biosynthesis, expanding the known repertoire of S-AdoMet enzyme functions.
• The ability to use fluorinated substrates opens avenues for producing novel halogenated thiopeptides.