Fig. 2: Current LIAS reaction mechanism.

Reduction of the RS iron/sulfur ([Fe₄S₄]_RS) cluster¹ results in cleavage of SAM to generate a 5’-dA•, which abstracts the C6 pro-R hydrogen from the octanoyllysyl substrate². The resulting C6 substrate radical attacks a bridging µ-sulfido ion of the auxiliary iron/sulfur ([Fe₄S₄]_AUX) cluster with dissociation of the Ser352 ligand and concomitant loss of Fe²⁺ (Fe²⁺ shown in green; Fe³⁺ shown in red) and an electron³ to yield a [Fe₃S₃:1 mercaptooctanoyllysyl]⁰ intermediate adduct. In the second half-reaction, a second SAM molecule binds⁴ and is cleaved to a second 5’-dA•⁵, which abstracts a C8 hydrogen atom⁶. The resulting C8 radical attacks a second bridging sulfido ion of the auxiliary cluster with concomitant reduction of a Fe³⁺ to Fe²⁺⁷. The resulting unstable species breaks apart, releasing 3Fe and 2S^2–, as well as the lipoyllysyl group, upon the addition of two protons⁸.