Fatty Acyl‑AMP Ligases as Mechanistic Variants of ANL Superfamily and Molecular Determinants Dictating Substrate Specificities

Abstract

Fatty acyl-AMP ligases (FAAL) are enzymes that establish
the crosstalk between fatty acid synthases and polyketide synthases
or non-ribosomal peptide synthetases by activating newly synthesized
fatty acids, shuttling them towards polyketide synthesis. These enzymes
are unique as they have evolved a strict rejection mechanism for the
coenzyme-A but can recognize and react with the phosphopantetheine
of acyl-carrier proteins. A strategically placed insertion in the N-terminal
domain and the rigidity of the hydrophobic anchor holding the insertion
is at the heart of such a discrimination mechanism, the molecular details
of which is yet to be clearly understood. The unique structural features of
the insertion have been exploited to filter out FAALs from other members
of the superfamily, in silico. Interestingly, several independent studies
have characterized FAALs from different organisms such as Legionella,
Myxococcus, Ralstonia, Pseudoalteromonas, Sorangium, etc. to name
a few, laying emphasis on the usage of a FAAL-specific biochemistry
in these organisms, particularly for the production of important bioactive
molecules. These bioactive molecules help in improving the fitness
of these systems to tide over the competition for nutritional resources in
their local niche. Substrate specificity of these enzymes is another interesting
aspect, which may hint at their potential roles in the cell. Various
substrate-bound crystal structures have been used to identify the determinants
of chain-length specificity and predict the preferences for different
FAALs (both mycobacterial and non-mycobacterial). The fascinating
details of the mechanistic variation of these enzymes and the molecular
determinants that define the chain-length specificity have been discussed
herewith.