Non-ribosomal peptide synthetase adenylation domain (NRPS A-domain)

Non-ribosomal peptide synthetase (NRPS) adenylation (A) domains are the primary substrate-selection and activation modules within the massive multi-enzyme complexes that synthesize non-ribosomal peptides (Süssmuth & Mainz, 2017). These domains catalyze a two-step reaction: the ATP-dependent formation of an aminoacyl-adenylate intermediate followed by the transfer of the activated acyl group to a phosphopantetheinyl cofactor on a neighboring thiolation domain (Gulick, 2009). NRPS A-domains are critical for the production of diverse microbial metabolites, including antibiotics like vancomycin, immunosuppressants like cyclosporine, and siderophores like mycobactin, which is essential for the survival of Mycobacterium tuberculosis (Ferreras et al., 2005). Because these domains are often essential for the virulence and viability of pathogenic bacteria and fungi, they are considered high-value targets for the development of novel anti-infectives (Duckworth et al., 2012). Therapeutic strategies typically involve the use of bisubstrate analogs, such as sulfamoyl adenosine derivatives, which mimic the transition state of the adenylation reaction to potently and selectively inhibit the enzyme (Cisar et al., 2007).

Other names

Adenylation domainA-domainNRPS adenylating enzymeAmino acid-activating domain

Competitive inhibition of the adenylation step by mimicking the aminoacyl-adenylate intermediate, thereby blocking the activation of substrate monomers and halting the assembly of essential secondary metabolites (Ferreras et al., 2005).